Place cell references

•Alexandrov, Y.I., Grinchenko, Y.V., Laukka, S., Jarvilehto, T., Maz, V.N. & Korpusova, A.V. (1993). Effect of ethanol on hippocampal neurons depends on their behavioural specialization. Acta Physiologica Scandinavica 149: 105-115.

•Brown, E.N., Frank, L.M., Tang, D., Quirk, M.C. & Wilson, M.A. (1998). A statistical paradigm for neural spike train decoding applied to position prediction from ensemble firing patterns of rat hippocampal place cell. Journal of Neuroscience 18(18): 7411-7425. The problem of predicting the position of a freely foraging rat based on the ensemble firing patterns of place cells recorded from the CA1 region of its is used to develop a two-stage statistical paradigm for neural spike train decoding. In the first, or stage, place cell spiking activity is modeled as an inhomogeneous Poisson process whose instantaneous rate is a function of the animal's position in space and phase of its theta rhythm. The animal's path is modeled as a Gaussian random walk. In the second, or decoding stage, a Bayesian statistical paradigm is used to derive a nonlinear recursive causal filter algorithm for predicting the position of the animal from the place cell ensemble firing patterns. The algebra of the decoding algorithm defines an explicit map of the discrete spike trains into the position prediction. The confidence regions for the position predictions quantify spike train information in terms of the most probable locations of the animal given the ensemble firing pattern. Under our inhomogeneous Poisson model position was a three to five times stronger modulator of the place cell spiking activity than theta phase in an open circular environment. For animal 1 (2) the median decoding error based on 34 (33) place cells recorded during 10 min of foraging was 8.0 (7.7) cm. Our statistical paradigm provides a reliable approach for quantifying the spatial information in the ensemble place cell firing patterns and defines a generally applicable framework for studying information encoding in neural systems.

•Anderson, M.I. & Jeffery, K.J. (2001). Interaction of sensory cues in the control of place cell remapping. Society for Neuroscience Abstracts 31(744.5): 383.

•Aota, Y., Yamaguchi, Y., Lipa, P., Sofukiu, T. & McNaughton, B.L. (2001). The two components of theta in rat hippocampal neurons. Society for Neuroscience Abstracts 31(643.18): 330. Hippocampal place cells in freely running rats exhibit a characteristic relation between the position and the firing phase with respect to the theta rhythm. Yamaguchi and McNaughton (1998) proposed that the distribution consists of two components, one with strong correlation Page 1 Place cell references between phase and position (C1) and the other with no correlation (C2). In the present paper, quantitative analyses, based on the two components hypothesis, of the distribution of spikes in the phase-position plane were carried out for several experimental data sets in which the animals performed different simple appetitively motivated spatial tasks on a linear track, a circular track and triangular track. The probability density of spikes in the phase-position plane was quantified by a function consisting of two normal functions by means of the EM algorithm. The results show that the two components hypothesis is well applicable in each data set. The C1 at DG is advanced to CA1 in phase by 0.2 theta cycle (as shown in the figure), which strongly suggests that C1 is generated at an earlier stage than DG and projected to CA region. C2 is found only in CA1 and its magnitude differs in different cells. Furthermore, the correlation between the two components suggests some functional relevance of their interactions. Supported by: JST CREST & MH01565

•Barbieri, R., Frank, L.M., Quirk, M.C., Wilson, M.A. & Brown, E.N. (2000). Construction and analysis of the inhomogeneous general inverse Gaussian probability model of place cell spiking activity. Society for Neuroscience Abstracts 30. Neural systems represent information about stimuli from the outside world in the stochastic structure of their firing patterns. Accurate characterization of this stochastic structure is crucial for deciphering how neural systems encode and transmit information. We introduce a new description of hippocampal place cell spiking activity as a function of position based on the inhomogeneous general inverse Gaussian (IGIG) probability model. This model class has the inhomogeneous Poisson (IP), gamma (IG) and inverse Gaussian (IIG) probability densities as special cases. We apply this model to hippocampal place cells recorded from rats running in an open field environment and to both hippocampal and entorhinal place cells recorded from rats running in a linear environment. Q-Q and K-S plot goodness-of-fit methods based on the time-rescaling theorem provide a readily interpretable, graphical summaries of the model fits to the spike train data. Both the IG and IIG give significantly better descriptions of place cell spiking activity than the IP model; the former in its representation of long ISI’s and the latter in its representation of bursts. The IGIG model offers a further significant improvement by combining these characteristics of both the IG and IIG models. These findings thus far suggest a flexible framework for modeling place cell spiking activity under varied experimental conditions. Supported by: US NIMH grants MH59733 and MH61637

•Barbieri, R., Frank, L.M., Quirk, M.C., Wilson, M.A. & Brown, E.N. (2001). Page 2 Place cell references Measuring the precision of spatial information representation by decoding ensemble place cell spiking activity. Society for Neuroscience Abstracts 31(953.3). Position prediction based on the ensemble firing patterns of CA1 place cells may yield important insights on how neural populations encode information. Our previous decoding algorithm assumed the animals path to be a random walk and that place cell spiking activity obeyed an inhomogeneous Poisson (IP) model with rate as a function of position. Goodness-of-fit analysis showed that path increments are more consistent with a low-order autoregressive (AR) model than a random walk, and that an inhomogeneous gamma (IG) model gave a more accurate description of place cell spiking activity than IP. We present a new decoding algorithm to predict the animal's path from the spike train ensemble based on a nonlinear recursive causal filter constructed using the AR and IG models. The simultaneous activity of 37 place cells was recorded from a Long-Evans rat foraging in an open, circular environment for 23 minutes, and the animals position was measured at 30 Hz. We estimated the AR and IG model parameters from the first 13 minutes and then applied the decoding algorithms to the last 10 minutes of data. Our decoding analysis illustrates how the neural representation of position can be decoded from the ensemble firing patterns, and shows that better predictions (accuracy and coverage probability) of the animals position in the open environment can be made from the ensemble firing pattern of as few as 30 place cells by modeling the non- Poisson spiking activity behavior and the correlation structure in the animals path. Supported by: Grants NIMH MH59733, MH61637, and NSF IBN-0081548

•Best, P.J., White, A.M. & Minai, A. (2001). Spatial processing in the brain: The activity of hippocampal place cells. Annual Reviews of Neuroscience 24: 459- 486.

•Bezzi, M., Leutgeb, S., Treves, A. & Mizumori, S.J.Y. (2000). Information analysis of location-selective cells in hippocampus and lateral septum. Society for Neuroscience Abstracts 30. In addition to location-specific representations of the environment, hippocampus receives and encodes in its principal cells information about movement. Lateral septal cells also code for location and movement. Information analysis was used to investigate the coding properties of simultaneously recorded hippocampal and lateral septal cells. In both areas, synergy and redundancy was observed for the encoding of location and velocity. Information for each property was differentially affected in the absence of visual cues. For hippocampal principal cells, the information for both velocity and position was decreased in darkness; velocity coding was affected to a larger extent compared to Page 3 Place cell references position coding. In contrast, lateral septal cells only showed a decrease in information for position while velocity information remained unaffected by the changes in the visual environment. This dissociation in the encoding of the two types of information may be a consequence of convergent hippocampal projections to lateral septum or due to other afferent information to lateral septum. In addition, we randomized the temporal structure of spike trains in hippocampus and lateral septum while leaving the spatial structure of the rate coding for position intact. This analysis confirmed that differences in the distribution of the crosscorrelation coefficients between light and dark are not directly related to the changes in the spatial properties of septal and hippocampal cells, but related to the temporal relation of single-unit activity in both areas. The relative timing of neural activity may therefore be critical for the selective transfer of hippocampal rate codes for location and velocity to subcortical structures. Supported by: HFSP RG 01101998B and MH58755

•Bland, B.H. & Oddie, S.D. (2001). Theta band oscillation and synchrony in the and associated structures: The case for its role in sensorimotor integration. Review. Behavioral Brain Research 127(1-2): 119-136. The current review advances the argument that it is naive to ascribe a unitary function to the hippocampal formation (HPC). Rather, it is more productive to consider the hippocampal formation as consisting of a number of subsystems, each subsystem defined by its own particular neural circuitry. Among examples of neural circuitry appearing in current hippocampal literature are theta, beta and gamma oscillations, sharp waves, place cells and head orientation cells. Data are reviewed supporting the case that theta band oscillation and synchrony is involved in mechanisms underlying sensorimotor integration. Specifically, the neural circuitry underlying the production of oscillation and synchrony (theta) in limbic cortex and associated structures function in the capacity of providing voluntary motor systems with continually updated feedback on their performance relative to changing environmental (sensory) conditions. A crucial aspect of this performance is the intensity with which the motor programs are initiated and maintained. The ascending brainstem HPC synchronizing pathways make the primary contribution in this regard. These pathways originate in the rostral pontine region, ascend and synapse with caudal diencephalic nuclei, which in turn send projections to the medial septal region. The medial septum functions as the node in the ascending pathways, sending both cholinergic and GABA-ergic projections to the HPC. An updated version of the sensorimotor integration model including anatomical details is presented and discussed. Page 4 Place cell references

•Booth, V. & Bose, A. (2001). Neural mechanisms for generating rate and temporal codes in model CA3 pyramidal cells. Journal of Neurophysiology 85(6): 2432-2445. The effect of synaptic inhibition on burst firing of a two-compartment model of a CA3 pyramidal cell is considered. We show that, depending on its timing, a short dose of fast decaying synaptic inhibition can either delay or advance the timing of firing of subsequent bursts. Moreover, increasing the strength of the inhibitory input is shown to modulate the burst profile from a full complex burst, to a burst with multiple spikes, to single spikes. We additionally show how slowly decaying inhibitory input can be used to synchronize a network of pyramidal cells. Implications for the phase precession phenomenon of hippocampal place cells and for the generation of temporal and rate codes are discussed.

•Bose, A. & Recce, M. (2001). Phase precession and phase-locking of hippocampal pyramidal cells. Hippocampus 11(3): 204-215. We propose that the activity patterns of CA3 hippocampal pyramidal cells in freely running rats can be described as a temporal phenomenon, where the timing of bursts is modulated by the animal's running speed. With this hypothesis, we explain why pyramidal cells fire in specific spatial locations, and how place cells phase-precess with respect to the EEG theta rhythm for rats running on linear tracks. We are also able to explain why wheel cells phase-lock with respect to the theta rhythm for rats running in a wheel. Using biophysically minimal models of neurons, we show how the same network of neurons displays these activity patterns. The different rhythms are the result of inhibition being used in different ways by the system. The inhibition is produced by anatomically and physiologically diverse types of interneurons, whose role in controlling the firing patterns of hippocampal cells we analyze. Each firing pattern is characterized by a different set of functional relationships between network elements. Our analysis suggests a way to understand these functional relationships and transitions between them.

•Bower, M.R., Euston, D.R., Gebara, N.M. & McNaughton, B.L. (2001). The role of the hippocampus in disambiguating context in a sequence task. Society for Neuroscience Abstracts 31(316.7). Theories of how sequences are encoded in the brain have postulated an asymmetric, associative strengthening of connections between cells representing sequential elements. One difficulty with this notion concerns the problem of disambiguating the sequential context of repeated segments. For example, to retrieve the sequential relationship ABCDCEF, it would be necessary to encode the element C differently in its two sequential contexts Page 5 Place cell references (i.e., to "orthogonalize" the two representations of C). Wood et al. (2000) convincingly showed this effect in the hippocampus of rats running a simple alternation task on a "T" maze. Many pyramidal cells fired selectively in the stem of the "T" depending on the direction of the upcoming turn. These data strongly suggest that the hippocampus per se may provide the essential disambiguating code. Experiments addressing the same problem were ongoing in this lab at the time of the Wood et al. report. Rats were trained to run for rewarding brain stimulation to a sequence of goal locations marked by illuminated diodes, located around the perimeter of a 1.5 meter diameter circular arena (e.g., the rat ran to numbered zones 2-4-1-5-2-4-1-3). After training, rats were required to run the sequence without cues. Rats acquired novel sequences within 4-5 50 minute sessions and showed few errors even on the repeated segments. 30-50 dorsal CA1 pyramidal cells were recorded during each experimental session. In contrast to the results of Wood et al., place fields were indistinguishable on all repeated segments. It appears that orthogonalization of repeated elements within the hippocampus may not be necessary for disambiguating the sequential context of repeated segments. Supported by: NS20331, MH01565 & JST CREST

•Brown, E.N., Nguyen, D.P., Frank, L.M., Wilson, M.A. & Solo, V. (2001). An analysis of neural receptive field plasticity by point process adaptive filtering. Proceedings of the National Academy of Sciences USA 98(21): 12261-12266. Neural receptive fields are plastic: with experience, neurons in many brain regions change their spiking responses to relevant stimuli. Analysis of receptive field plasticity from experimental measurements is crucial for understanding how neural systems adapt their representations of relevant biological information. Current analysis methods using histogram estimates of spike rate functions in nonoverlapping temporal windows do not track the evolution of receptive field plasticity on a fine time scale. Adaptive signal processing is an established engineering paradigm for estimating time-varying system parameters from experimental measurements. We present an adaptive filter algorithm for tracking neural receptive field plasticity based on point process models of spike train activity. We derive an instantaneous steepest descent algorithm by using as the criterion function the instantaneous log likelihood of a point process spike train model. We apply the point process adaptive filter algorithm in a study of spatial (place) receptive field properties of simulated and actual spike train data from rat CA1 hippocampal neurons. A stability analysis of the algorithm is sketched in the. The adaptive algorithm can update the place field parameter estimates on a millisecond time scale. It reliably tracked the migration, changes in scale, and Page 6 Place cell references changes in maximum firing rate characteristic of hippocampal place fields in a rat running on a linear track. Point process adaptive filtering offers an analytic method for studying the dynamics of neural receptive fields.

•Brun, V.H., Otnaess, M.K., Witter, M.P., Moser, M.B. & Moser, E.I. (2001). Place representation in hippocampal area CA1 in the absence of input from area CA3. Society for Neuroscience Abstracts 31(643.6): 329. The indirect pathway to CA1 from the (EC) through the trisynaptic circuit has been regarded as the main excitatory input to CA1. However, the CA1 also receives a strong direct projection from layer III neurons of the EC. We examined whether the direct input is sufficient for establishing and maintaining location-specific activity in CA1 pyramidal cells. To disconnect CA3 from CA1, localized knife-cuts were made along the septo-temporal axis of the dorsal hippocampus, and tetrodes were then implanted in the dorsal CA1. The contralateral hippocampus was removed by ibotenic acid. CA1 pyramidal cell activity was recorded while the rats were walking on a linear track or in a square black box (1 m2) with a white cue card on one of the sidewalls. CA1 cells showed place fields both on the treadmill and in the box, and many fields remained stable between trials and days. Histological examination revealed that the cut had separated the CA1 from the CA3 along most of the dorsal hippocampus. Fluorogold injections at the recording site showed no or only a few retrogradely labeled neurons in the CA3. These results suggest that the indirect pathway to CA1 through CA3 is not necessary for establishing and maintaining place fields, although it cannot be excluded yet that the remaining very small subset of CA3 axons is sufficient for establishing and maintaining place fields in single CA1 pyramidal cells. Supported by: EU (QLG3-CT-1999-00192), Norw. Res. Council and T. Erbo's Foundation

•Burgess, N. & O'Keefe, J. (1996). Cognitive graphs, resistive grids, and the hippocampal representation of space. Review. Journal of General Physiology 107(6): 659-662.

•Burgess, N. & O'Keefe, J. (1996). Neuronal computations underlying the firing of place cells and their role in navigation. Hippocampus 6(6): 749-762. Our model of the spatial and temporal aspects of place cell firing and their role in rat navigation is reviewed. The model provides a candidate mechanism, at the level of individual cells, by which place cell information concerning self-localization could be used to guide navigation to previously visited reward sites. The model embodies specific predictions regarding the formation of place fields, the phase coding of place cell Page 7 Place cell references firing with respect to the hippocampal theta rhythm, and the formation of neuronal population vectors downstream from the place cells that code for the directions of goals during navigation. Recent experiments regarding the spatial distribution of place cell firing have confirmed our initial modeling hypothesis, that place fields are formed from Gaussian tuning curve inputs coding for the distances from environmental features, and enabled us to further specify the functional form of these inputs. Other recent experiments regarding the temporal distribution of place cell firing in two-dimensional environments have confirmed our predictions based on the temporal aspects of place cell firing on linear tracks. Directions for further experiments and refinements to the model are outlined for the future.

•Burgess, N., Becker, S., King, J.A. & O'Keefe, J. (2001). Memory for events and their spatial context: Models and experiments. Review. Philosophical Transactions of the Royal Society (London), Series B: Biological Sciences 356(1413): 1493-1503. The computational role of the hippocampus in memory has been characterized as: (i) an index to disparate neocortical storage sites; (ii) a time- limited store supporting neocortical long-term memory; and (iii) a content- addressable associative memory. These ideas are reviewed and related to several general aspects of , including the differences between episodic, recognition and semantic memory, and whether hippocampal lesions differentially affect recent or remote memories. Some outstanding questions remain, such as: what characterizes episodic retrieval as opposed to other forms of read-out from memory; what triggers the storage of an event memory; and what are the neural mechanisms involved? To address these questions a neural-level model of the medial temporal and parietal roles in retrieval of the spatial context of an event is presented. This model combines the idea that retrieval of the rich context of real- life events is a central characteristic of episodic memory, and the idea that medial temporal allocentric representations are used in long-term storage while parietal egocentric representations are used to imagine, manipulate and re-experience the products of retrieval. The model is consistent with the known neural representation of spatial information in the brain, and provides an explanation for the involvement of Papez's circuit in both the representation of heading direction and in the recollection of episodic information. Two experiments relating to the model are briefly described. A functional neuroimaging study of memory for the spatial context of life-like events in virtual reality provides support for the model's functional localization. A neuropsychological experiment suggests that the hippocampus does store an allocentric representation of spatial locations.

Page 8 Place cell references •Burgess, N., Donnett, J.G. & O'Keefe, J. (1998). The representation of space and the hippocampus in rats, robots and humans. Z Naturforsch 53(7-8): 504-509. Experimental evidence suggests that the hippocampus represents locations within an allocentric representation of space. The environmental inputs that underlie the rat's representation of its own location within an environment (in the firing of place cells) are the distances to walls, and different walls are identified by their allocentric direction from the rat. We propose that the locations of goals in an environment is stored downstream of the place cells, in the subiculum. In addition to firing rate coding, place cells may use phase coding relative to the theta rhythm of the EEG. In some circumstances may be used, in addition to environmental information, as an input to the hippocampal system. A detailed computational model of the hippocampus successfully guides the navigation of a mobile robot. The model's behaviour is compared to electrophysiological and behavioural data in rats, and implications for the role of the hippocampus in primates are explored.

•Burgess, N., Donnett, J.G., Jeffery, K.J. & O'Keefe, J. (1997). Robotic and neuronal simulation of the hippocampus and rat navigation. Review. Philosophical Transactions of the Royal Society of London - Series B: Biological Sciences 352(1360): 1535-1543. The properties of hippocampal place cells are reviewed, with particular attention to the nature of the internal and external signals that support their firing. A neuronal simulation of the firing of place cells in open-field environments of varying shape is presented. This simulation is coupled with an existing model of how place-cell firing can be used to drive navigation, and is tested by implementation as a miniature mobile robot. The sensors on the robot provide visual, odometric and short-range proximity data, which are combined to estimate the distance of the walls of the enclosure from the robot and the robot's current heading direction. These inputs drive the hippocampal simulation, in which the robot's location is represented as the firing of place cells. If a goal location is encountered, occurs in connections from the concurrently active place cells to a set of 'goal cells', which guide subsequent navigation, allowing the robot to return to an unmarked location. The system shows good agreement with actual place- cell firing, and makes predictions regarding the firing of cells in the subiculum, the effect of blocking long-term synaptic changes, and the locus of search of rats after deformation of their environment.

•Burgess, N., Jackson, A., Hartley, T. & O'Keefe, J. (2000). Predictions derived from modelling the hippocampal role in navigation. Biological Cybernetics Page 9 Place cell references 83(3): 301-312. A computational model of the lesion and single unit data from navigation in rats is reviewed. The model uses external (visual) and internal (odometric) information from the environment to drive the firing of simulated hippocampal place cells. Constraints on the functional form of these inputs are drawn from experiments using an environment of modifiable shape. The place cell representation is used to guide navigation via the creation of a representation of goal location via Hebbian modification of synaptic strengths. The model includes consideration of the phase of firing of place cells with respect to the theta rhythm of hippocampal EEG. A series of predictions for behavioural and single-unit data in rats are derived from the input and output representations of the model.

•Cho, J., Elgersma, Y., Bombadil, T., Eichenbaum, H., Honavar, V. & Silva, A.J. (2000). Activity of hippocampal CA1 place cells in alpha-CAMKIIT305D mice. Society for Neuroscience Abstracts 30. Place cells are thought to encode spatial information because they fire only when the animal is in specific regions of the environment (place fields). Place fields form rapidly when animals navigate in novel environments, and the spatial selectivity of place cells also improves rapidly as animals explore new environments (Wilson & McNaughton, Science,261,p1055). These phenomena appear to reflect the circuit processes that govern the incorporation of information about a novel environment. Individual place cells tend to show stable place fields upon revisits to familiar environments. The present study investigates the activity of pyramidal cells in region CA1 of mice with a threonine to aspartate mutation at position 305 of the a-calmodulin kinase II (a- CaMKIIT305D). This mutation interferes with calmodulin binding and therefore with kinase activation, and results in severe impairments in a spatial learning task (Morris water maze) and in impaired LTP in the CA1 region of the hippocampus (Elgersma, Fedorov,& Silva, unpublished data). This suggests that the mutation disrupts formation of new memories and/or maintenance and consolidation of memory. Importantly, spatial tasks require learning and incorporation of memory about places. Previous studies reported unstable place fields in a-CaMKII mutant mice. Although the place cells in these mutant mice showed stability during a recording session, they were unstable across several recording sessions (Cho et al., Science,279,p867; Rotenberg et al., Cell,87,p1351). Supported by: NIH (AG13622)

•Cowen, S.L., Kudrimoti, H.S., Gerrard, J.L., McNaughton, B.L. & Barnes, C.A. (2000). Three measures of neural ensemble reactivation in the hippocampus fail to reflect reward probabilities present in a familiar task. Society for Neuroscience Abstracts 30. The discovery that waking neural patterns are Page 10 Place cell references reactivated in the hippocampus after behavior presents a possible neural correlate to the process (Wilson and McNaughton, 1994). Consolidation is often affected by level of reward (Kesner et al., 1989). Accordingly, this experiment sought to determine whether hippocampal neural activity associated with high reward locations is preferentially reactivated relative to low reward sites. Three rats were implanted with microdrives, and multiple single-unit activity was recorded from the CA1 layer of the hippocampus. Each rat traversed a T shaped maze during 8 experimental sessions (1 per day). Reward sites were located at the end of each arm and had differential probabilities of containing food (20%, 50%, and 80%). After the fourth session, the location of the 80% and 20% reward sites were exchanged. Maze running periods were preceded and followed by at least 30 minutes of rest. An average of 34 simultaneously recorded units were present during each session. Reactivation during post-exploration periods was assessed using three measures. These measures allowed us to determine whether patterns were reactivated more often and/or with greater intensity. All three measures failed to show a significant relationship between reactivation and reward probability. This result is consistent with the 'incidental' nature of spatial learning and suggests that any enhancement of that may result from positive reinforcement is likely to involve encoding processes outside the hippocampus. Supported by: MH46823, AG07434, MH01565, ARCS

•Cressant, A., Muller, R.U. & Poucet, B. (2002). Remapping of place cell firing patterns after maze rotations. Experimental Brain Research 143(4): 470-479. When place cells are recorded from rats running on an elevated T-maze inside a curtained enclosure that contains distinct, experimenter selected stimuli, rotations of the maze plus stimuli cause equal rotations of firing fields. Here, we examined the effects of conflicting rotations of a T-maze relative to a laboratory frame that contained a large number of fixed stimuli in the environment and asked whether positional firing patterns stayed in register with the maze or the room cues or were modified in some more complex way. After maze rotations of 90 degrees, 180 degrees or 270 degrees, firing fields were stable in the laboratory frame and thus shifted to a different maze arm. In contrast, rotations of 45 degrees or -45 degrees resulted in dramatic changes of positional firing patterns regardless of their initial position on the maze. Crucially, even cells whose fields were initially on the central platform underwent major firing pattern alterations although the view of the environment from the platform was unchanged by such rotations. Finally, we found that altering the visual appearance by removing without rotation one or two maze arms did not alter firing fields on the remaining part of the maze. Thus, the Page 11 Place cell references "remappings" caused by 45 degrees rotations could result from the disturbed relationship between all arms and the room cues or from the changes in the possible paths the animal can take in the environment. Taken together, our results provide an example of combinatorial coding by the hippocampus, in which the place cell representation of the environment was seen to be modified as a unit and not piecewise according to locally available stimuli.

•de Araujo, I.E.T., Rolls, E.T. & Stringer, S.M. (2001). A view model which accounts for the spatial fields of hippocampal primate and rat place cells. Hippocampus 11(6): 699-706. Hippocampal spatial view cells found in primates respond to a region of visual space being looked at, relatively independently of where the monkey is located. Rat place cells have responses which depend on where the rat is located. We investigate the hypothesis that in both types of animal, hippocampal cells respond to a combination of visual cues in the correct spatial relation to each other. In rats, which have a wide visual field, such a combination might define a place. In primates, including humans, which have a much smaller visual field and a fovea which is directed towards a part of the environment, the same mechanism might lead to spatial view cells. A computational model in which the neurons become organized by learning to respond to a combination of a small number of visual cues spread within an angle of a 30° receptive field resulted in cells with visual properties like those of primate spatial view cells. The same model, but operating with a receptive field of 270°, produced cells with visual properties like those of rat place cells. Thus a common hippocampal mechanism operating with different visual receptive field sizes could account for some of the visual properties of both place cells in rodents and spatial view cells in primates.

•Dees, J.A., Terrazas, A., Bohne, K.M., Krause, M., McNaughton, B.L. & Barnes, C.A. (2001). Presence of hippocampal theta during navigation without actual movement. Society for Neuroscience Abstracts 31(643.13): 329. The type-I hippocampal theta rhythm reliably accompanies spatially-directed movements and plays a central role in many computational models of spatial navigation in the mammalian hippocampus. The degree to which self-motion signals such as ambulatory proprioception, optic flow and vestibular inputs drive the theta rhythm is not known. To examine these relationships, rats were trained to drive a car to goal locations on a circular track while differential recordings of the hippocampal EEG were acquired. The car and the platform were driven independently by stepper motors, thus requiring the rat to navigate using primarily optic flow signals when the platform is engaged (WORLD) and optic flow plus vestibular signals when the car is Page 12 Place cell references engaged (CAR). Wavelet analysis was performed on the unfiltered EEG timeseries to determine if any qualitative differences were apparent across spectral bands. In all cases, a prominent 7-9Hz rhythm was easily distinguishable during movement of the CAR and the WORLD and was characteristically reduced during rest. For a subset of sessions (n=4), the animal drove both the CAR and the WORLD on different trials within the same session. Group t-tests comparing the average power in the 7-9Hz band for individual trials in these sessions revealed no significant differences between conditions. These results demonstrate that actual movement is not necessary for the presence of robust hippocampal theta. Supported by: DFG, AG12609 & MH01565

•Eichenbaum, H., Dudchenko, P., Wood, E., Shapiro, M. & Tanila, H. (1999). The hippocampus, memory, and place cells: Is it spatial memory or a memory space? Neuron 23(209-226).

•Foster, D.J., Morris, R.G.M. & Dayan, P. (2000). A model of hippocampally dependent navigation, using the temporal difference learning rule. Hippocampus 10(1): 1-16. This paper presents a model of how hippocampal place cells might be used for spatial navigation in two watermaze tasks: the standard reference memory task and a delayed matching-to-place task. In the reference memory task, the escape platform occupies a single location and rats gradually learn relatively direct paths to the goal over the course of days, in each of which they perform a fixed number of trials. In the delayed matching-to-place task, the escape platform occupies a novel location on each day, and rats gradually acquire one-trial learning, i.e., direct paths on the second trial of each day. The model uses a local, incremental, and statistically efficient connectionist algorithm called temporal difference learning in two distinct components. The first is a reinforcement-based actor-critic network that is a general model of classical and instrumental conditioning. In this case, it is applied to navigation, using place cells to provide information about state. By itself, the actor-critic can learn the reference memory task, but this learning is inflexible to changes to the platform location. We argue that one-trial learning in the delayed matching-to-place task demands a goal-independent representation of space. This is provided by the second component of the model: a network that uses temporal difference learning and self-motion information to acquire consistent spatial coordinates in the environment. Each component of the model is necessary at a different stage of the task; the actor-critic provides a way of transferring control to the component that performs best. The model successfully captures gradual acquisition in both tasks, and, in particular, the ultimate development of one-trial Page 13 Place cell references learning in the delayed matching-to-place task. Place cells report a form of stable, allocentric information that is well-suited to the various kinds of learning in the model.

•Frank, L.M., Brown, E.N. & Wilson, M.A. (2000). Trajectory encoding in the hippocampus and entorhinal cortex. Neuron 27: 169-178. We recorded from single neurons in the hippocampus and entorhinal cortex (EC) of rats to investigate the role of these structures in navigation and memory representation. Our results revealed two novel phenomena: first, many cells in CA1 and the EC fired at significantly different rates when the animal was in the same position depending on where the animal had come from or where it was going. Second, cells in deep layers of the EC, the targets of hippocampal outputs, appeared to represent the similarities between locations on spatially distinct trajectories through the environment. Our findings suggest that the hippocampus represents the animal's position in the context of a trajectory through space and that the EC represents regularities across different trajectories that could allow for generalization across experiences.

•Frank, L.M., Brown, E.N. & Wilson, M.A. (2001). A comparison of the firing properties of putative excitatory and inhibitory neurons from CA1 and the entorhinal cortex. Journal of Neurophysiology 86(4): 2029-2040. The superficial layers of the entorhinal cortex (EC) provide the majority of the neocortical input to the hippocampus, and the deep layers of the EC receive the majority of neocortically bound hippocampal outputs. To characterize information transmission through the hippocampal and EC circuitry, we recorded simultaneously from neurons in the superficial EC, the CA1 region of hippocampus, and the deep EC while rodents ran for food reward in two environments. Spike waveform analysis allowed us to classify units as fast-spiking (FS) putative inhibitory cells or putative excitatory (PE) cells. PE and FS units' firing were often strongly correlated at short time scales, suggesting the presence a monosynaptic connection from the PE to FS units. EC PE units, unlike those found in CA1, showed little or no tendency to fire in bursts. We also found that the firing of FS and PE units from all regions was modulated by the approximately 8 Hz theta rhythm, although the firing of deep EC FS units tended to be less strongly modulated than that of the other types of units. When we examined the spatial specificity of FS units, we determined that FS units in all three regions showed low specificity. At the same time, retrospective coding, in which firing rates were related to past position, was present in FS units from all three regions and deep EC FS units often fired in a Page 14 Place cell references "path equivalent" manner in that they were active in physically different, but behaviorally related positions both within and across environments. Our results suggest that while the firing of FS units from CA1 and the EC show similarly low levels of position specificity, FS units from each region differ from one another in that they mirrored the associated PE units in terms of their tendency to show more complex positional firing properties like retrospective coding and path equivalence.

•Frank, L.M., Eden, U.T., Solo, V., Wilson, M.A. & Brown, E.N. (2002). Contrasting patterns of receptive field plasticity in the hippocampus and the entorhinal cortex: An adaptive filtering approach. Journal of Neuroscience 22(9): 3817-3830. Neural receptive fields are frequently plastic: a neural response to a stimulus can change over time as a result of experience. We developed an adaptive point process filtering algorithm that allowed us to estimate the dynamics of both the spatial receptive field (spatial intensity function) and the interspike interval structure (temporal intensity function) of neural spike trains on a millisecond time scale without binning over time or space. We applied this algorithm to both simulated data and recordings of putative excitatory neurons from the CA1 region of the hippocampus and the deep layers of the entorhinal cortex (EC) of awake, behaving rats. Our simulation results demonstrate that the algorithm accurately tracks simultaneous changes in the spatial and temporal structure of the spike train. When we applied the algorithm to experimental data, we found consistent patterns of plasticity in the spatial and temporal intensity functions of both CA1 and deep EC neurons. These patterns tended to be opposite in sign, in that the spatial intensity functions of CA1 neurons showed a consistent increase over time, whereas those of deep EC neurons tended to decrease, and the temporal intensity functions of CA1 neurons showed a consistent increase only in the "theta" (75-150 msec) region, whereas those of deep EC neurons decreased in the region between 20 and 75 msec. In addition, the minority of deep EC neurons whose spatial intensity functions increased in area over time fired in a significantly more spatially specific manner than non-increasing deep EC neurons. We hypothesize that this subset of deep EC neurons may receive more direct input from CA1 and may be part of a neural circuit that transmits information about the animal's location to the neocortex.

•Fuhs, M.C., Skaggs, W.E. & Touretzky, D.S. (2000). Modeling experience- dependent remapping in rat hippocampus. Society for Neuroscience Abstracts 30. Small environmental changes can cause radical rearrangement of hippocampal place fields ("remapping"). In some cases remapping occurs abruptly, but only after several exposures (Bostock et al. 1990), implying that remapping may depend on Page 15 Place cell references learning. We have implemented a neural network model of this phenomenon based on attractor dynamics and Hebbian learning. The model contains three groups of cells, representing entorhinal cortex, granule cells, and a group of inhibitory interneurons. The granule cells and interneurons are assumed to inhibit each other via modifiable connections, and to receive excitatory input from the entorhinal cells. Recurrent connections among granule cells give rise to multiple stable attractor basins. In an unfamiliar environment, strengthening of connections from granule to inhibitory cells counteracts the entorhinal input to the inhibitory cells, eventually suppressing inhibitory cell activity. Once the environment becomes familiar, the granule-to-interneuron connections cease to be modifiable. If small changes are then made to the environment, the resulting change in EC activity permits a small subset of interneurons to become active. When this happens repeatedly, the active interneuron-to-granule-cell connections potentiate, eventually resulting in destabilization of the granule cell attractor basin. The system then settles into a new basin and begins learning the features of this "new" environment. The model predicts that the probability of remapping as a function of exposures should be bimodally distributed, and that a subset of DG interneurons should show elevated activity in novel environments.Supported by: NSF 9720350 and NSF graduate fellowship

•Fuhs, M.C., Touretzky, D.S. & Skaggs, W.E. (2001). Do hippocampal place cell ensembles behave coherently in stretched environments? Society for Neuroscience Abstracts 31(643.11): 329. O'Keefe and Burgess (1996) measured hippocampal place fields in a rectangular environment whose walls could be stretched. They found fields altered in a way that resembled a sum of up to four Gaussians, each tuned to the distance from the field center to one of the walls. Stretching shifts the Gaussians relative to each other, changing the field shapes and the relationships between fields. The current experiment examined whether place cell activity could be better explained by a rigid map whose binding to the environment shifts as the rat moves in the stretched arena, thus producing the observed place field distortions. Data were recorded simultaneously from multiple CA1 pyramidal cells in both a control session and multiple stretched sessions, using a 12 tetrode recording system. Each neuron's stretched session activity at each timestep was estimated by using the ensemble activity pattern of the other cells to compute a similarity- weighted average of the neuron's control session activity. If the map is rigid, this ensemble prediction should be accurate. In a data set with 25 cells, the ensemble method did slightly better than the sum of Gaussians in predicting cell activity, but the difference was not statistically significant. Thus, the test was inconclusive. Page 16 Place cell references However, the comparison was impaired by a relatively low yield of simultaneously recorded cells. Future data will test whether the performance of the ensemble method improves when ensembles containing larger numbers of neurons are used. Supported by: NSF Graduate Research Fellowship (Fuhs) and NSF DGE-9987588

•Gaussier, P., Revel, A., Banquet, J.P. & Babeau, V. (2002). From view cells and place cells to learning: processing stages of the hippocampal system. Biological Cybernetics 86(1): 15-28. The goal of this paper is to propose a model of the hippocampal system that reconciles the presence of neurons that look like "place cells" with the implication of the hippocampus (Hs) in other cognitive tasks (e.g., complex conditioning acquisition and memory tasks). In the proposed model, "place cells" or "view cells" are learned in the perirhinal and entorhinal cortex. The role of the Hs is not fundamentally dedicated to navigation or map building, the Hs is used to learn, store, and predict transitions between multimodal states. This transition prediction mechanism could be important for novelty detection but, above all, it is crucial to merge planning and sensory-motor functions in a single and coherent system. A neural architecture embedding this model has been successfully tested on an autonomous robot, during navigation and planning in an open environment.

•Gerrard, J.L., Bower, M.R., Insel, N., Lipa, P., Barnes, C.A. & McNaughton, B.L. (2001). A long day's journey into night. Society for Neuroscience Abstracts 31(643.12): 329. Are patterns of coactivity of hippocampal neurons selected at random, or is there a propensity for some cells to exhibit strong correlations over many different experiences? This question has been the subject of controversy for several decades. Most studies have been performed in one or a few rather small environments in which the sample of the possible "state space" of the network is small. CA1 pyramidal cell activity was recorded while rats walked down and back along a long (13m x 2m) corridor. Few locations were visited more than once. As predicted by the random allocation model, the variance of the distribution of firing rate correlations became compressed around zero as compared to typical periods of repetitive track running. Moreover, the distribution of mean firing rates became significantly less sparse, again in agreement with the random model. This suggests that synaptic weight vectors of CA1 pyramidal cells are essentially uncorrelated. The degree of memory trace reactivation (Wilson and McNaughton, Science, 265:676-679, 1994; Kudrimoti et al., J. Neurosci., 19:4090- 4101, 1999) was also assessed during sleep following the long corridor experience, and compared to rats which ran repetitively around a small track. The population Page 17 Place cell references vector overlap between behavior and subsequent sleep, and the percent of the firing rate correlation variance during sleep that was statistically explained by the pattern during behavior (robust measures of reactivation) were significantly lower in the long corridor experiment than for the typical case of repetitious behavior, suggesting that repetition facilitates memory trace reactivation. Supported by: AG12609, MH01565, MH46823 & ARCS

•Gothard, K.M., Skaggs, W.E. & McNaughton, B.L. (1996). Dynamics of mismatch correction in the hippocampal ensemble code for space: Interaction between path integration and environmental cues. Journal of Neuroscience 16: 8027-8040. Populations of hippocampal neurons were recorded simultaneously in rats shuttling on a track between a fixed reward site at one end and a movable reward site, mounted in a sliding box, at the opposite end. While the rat ran toward the fixed site, the box was moved. The rat returned to the box in its new position. On the initial part of all journeys, cells fired at fixed distances from the origin, whereas on the final part, cells fired at fixed distances from the destination. Thus, on outward journeys from the box, with the box behind the rat, the position representation must have been updated by path integration. Farther along the journey, the place field map became aligned on the basis of external stimuli. The spatial representation was quantified in terms of population vectors. During shortened journeys, the vector shifted from an alignment with the origin to an alignment with the destination. The dynamics depended on the degree of mismatch with respect to the full-length journey. For small mismatches, the vector moved smoothly through intervening coordinates until the mismatch was corrected. For large mismatches, it jumped abruptly to the new coordinate. Thus, when mismatches occur, path integration and external cues interact competitively to control place- cell firing. When the same box was used in a different environment, it controlled the alignment of a different set of place cells. These data suggest that although map alignment can be controlled by landmarks, hippocampal neurons do not explicitly represent objects or events.

•Gothard, K.M., Skaggs, W.E., Moore, K.M. & McNaughton, B.L. (1996). Binding of hippocampal CA1 neural activity to multiple reference frames in a landmark-based navigation task. Journal of Neuroscience 16: 823-835. The behavioral correlates of rat hippocampal CA1 cells were examined in a spatial navigation task in which two cylindrical landmarks predicted the location of food. The landmarks were maintained at a constant distance from each other but were moved from trial to trial within a large arena surrounded by static background cues. Page 18 Place cell references On each trial, the rats were released from a box to which they returned for additional food after locating the goal. The box also was located variably from trial to trial and was moved to a new location while the animals were searching for the goal site. The discharge characteristics of multiple, simultaneously recorded cells were examined with respect to the landmarks, the static background cues, and the box in which each trial started and ended. Three clear categories of cells were observed: (1) cells with location-specific firing (place cells); (2) goal/landmark- related cells that fired in the vicinity of the goal or landmarks, regardless of their location in the arena; and (3) box-related cells that fired either when the rat was in the box or as it was leaving or entering the box, regardless of its location in the arena. Disjunctive cells with separate firing fields in more than one reference frame also were observed. These results suggest that in this task a subpopulation of hippocampal cells encodes location in the fixed spatial frame, whereas other subpopulations encode location with respect to different reference frames associated with the task-relevant, mobile objects.

•Guazzelli, A., Bota, M. & Arbib, M.A. (2001). Competitive Hebbian learning and the hippocampal place cell system: Modeling the interaction of visual and path integration cues. Hippocampus 11(3): 216-239. The hippocampus has long been thought essential for implementing a cognitive map of the environment. However, almost 30 years since place cells were found in rodent hippocampal field CA1, it is still unclear how such an allocentric representation arises from an ego-centrically perceived world. By means of a competitive Hebbian learning rule responsible for coding visual and path integration cues, our model is able to explain the diversity of place cell responses observed in a large set of electrophysiological experiments with a single fixed set of parameters. Experiments included changes observed in place fields due to exploration of a new environment, darkness, inactivation, and removal, rotation, and permutation of landmarks. To code for visual cues for each landmark, we defined two perceptual schemas representing landmark bearing and distance information over a linear array of cells. The information conveyed by the perceptual schemas is further processed through a network of adaptive layers which ultimately modulate the resulting activity of our simulated place cells. In path integration terms, our system is able to dynamically remap a bump of activity coding for the displacement of the animal in relation to an environmental anchor. We hypothesize that path integration information is computed in the rodent posterior parietal cortex and conveyed to the hippocampus where, together with visual information, it modulates place cell activity. The resulting network yields a more direct treatment of partial remapping of place fields than Page 19 Place cell references other models. In so doing, it makes new predictions regarding the nature of the interaction between visual and path integration cues during new learning and when the system is challenged with environmental changes.

•Guzowski, J.F., Chawla, M.K., McNaughton, B.L., Worley, P.F. & Barnes, C.A. (2000). Massed, but not spaced, exposure to a single environment attenuates transcription of the immediate-early gene Arc in hippocampal CA1 neurons. Society for Neuroscience Abstracts 30. Previously, we showed that Arc RNA expression was induced in a single population of CA1 neurons following sequential exposure of rats to a single novel environment, and in two statistically independent populations following sequential exposure to two different environments (J.F. Guzowski et al., Nature Neurosci. 2:1120-1124). We next investigated Arc RNA induction in CA1 neurons of rats with different levels of exposure to a single environment "A". Rats exposed to environment A for the 1st time or for the 9th consecutive day expressed Arc RNA in ~40% of CA1 neurons. The lack of habituation of Arc RNA expression with spaced exposure to a single environment is consistent with the hypothesis that Arc transcription is induced in CA1 neurons following periods of place cell activity. In contrast, rats that were exposed to environment A for 9 times in a single day, with 30’ between each exposure, showed Arc RNA expression in only ~15% of CA1 neurons. However, this "saturation" of Arc transcription was specific to the neuronal population activated by environment A—rats that were exposed to a different environment, "B", for 8 times in a single day and then exposed to environment A showed Arc RNA expression in ~30% of CA1 neurons. It remains to be determined whether this saturation effect is a consequence of altered neuronal activity or a change in the relationship between activity and gene expression. Supported by: MH60123, MH01565, MH01152, AG09219

•Harris, K.D., Hirase, H., Czurko, A., Henze, D.A., Csicsvari, J. & Buzsaki, G. (2000). Temporal and spatial correlates of complex spike bursts in hippocampal pyramidal cells. Society for Neuroscience Abstracts 30. Many cells in the brain fire in two modes: single isolated spikes, or complex spike bursts. We investigated the conditions under which complex spike bursts are produced in CA1 pyramidal cells in the behaving rat. Because burst firing leads to reduction in extracellular amplitude, only cells that were well-isolated by quantitative criteria were investigated. The dependence of burst firing on spatial location was investigated using a measure of place field specificity (Skaggs et al 1993). After compensating for dependence on the total number of spikes, no significant specificity difference was found between bursts and single spikes. We also investigated the relationship Page 20 Place cell references of bursting to theta rhythm phase. Single spikes showed stronger phase modulation than bursts. For both bursts and single spikes, extracellular amplitude was phase dependent, with largest amplitudes on the rising phase. Complex spike firing was also dependent on the prior activity of the cell. If the previous interspike interval (ISI) was long (>50ms), burst initiation was more likely than if the previous ISI was short (10-50ms). This effect was seen in both theta behavior and slow-wave sleep. The length of the previous ISI was positively correlated with extracellular amplitude. Furthermore, extracellular amplitude was positively correlated with burst initiation probability, even after controlling for previous ISI length. We suggest that a single cellular mechanism may be responsible for the joint activity- dependent modulation of extracellular amplitude and burst initiation probability. Inactivation of voltage-dependent sodium channels is one mechanism with many of the right properties. Supported by: NIH, NS34994 & MH54671

•Hartley, T., Burgess, N., Lever, C., Cacucci, F. & O'Keefe, J. (2000). Modeling place fields in terms of the cortical inputs to the hippocampus. Hippocampus 10(4): 369-379. A model of place-cell firing is presented that makes quantitative predictions about specific place cells' spatial receptive fields following changes to the rat's environment. A place cell's firing rate is modeled as a function of the rat's location by the thresholded sum of the firing rates of a number of putative cortical inputs. These inputs are tuned to respond whenever an environmental boundary is at a particular distance and allocentric direction from the rat. The initial behavior of a place cell in any environment is simply determined by its set of inputs and its threshold; learning is not necessary. The model is shown to produce a good fit to the firing of individual place cells, and populations of place cells across environments of differing shape. The cells' behavior can be predicted for novel environments of arbitrary size and shape, or for manipulations such as introducing a barrier. The model can be extended to make behavioral predictions regarding spatial memory.

•Hetherington, P.A. & Shapiro, M.L. (1993). A simple network model simulates hippocampal place fields. 2. Computing goal-directed trajectories and memory fields. Behavioral Neuroscience 107(3): 434-443. Place cells have been described as the computational elements of a neuronal cognitive mapping system that encodes and stores relationships among spatial stimuli (O'Keefe & Nadel, 1978). Furthermore, place cells seem to encode remembered locations because neural activity is maintained when the visual stimuli that influence place field location are vastly degraded, such as when cues are removed or the lights are turned off (O'Keefe & Page 21 Place cell references Speakman, 1987; Quirk, Muller, & Kubie, 1990). A feed-forward network model that mapped visual input onto a representation of location simulated some basic properties of hippocampal place fields, including resistance to disruption after partial cue removal (Shapiro & Hetherington, 1993). However, the stimulated place fields required visual input for their activation. We now report that a network that incorporates feedback (a) computed correct trajectories toward simulated goals and (b) simulated place fields that persist in the absence of visual input. The simulation suggests that feedback properties can provide a computational account of O'Keefe and Speakman's data.

•Hirase, H., Leinekugel, X., Czurko, A., Csicsvari, J. & Buzsaki, G. (2000). Correlation of firing rates of hippocampal neurons during sleep and awake activity in behaving animals. Society for Neuroscience Abstracts 30. What determines the firing rate of cortical neurons in the absence of external perceptual reference or motor behavior, such as sleep? Previous studies have suggested that the firing patterns of hippocampal pyramidal neurons during sleep can be influenced by the subgroup of neurons that were active in the awake behavior. However, the effect of experience on the discharge frequency of neurons during sleep is controversial. Here we report that, in familiar environments, the discharge frequency structure of simultaneously recorded hippocampal CA1 pyramidal cells remains similar across various network states, including exploratory and consummatory behaviors, slow waves sleep (SWS) and rapid eye movement (REM) sleep. These findings suggest that the relative activity of CA1 pyramidal cells in a familiar environment is determined by afferents or intrinsic properties of the cells which remain similar in both the awake and sleeping rat. Activity-dependent modification of the CA3-CA1 synaptic connections is a candidate mechanism for altering firing rates. Supported by: HFSP, NIH, Uehara Memorial Foundation

•Hoffman, K.L., McNaughton, B.L., Lipa, P., Ellmore, T.M. & Stengel, K. (2001). Spontaneous reactivation of recent memory traces in macaque neocortical ensembles. Society for Neuroscience Abstracts 31(643.15): 330. In rodents, neural activity patterns which occur during a behavior tend to recur during subsequent periods of inactivity. Moreover, the correlation structure of neural activity following experience is a closer match to that of behavior than the correlation structure of activity preceding experience, suggesting memory traces are reactivated. Although memory trace reactivation has been shown in the hippocampus and parietal neocortex of rats, it is not known whether a similar process occurs in primates. Extracellular recordings of groups of over 25 cells were made Page 22 Place cell references simultaneously from primary somatosensory and prefrontal cortex as a monkey performed a repeated sequence of behaviors lasting 10-20 minutes. Before and after the task, the monkey rested up to 30 minutes in a small darkened chamber. Reactivation was assessed using the explained variance method (Kudrimoti et al., 1999) in which pairwise correlations of neural activity were calculated separately for each of the three epochs: pre-task rest (R1), task (T) and post-task rest (R2). A partial regression of the T and R2 correlations, factoring out the variance accounted for by the R1 correlations, produced an EV of between 10-20%, comparable to that seen in rats. As a control, the reverse EV analysis using the regression of T and R1 correlations, factoring out the contribution of R2, produced EVs < 0.1%. These results suggest that in non-human primates, as in rats, patterns of neocortical neural activity expressed during an experience are reactivated following that experience. Such reactivation could contribute to the process of memory consolidation. Supported by: JST CREST, NSF & MH01565

•Hollup, S.A., Molden, S., Donnett, J.G., Moser, M.B. & Moser, E.I. (2001). Accumulation of hippocampal place fields at the goal location in an annular watermaze task. Journal of Neuroscience 21: 1635-1644. To explore the plastic representation of information in spatially selective hippocampal pyramidal neurons, we made multiple single-unit recordings in rats trained to find a hidden platform at a constant location in a hippocampal-dependent annular watermaze task. Hippocampal pyramidal cells exhibited place-related firing in the watermaze. Place fields tended to accumulate near the platform, even in probe trials without immediate escape. The percentage of cells with peak activity around the hidden platform was more than twice the percentage firing in equally large areas elsewhere in the arena. The effect was independent of the actual position of the platform in the room frame. It was dissociable from ongoing motor behavior and was not related to linear or angular speed, swim direction, or variation in hippocampal theta activity. There was no accumulation of firing in any particular region in rats that were trained with a variable platform location. These training-dependent effects suggest that regions of particular behavioral significance may be over-represented in the hippocampal spatial map, even when these regions are completely unmarked.

•Hollup, S.A., Molden, S., Donnett, J.G., Moser, M.B. & Moser, E.I. (2001). Place fields of rat hippocampal pyramidal cells and spatial learning in the watermaze. European Journal of Neuroscience 13: 1197-1208. To provide a background for studying place-related activity in hippocampal neurons during spatial learning, we compared the activity of hippocampal place cells in an annular Page 23 Place cell references watermaze and an analogous land-based task. Complex-spike cells had robust place correlates in both conditions, and a significant proportion of the cells had place fields at the same locations. However, the in-field firing rates were slightly higher in the wet condition. Elevated firing was observed also in an open water task. There was no enhancement when the platform location was varied randomly or when there was no platform at all. Second, the place fields were under stronger directional modulation during swimming. In the annular task, directional sensitivity appeared regardless of whether the animals were trained to find a platform or not. There were directionally modulated units also in the open watermaze, but the number was smaller than in the corridor. Altogether, these observations suggest that place fields in the watermaze are largely controlled by the same factors as on dry land, in spite of the differences in kinaesthetic and vestibular input. Differences in firing rate and directional control may depend on the geometric and cognitive structure of the task rather than the medium on which the rats are moving.

•Hollup, S.A., Otnaess, M.K., Donnett, J.G., Mustaparta, H., Moser, M.B. & Moser, E.I. (2001). A new odour-based memory task for hippocampal unit recording. Society for Neuroscience Abstracts 31(643.7): 329. The search for memory-related activity in the hippocampus during theta-related behavior would be easier if specific mnemonic events could be identified with temporal precision. Recent data suggest that many hippocampal neurons fire in response to specific odors (Wood et al., 1999). We have constructed an odour-based memory task in which odours are presented with an exact onset and offset during theta-associated locomotion. Specifically, rats are trained to find a platform at a given position in an annular water maze (Hollup et al., 2001). The platform is made available only after the rat has swum at least one lap through the corridor. While the rat is swimming, clean air is delivered through a continuous slit along a slanting outer corridor wall. An array of auxiliary injector nozzles is distributed at short distances along the outer wall of the swim corridor. For a predetermined brief period (e.g. 1 s), a specific odour is injected through one of these nozzles on top of the background airflow. The slanting inner wall contains an equal slit through which air and odor are removed. Odour delivery is controlled electronically and can be made contingent on position, behavior and/or recorded neuronal activity of the animal. Odours may for example indicate where or when a platform is likely to appear. Information about odour content and odour location is likely to be encoded within the time window defined by the odour pulse, which makes the identification of relevant spike patterns and spike-phase relationships significantly easier. Supported by: Norwegian Research Council Page 24 Place cell references

•Houston, F.P., Lipa, P., Guzowski, J.F., Worley, P.F., McNaughton, B.L. & Barnes, C.A. (2001). Massed versus spaced exposure to an environment dissociates place-specific hippocampal cell firing and experience-induced Arc transcription. Society for Neuroscience Abstracts 31(316.3). When ensembles of dorsal hippocampal cells are recorded in rats engaged in spatial foraging behaviors in typical recording environments (e.g., 0.5-1.0 m2), ~30-50% of cells show place- specific firing activity. Transcription of the immediate-early gene Arc is induced in hippocampal CA1 neurons in this same proportion (Guzowski et al., Nature Neurosci. 2:1120-1124, 1999). Recently, Arc RNA induction was examined in rats with different levels of exposure to a single environment "A" (Guzowski et al., Soc. Neurosci. Abst. 26:981, 1999). Rats exposed to "A" for the 1st time or for the 9th consecutive day expressed Arc RNA in ~40% of CA1 neurons. By contrast, rats that were exposed to "A" for 9 times in a single day, with 30 min between each exposure, expressed Arc in only ~15% of CA1 neurons, but this saturation of Arc transcription was specific to the neuronal population activated by "A". The question addressed in the present study is whether there is also an attenuation of single unit firing rates following multiple exposures to a single environment. Ensemble recordings were made from CA1 in three rats during the massed exposure paradigm. Rats were exposed to environment "A" 9 times (5 min each) at 30 min intervals within a single day. Neither the mean firing rates nor interspike interval distributions of CA1 neurons changed significantly with these repeated exposures. Thus, the decrement of CA1 Arc expression during massed behavioral trials does not appear to be due to a change in firing statistics of pyramidal cells.Supported by: AG09219, MH60123 & MH01565

•Huxter, J.R., Thorpe, C.M., Martin, G.M. & Harley, C.W. (2001). Spatial problem solving and hippocampal place cell firing in rats: Control by an internal sense of direction carried across environments. Behavioral Brain Research 123(1): 37-48. Rats learned to find the baited corner of a box surrounded by a curtain, regardless of whether they had a fixed or random point of entry (POE) through the curtain. On probe trials, rats used an internal direction sense carried from outside the curtain to solve the problem, and only used the visual cue inside the curtain if disoriented and denied access to a view of the room en route. Similar disorientation procedures were required to obtain cue control of hippocampal place fields. The results suggest that: (1) POE effects previously found in the water maze may be task-specific; (2) an undisrupted internal sense of direction carried from one environment to another may provide the preferred solution to spatial problems in Page 25 Place cell references the second environment, even when this second environment is a familiar one with stable visual cues; and (3) choice behaviour is sometimes, but not always, representative of the hippocampal representation of space.

•Ikonen, S., McMahan, R., Gallagher, M., Eichenbaum, H. & Tanila, H. (2002). Cholinergic system regulation of spatial representation by the hippocampus. Hippocampus 12(3): 386-397. The role of the basal forebrain cholinergic system in hippocampal spatial representation was explored by examining the effects of immunotoxic lesions of the septo-hippocampal cholinergic neurons on the firing patterns of hippocampal place cells as rats explored familiar and novel environments. In a highly familiar environment, the basic qualities and stability of place fields were unaffected by the lesion. When first exposed to a set of novel environmental cues without otherwise disorienting the animals, place cells in both normal and lesioned animals responded with similar alterations in their firing patterns. Upon subsequent repetitive exposures to the new environment, place cells of normal rats developed a spatial representation distinct from that of the familiar environment. By contrast, place cells of lesioned animals reconverged in the direction of the representation associated with the familiar environment. These results suggest that cholinergic input may determine whether new visual information or a stored representation of the current environment will be actively processed in the hippocampal network.

•Jarosiewicz, B. & Skaggs, W.E. (2001). Hippocampal place-related activity during the small-amplitude irregular activity state in the rat. Society for Neuroscience Abstracts 31(643.10): 329. The hippocampus of the sleeping rat cycles between two well characterized sleep states, SWS and REM. Inspection of the activity of ensembles of hippocampal CA1 complex-spike cells along with EEG reveals a third physiological state, distinct from both SWS and REM. This state occupies 20% of total sleep, occurring repeatedly within SWS and following nearly every REM episode, but never occurs just before or within REM. During this state, the hippocampal EEG flattens, probably corresponding to small-amplitude irregular activity (SIA) described in the literature to occur during alert but motionless behavioral states. At the same time, a small subset of complex-spike cells becomes very active while the rest of the cells remain nearly silent, with the same subset of cells active across long sequences of SIA episodes. This study was aimed at clarifying the factors that determine which particular cells are active during SIA. One possibility is that the SIA found during sleep is a state of increased wakefulness, predicting that SIA-active cells are those cells with place fields in Page 26 Place cell references the location where the rat sleeps. To test this hypothesis, we examined correlations between place-related ensemble activity while the rat ran for randomly scattered food reward in the environment, and ensemble activity during SIA while the rat slept. Significantly above-chance correlations were found specifically in the location of the sleeping-nest, thus supporting the hypothesis that SIA-active cells are, more often than chance, cells that have place fields in the location where the rat sleeps. Supported by: U. Pittsburgh, the Center for the Neural Basis of Cognition, and a National Science Foundation Graduate Fellowship

•Jeffery, K.J. & O'Keefe, J. (1999). Learned interaction of visual and idiothetic cues in the control of place field orientation. Exp Brain Res 127(2): 151-161. In a symmetrical environment (like a square box) hippocampal place cells use a mixture of visual and idiothetic (movement) information to tell them which way the environment is oriented. The present experiment tested the hypothesis that if the visual landmarks were mobile, place cells would learn to disregard these and rely on idiothetic cues instead. Place cells were recorded in a square box surrounded by circular black curtains. A cue card hung on the curtain behind one of the walls to break the fourfold symmetry. The relative influence of this card on the location of place fields was assessed each day by confining the rat on a rotating platter underneath an opaque cover, and then rotating the card and the platter by different amounts, to see whether subsequently recorded place fields had rotated with the card or with the rat. For some rats, these trials had been preceded by trials in which the card had been visibly moved from trial to trial, so that the rats had seen that it was mobile. Other rats received no prior visual information that the card was mobile. In the rats that had previously seen the card move, place fields initially rotated with the card but by the end of five sessions usually rotated with the rat instead. For rats that had never seen the card move, place fields always followed the card. Thus, the cells were able to "learn" that their preferred directional input, the card, was unreliable. A third group of rats, who were covered only for 30 s while the card was moved, showed mixed behaviour, suggesting a degradation of the idiothetic trace with time.

•Jeffery, K.J., Donnett, J.G., Burgess, N. & O'Keefe, J. (1998). Directional control of hippocampal place fields. Exp Brain Res 117(1): 131-142. Pyramidal cells in the rat hippocampus fire whenever the animal is in a particular place, suggesting that the hippocampus maintains a representation of the environment. Receptive fields of place cells (place fields) are largely determined by the distance of the rat from environmental walls. Because these walls are sometimes Page 27 Place cell references distinguishable only by their orientation with respect to the outside room, it has been hypothesised that a polarising directional input enables the cells to locate their fields off-centre in an otherwise symmetrical environment. We tested this hypothesis by gaining control of the rat's internal directional sense, independently of other cues, to see whether manipulating this sense could, by itself, produce a corresponding alteration in place field orientation. Place cells were recorded while rats foraged in a rectangular box, in the absence or presence of external room cues. With room cues masked, slow rotation of the rat and the box together caused the fields to rotate accordingly. Rotating the recording box alone by 180 degrees rarely caused corresponding field rotation, while rotating the rat alone 180 degrees outside the environment and then replacing it in the recording box almost always resulted in a corresponding rotation of the fields. This shows that place field orientation can be controlled by controlling the internal direction-sense of the rat, and it opens the door to psycho-physical exploration of the sensory basis of the direction sense. When room cues were present, distal visual cues predominated over internal cues in establishing place field orientation.

•Jensen, O. & Lisman, J.E. (1996). Hippocampal CA3 region predicts memory sequences: accounting for the phase precession of place cells. Learn Mem 3(2-3): 279-87. Hippocampal recordings show that different place cells fire at different phases during the same theta oscillation, probably at the peak of different gamma cycles. As the rat moves through the place field of a given cell, the phase of firing during the theta cycle advances progressively. In this paper we have sought to determine whether a recently developed model of hippocampal and cortical memory function can explain this phase advance and other properties of place cells. According to this physiologically based model, the CA3 network stores information about the sequence of places traversed during learning. Here we show that the phase advance can be understood if it is assumed that the hippocampus is in a mode that operates when the animal is already familiar with a path. In this mode, sensory information about the current position triggers recall of the upcoming 5-6 places (memories) in the path at a rate of one memory per gamma cycle. The model predicts that the average phase advance will be one gamma cycle per theta cycle, a value in reasonable agreement with the data. The model also correctly accounts for (1) the fact that the firing of a place cell occurs during approximately 7 theta cycles (on average) as the animal crosses the place field; (2) the observation that the phase of place cell firing depends more systematically on position than on time; and (3) the fact that traversal of an already familiar path produces further modifications (shifts the firing of a cell to an earlier position in the path). This later finding Page 28 Place cell references suggests that recall of previously stored information strengthens the memory of that information. In the model, this occurs because of a novel role of N-methyl-D- aspartate channels in recall. The general success of the model provides support for the idea that the hippocampus stores sequence information and makes predictions of expected positions during gamma-frequency recall.

•Jensen, O. (2001). Information transfer between rhythmically coupled networks: Reading the hippocampal phase code. Neural Compututation 13(12): 2743-2761. There are numerous reports on rhythmic coupling between separate brain networks. It has been proposed that this rhythmic coupling indicates exchange of information. So far, few computational models have been proposed that explore this principle and its potential computational benefits. Recent results on hippocampal place cells of the rat provide new insight; it has been shown that information about space is encoded by the firing of place cells with respect to the phase of the ongoing theta rhythm. This principle is termed phase coding and suggests that upcoming locations (predicted by the hippocampus) are encoded by cells firing late in the theta cycle, whereas current location is encoded by early firing in the theta cycle. A network reading the hippocampal output must inevitably also receive an oscillatory theta input in order to decipher the phase-coded firing patterns. In this article, I propose a simple physiologically plausible mechanism implemented as an oscillatory network that can decode the hippocampal output. By changing only the phase of the theta input to the decoder, qualitatively different information is transferred: the theta phase determines whether representations of current or upcoming locations are read by the decoder. The proposed mechanism provides a computational principle for information transfer between oscillatory networks and might generalize to brain networks beyond the hippocampal region.

•Kentros, C., Hargreaves, E., Hawkins, R.D., Kandel, E.R., Shapiro, M. & Muller, R.U. (1998). Abolition of long-term stability of new hippocampal place cell maps by NMDA receptor blockade. Science 280: 2121-2126. Hippocampal pyramidal cells are called place cells because each cell tends to fire only when the animal is in a particular part of the environment-the cell's firing field. Acute pharmacological blockade of N-methyl-D-aspartate (NMDA) glutamate receptors was used to investigate how NMDA-based synaptic plasticity participates in the formation and maintenance of the firing fields. The results suggest that the formation and short-term stability of firing fields in a new environment involve plasticity that is independent of NMDA receptor activation. By contrast, the long- term stabilization of newly established firing fields required normal NMDA Page 29 Place cell references receptor function and, therefore, may be related to other NMDA-dependent processes such as long-term potentiation and spatial learning.

•Khabbaz, A., Fee, M.S., Tsien, J.Z. & Tank, D.W. (2000). A compact converging-electrode microdrive for recording head direction cells in mice. Society for Neuroscience Abstracts 30. Head direction (HD) cells selectively discharge in relation to the animal's head direction in the horizontal plane. They have been observed in both rats and primates. An analysis of the cellular and circuit mechanisms of activity would be greatly aided by combining multiple microelectrode recording techniques with transgenic technology developed for the mouse. However, electrophysiological investigation of HD cells in the normal or transgenic mouse is more difficult than in the rat because brain structures of interest are much smaller. For example, HD cells are found in the anterior dorsal thalamus (ADN) of the rat, but in the mouse this nucleus is about 3 mm deep and only 250 microns wide, making it difficult to position multiple extracellular microelectrodes within the structure. To address this problem, we have modified a compact lightweight microdrive (S. Venkatachalam, M.S.Fee, and D. Kleinfeld, J. Neurosci. Methods 90:37(1999)) to record from multiple neurons in a nucleus the size of ADN. The drive independently advances 6 metal microelectrodes and has a total weight of <2.5 grams. The electrodes are arranged in a circle and a conical guide assembly causes the electrodes to converge to a point at a predetermined depth below the surface of the brain. Using this drive, we have recorded head direction cells in the mouse in or near the ADN. Although designed for the ADN, our methods should be applicable to many other small nuclei in transgenic mice. Supported by: Lucent Tech., NIH

•Kim, J.J., Lee, H.J. & Sharp, P.E. (2000). Effects of stress on hippocampal long-term potentiation (LTP), spatial memory, and place cell properties. Society for Neuroscience Abstracts 30. Uncontrollable stress has been found to impair both hippocampal-dependent (e.g., spatial) memory tasks and hippocampal LTP in rodents, suggesting that memory deficits associated with stress may in part be due to alterations in LTP (or other forms of synaptic plasticity) in the hippocampus. Recent mutant mice studies indicate that genetic manipulations that impair hippocampal LTP and spatial memory also disrupt the properties of hippocampal place cells, which preferentially fire when the animal is in a specific spatial location in an environment (i.e., place fields) and are thought to be important in spatial navigation. In the present study, we investigated the effects of stress (2-hr exposures to bright light and intermittent loud sounds) on hippocampal LTP, spatial memory, and Page 30 Place cell references place cell properties. When initial slopes of field-EPSPs were examined in stratum radiatum in CA 1 following stimulation of Schaffer collateral/commissural fibers, we observed that hippocampal slices from stressed animals exhibited significantly impaired LTP after tetanus in comparison to slices from unstressed control animals. Behaviorally, the same stress also affected spatial memory in a hidden platform version of the Morris water maze. Importantly, preliminary results indicate that while previously established place fields (in a familiar chamber) are not significantly affected following stress, fields tested in a novel environment after stress seem to be unstable. Thus, stress, by altering hippocampal synaptic plasticity, may alter the characteristics of place cells and thereby exert its influence on spatial memory. Supported by: A grant from the Whitehall Foundation.

•Kjelstrup, K.G., Tuvnes, F.A., Moser, E.M. & Moser, M.B. (2001). Does the hippocampus have a role in fear expression? Society for Neuroscience Abstracts 31(643.2). Converging evidence suggests that the hippocampus is essential for spatial and contextual learning in particular, and probably also for episodic or declarative learning more generally. However, connections between the hippocampus and several nuclei of the amygdala and hypothalamus suggest that the hippocampus may also influence non-mnemonic functions such as emotional behaviour and internal state. In this study we ask whether the hippocampus has a role in expression of unconditioned fear in rats. Lesions of the hippocampus were made by ibotenic acid. After recovery and handling, unconditioned fear was measured during a 10 min exposure to an unfamiliar elevated plus-maze with two open arms and two closed arms. Animals with hippocampal damage exhibited less fear behaviour in the elevated plus maze. Whereas the sham-operated control animals spent most of the trial time within the closed arms, rats in the hippocampal group visited the open arms both more often and for longer periods. They also spent more time in the central area. The groups did not differ significantly in total path length, total time moving or freezing. There was no differential preference on a subsequent test with all four arms closed. The spatial learning ability of the same animals was tested in a watermaze. As expected, the rats with hippocampal damage had longer escape latencies in the watermaze, than the sham-operated control animals, and failed to show any preference for the platform area on the probe trials. Hippocampal lesions reduced unconditioned fear, suggesting that the hippocampus also regulates some non-mnemonic functions. Supported by: Norw.Res.Council

•Knierim, J.J., Kudrimoti, H.S. & McNaughton, B.L. (1995). Place cells, head direction cells, and the learning of landmark stability. Journal of Neuroscience 15: Page 31 Place cell references 1648-1659. Previous studies have shown that hippocampal place fields are controlled by the salient sensory cues in the environment, in that rotation of the cues causes an equal rotation of the place fields. We trained rats to forage for food pellets in a gray cylinder with a single salient directional cue, a white card covering 90 degrees of the cylinder wall. Half of the rats were disoriented before being placed in the cylinder, in order to disrupt their internal sense of direction. The other half were not disoriented before being placed in the cylinder; for these rats, there was presumably a consistent relationship between the cue card and their internal direction sense. We subsequently recorded hippocampal place cells and thalamic head direction cells from both groups of rats as they moved in the cylinder; between some sessions the cylinder and cue card were rotated to a new direction. All rats were disoriented before recording. Under these conditions, the cue card had much weaker control over the place fields and head direction cells in the rats that had been disoriented during training than in the rats that had not been disoriented. For the former group, the place fields often rotated relative to the cue card or completely changed their firing properties between sessions. In all recording sessions, the head direction cells and place cells were strongly coupled. It appears that the strength of cue control over place cells and head direction cells depends on the rat's learned perception of the stability of the cues.

•Knierim, J.J., Rao, G. & Lazott, L. (2000). Local surface cues can predominate over distal landmarks in the control of hippocampus place cell firing. Society for Neuroscience Abstracts 30. Recent studies demonstrated that salient local cues exerted an influence over place cells, although distal landmarks, when present, were still predominant. To test the relative influence of local vs. distal cues parametrically, 5 rats were trained to run clockwise on a circular track, each quarter of which was covered by surfaces that differed in color, visual pattern, and/or tactile texture. Six controlled distal cues were placed on the floor of the laboratory or on the curtains surrounding the room. An average of 9.5 cells with place fields on the track were recorded per session from CA1, CA3, and the dentate gyrus. Standard cue configuration trials were interleaved with trials in which the track was rotated counter-clockwise (CCW) and the controlled distal cues were rotated an equal amount clockwise (CW). Each rat experienced 2 sets of 4 rotation amounts: ±22.5° (total relative rotation of 45°), ±45° (90°), ±67.5° (135°), and ±90° (180°). Collapsing across all sessions and all cells, 63% of fields rotated (CW, CCW, or 0°) while 37% remapped (i.e., ceased firing or gained a field). Of the fields that rotated CW or CCW, 77% rotated CCW (i.e., local cues dominant) and 23% rotated CW (i.e., distal cues dominant); field rotations often overshot or undershot the cue Page 32 Place cell references rotations. In some sessions, a set of cells rotated CW while simultaneously recorded cells rotated CCW. The predominance of local cues was true for all rats (55%, 70%, 75%, 80%, and 98%), for all rotation amounts (range 73%-80%), and for all hippocampal fields (CA1: 78%, CA3: 75%, DG: 60%). These results show that under certain conditions, the most salient external cues that determine place field location are local surface cues, rather than distal landmarks. Supported by: NS39456.

•Kobayashi, T., Kato, H., Tran, H.A., Ono, T. & Matsumoto, G. (2000). Flexible changes of spatial and nonspatial activities of hippocampal place cells. Society for Neuroscience Abstracts 30. There is a great deal of evidence that the activity of hippocampal neurons has spatial correlates in the environment. Also recent studies have shown that hippocampal neurons show nonspatial activities. In the present study, in order to determine the task dependency of spatial and nonspatial correlates of hippocampal place cell activities, rats were trained two kinds of place tasks in which intracranial self-stimulation was used as rewards, and recorded neuron activities from the hippocampal formation. In the first task, rats were trained to search rewards delivered in random places in the circular open field, and place specific activities of hippocampal neurons were determined. In the second task, rewards were delivered in the two fixed places in the same environment, and one of these places was located in the place field which had been determined in the first task and the other place was located outside the place field. Spatial, reward, and behavioral correlates of hippocampal cell activities were analyzed and compared in these tasks. Many hippocampal neurons showed place fields, and had reward and behavioral correlates in the first task. In the second task, some hippocampal neurons changed their location of place fields and behavioral correlates. These changes appeared rapidly, and had close relation to conditions of reward delivery. Also some hippocampal neurons had no place field, but increased firing after reward in both tasks. These results suggest that hippocampal formation represents the environment and several features of ongoing behavior flexibly.

•Lenck-Santini, P.P., Save, E. & Poucet, B. (2001). Evidence for a relationship between place-cell spatial firing and spatial memory performance. Hippocampus 11(4): 377-390. The rat hippocampus contains place cells whose firing is location-specific. Although many properties of place cells have been uncovered, little is known about their actual contribution to the animal's spatial performance. In this study, we addressed this issue by recording place cells while rats solved a continuous spatial alternation task in which they had to alternate between the two Page 33 Place cell references arms of a Y-maze to get a food reward in the third (goal) arm. By manipulating the information available to the animals, we induced the cells to establish their fields in locations that were out of register relative to their standard position, thus making them inconsistent with the learned spatial task. When this happened, the rats' performance in the alternation task was markedly decreased. In addition, the nature of the behavioral errors during inconsistent field placements also changed dramatically in a way that was highly indicative of the rats' spatial disorientation. These results suggest that there is a functional relationship between the spatial firing patterns of place cells and the spatial behavior of the rat, thus strengthening the idea that these cells are part of a navigational system.

•Leutgeb, S., Bezzi, M. & Mizumori, S.J.Y. (2000). Contribution of septal projections to the new generation of new hippocampal codes for space. Society for Neuroscience Abstracts 30. A medial septal contribution to the reorganization of hippocampal place fields has been suggested by theoretical models of hippocampal function. The present study tested whether temporary inactivation of the septum delayed the formation of new hippocampal spatial representations. Recording sessions began in a familiar environment and were continued in a new environment after intraseptal tetracaine (n = 4) or vehicle (n = 7) injections. Behaviorally, the exposure to a new set of sensory cues increased the number of working memory errors irrespective of the experimental or control manipulation. In addition, the new environment resulted in a decreased spatial consistency of hippocampal CA1 cells and changes in the temporal pattern of single-unit discharges. A decreased probability for spike repetition at theta frequencies was observed in controls. Our data suggest that inactivation of the septal area did not change the effectiveness of the new environment for generating these initial changes in single-unit responses. The reorganization of the place fields was complete by the second day in the new environment after intraseptal vehicle injections, but we observed a trend for a continued reorganization on the day after septal inactivation. Inactivation of the septal area has previously been shown to result in decreased discharge rates of CA3 cells. The present results therefore suggest that sustained activation of the CA3 region by septal afferents is required to establish a consistent spatial representation in the CA1 area. Supported by Supported by: NIH [MH 58755] and HFSP [RG 01101998B].

•Lever, C., Wills, T., Cacucci, F., Burgess, N. & O'Keefe, J. (2002). Long- term plasticity in hippocampal place-cell representation of environmental geometry. Nature 416(6876): 90-94. The hippocampus is widely believed to be involved in Page 34 Place cell references the storage or consolidation of long-term memories. Several reports have shown short-term changes in single hippocampal unit activity during memory and plasticity experiments, but there has been no experimental demonstration of long-term persistent changes in neuronal activity in any region except primary cortical areas. Here we report that, in rats repeatedly exposed to two differently shaped environments, the hippocampal-place-cell representations of those environments gradually and incrementally diverge; this divergence is specific to environmental shape, occurs independently of explicit reward, persists for periods of at least one month, and transfers to new enclosures of the same shape. These results indicate that place cells may be a neural substrate for long-term incidental learning, and demonstrate the long-term stability of an experience-dependent firing pattern in the hippocampal formation.

•Lipa, P., Barnes, C.A. & McNaughton, B.L. (2000). Hippocampal pyramidal cells show indistinguishable firing properties in local cue rich and poor environments. Society for Neuroscience Abstracts 30. The hypothesis that hippocampal neurons encode specific information about sensory feature sets was tested by comparing CA1 neural ensemble activity in rats running on a ~180 cm linear track, sharply demarcated at the mid-point into local cue rich and poor zones. The rich zone contained many small 'junk' objects (screws, coins, tacks, cloth, gravel, cotton balls, etc.) and different olfactory stimuli. The poor zone consisted of the bare, uniformly painted track. Because sensory inputs changed rapidly in the rich zone, the feature set encoding hypothesis explicitly predicts smaller and more plentiful 'place' fields there, and possibly other differences in ensemble firing characteristics. 87 pyramidal cells in 2 animals were recorded during the rats' first experience on the track. Several measures (differential ensemble firing rate, place field sparsity, information, and spatial rate of change of population vector) were used to quantify possible effects of local cue-density. The rats initially exhibited clear differences in exploratory behavior in the two zones, indicating that they registered the differences in cue density; however, no difference in average firing rates or number and width of place fields could be established. Place fields covered the whole track almost uniformly. There was no evidence in any dependent measure that the hippocampus encoded the cue-rich vs. cue-poor distinction. Thus, at least for differences in cue density that are not task-relevant, hippocampal firing dynamics appear independent of the amount of information available at the sensory level. Supported by: NS20331, MH01565, Thanks to NS&B '99 students

•Liu, X., Huang, L.-T., Kubie, J., Rotenberg, A., Rivard, B., Cilio, M.R., Hu, Page 35 Place cell references Y., Muller, R.U. & Holmes, G.L. (2001). Seizure-induced changes in place cell physiology: Relationship to navigational learning. Society for Neuroscience Abstracts 31(744.4): 383. Status epilepticus (SE) is associated with impaired learning and memory in humans and animals. To investigate the electrophysiological basis of seizure-induced spatial memory impairment in rats we assayed CA1 place cell activity during a food foraging task and in the same rats measured performance in the water maze. Rats (n=20) were subjected to lithium-pilocarpine induced SE at postnatal (P) day 20. At P60, CA1 place cells were recorded from both SE and saline- treated control rats (n=10). Water maze training was done at P110. SE rats learned to find the hidden escape platform, but their asympototic swimming latencies were significantly longer than for controls. Correspondingly, place cells in SE rats had lower firing rates, decreased precision and were less stable than in controls. In another way of seeking links between place cells and maze performance, adult SE and control rats were subjected to flurothyl-induced seizures. After such seizures, water maze performance deteriorated greatly and in parallel place cells became virtually silent. Water maze performance improved as place cell activity recovered. These results suggest that coherent place cell activity is necessary for memory in a navigational task and that status epilepticus leads to permanent changes in place cell physiology. Supported by: NIH NS20686, NS31750, MRC-UK

•Louie, K. & Wilson, M.A. (2001). Reward bias of neuronal activity in the rodent hippocampus. Society for Neuroscience Abstracts 31(643.20): 330. Evidence for nonspatial behavioral correlates of hippocampal neuronal activity have extended theories of hippocampal function beyond the idea of a strictly spatial cognitive map. To examine the ability of the hippocampus to encode nonspatial information, we recorded the activity of hippocampal CA1 pyramidal neurons while rats performed a spatial locomotion task and determined whether a previous history of food reinforcement at distributed locations can bias the hippocampal representation of space. Analogous to recent results in an annular watermaze task (Hollup et al., 2001), we find that the hippocampus exhibits increased activity at previously reinforced versus nonreinforced locations. This population bias is mediated by a reinforcement bias across a subpopulation of cells, as evidenced by a higher density of place fields at previously reinforced locations. These results suggest that the hippocampal cognitive map encodes a spatial representation weighted by behavioral relevance rather than a strict allocentric representation of the environment. A similar bias may influence the selective reactivation of hippocampal traces in memory consolidation processes during post-behavior sleep. Supported by: The John Merck Fund and the RIKEN-MIT Neuroscience Research Center Page 36 Place cell references

•Ludvig, N. (1999). Place cells can flexibly terminate and develop their spatial firing. A new theory for their function. Physiol Behav 67(1): 57-67. In this study, hippocampal place cells were recorded in a behavioral paradigm previously not employed in place-cell research. Rats were exposed to the same fixed environment for as long as 8-24 h without interruption, while the firing of CA1 and CA3 place cells was monitored continuously. The first finding was that all place cells that were detected at the beginning of the recording sessions ceased to produce location-specific firing in their original firing fields within 2-12 h. This was observed despite the fact that the animals kept visiting the original firing fields, the hippocampal EEG was virtually unchanged, and the discriminated action potentials of the cells could be clearly recorded. The second finding was that some complex-spike cells that produced no spatially selective firing pattern at the beginning of the recording sessions developed location-specific discharges within 3- 12 h. Thus, place cells can flexibly terminate and develop their spatial firing. even in a fixed environment and during similar behaviors, if that environment is explored continuously for a prolonged period. To explain this phenomenon, a new place-cell theory is outlined. Accordingly, the high-frequency discharges of these neurons may serve to create, under multiple extrahippocampal control and within limited periods, stable engrams for specific spatial sites in the association cortex where the cognitive map probably resides. After the creation of a stable engram, or in the absence of favorable extrahippocampal inputs, place cells may suspend their location-specific firing in the original field, and initiate the processing of another spatial site.

•Ludvig, N., Gohil, B., Botero, J.M., Tang, H.M. & Kral, J.G. (2001). Spatial firing of hippocampal neurons of monkeys moving freely in 3 dimensions. Society for Neuroscience Abstracts 31(744.1): 383. The cellular mechanisms of spatial memory/cognitive map formation in primates are unclear. This is because the firing of temporal lobe neurons has not been studied in monkeys that move freely in 3 dimensions. Therefore, we developed a method for recording single neuronal firing from the hippocampus of squirrel monkeys (Saimiri sciureus) for many hours, while the animals climb on the walls and floor of a special test chamber (Ludvig et al., J. Neurosci. Meth. [2001] 106:179-187). During the recordings, the animal retrieved food-pellets from sixteen food-ports while interacting with another monkey caged outside the chamber. Modified Mapmaker software was used to analyze the 3- dimensional distribution of the firing of the cells. It was found that: (1) During movement complex-spike cells generate intermittent, 2-10 sec action potential Page 37 Place cell references bursts. (2) These bursts predominantly occur in one location in the chamber. (3) Similar bursts are occasionally produced in other parts of the chamber. This study demonstrated for the first time the feasibility of single-cell recording in unrestrained, freely moving monkeys. Our preliminary data suggest that primate hippocampal complex-spike cells generate spatially specific bursts. These discharges may well promote the consolidation of spatial memory engrams, contributing to the formation of the cognitive map. Supported by: A grant from SUNY Downstate Medical Center

•Markus, E.J., Barnes, C.A., McNaughton, B.L., Gladden, V.L. & Skaggs, W.E. (1994). Spatial information content and reliability of hippocampal CA1 neurons: Effects of visual input. Hippocampus 4: 410-421.The effects of darkness on quantitative spatial firing characteristics of 235 hippocampal CA1 "complex spike" (CS) cells were studied in young and old Fischer-344 rats during food- motivated performance of a randomized, forced-choice task on an eight-arm radial maze. The room lights were turned on or off on alternate blocks of all eight arms. In the dark, a lower proportion of CS cells had "place fields," and the fields were less specific and less reliable than in the light. A small number of cells had place fields unique to the dark condition. Like CS cells, Theta cells showed a reduction in spatially related firing in the dark. The specificity and reliability of the place fields under both light and dark conditions were similar for both age groups. Increasing the salience of the environment, by increasing the light level and the number of visual cues in the light condition, did not affect the specificity or reliability of the place fields. Even though all rats had substantial prior experience with the environment, and were placed on the maze center under normal illumination before the first dark trial, the correlation between the firing pattern in the light and dark increased after the rat first traversed the maze in the light. Thus, even after considerable experience with the environment over days, experiencing the illuminated environment from different locations on a given day was a significant factor affecting subsequent location and reliability of place fields in darkness. While the task was simple and errors rare, rats that made fewer errors (i.e., re- entries into the previously visited arm) also had more reliable place cells, but no such correlation was found with place cell specificity. Thus, the reliability of spatial firing in the hippocampus may be more important for spatial navigation than the size of the place fields per se. Alternatively, both spatial memory and place field reliability may be modulated by a common variable, such as attention.

•Markus, E.J., Qin, Y.L., Leonard, B., Skaggs, W.E. & McNaughton, B.L. Page 38 Place cell references (1995). Interactions between location and task affect the spatial and directional firing of hippocampal neurons. Journal of Neuroscience 15: 7079-7094.When rats forage for randomly dispersed food in a high walled cylinder the firing of their hippocampal "place" cells exhibits little dependence on the direction faced by the rat. On radial arm mazes and similar tasks, place cells are strongly directionally selective within their fields. These tasks differ in several respects, including the visual environment, configuration of the traversable space, motor behavior (e.g., linear and angular velocities), and behavioral context (e.g., presence of specific, consistent goal locations within the environment). The contributions of these factors to spatial and directional tuning of hippocampal neurons was systematically examined in rats performing several tasks in either an enriched or a sparse visual environment, and on different apparati. Place fields were more spatially and directionally selective on a radial maze than on an open, circular platform, regardless of the visual environment. On the platform, fields were more directional when the rat searched for food at fixed locations, in a stereotypic and directed manner, than when the food was scattered randomly. Thus, it seems that place fields are more directional when the animal is planning or following a route between points of special significance. This might be related to the spatial focus of the rat's attention (e.g., a particular reference point). Changing the behavioral task was also accompanied by a change in firing location in about one-third of the cells. Thus, hippocampal neuronal activity appears to encode a complex interaction between locations, their significance and the behaviors the rat is called upon to execute.

•Martin, P.D. & Berthoz, A. (2002). Development of spatial firing in the hippocampus of young rats. Hippocampus 12(4): 465-480. The hippocampal formation participates in learning and memory, particularly that of a spatial nature. In adult rats, individual CA1 pyramidal neurons only fire when the animal visits specific locations in an environment, the place field of the neuron. Other structures (postsubiculum, thalamus, cingulum) contain neurons that code for the animal's instantaneous head direction. Previous work has shown that the rat hippocampal formation undergoes anatomical and neurophysiological maturation during the first 2 months of life and that rats <40 days of age are impaired in spatial navigation tasks. Here we show that the locational firing of CA1 pyramidal neurons is both less specific and less stable in animals aged <50 days. However, preliminary results indicate that head directional firing recorded around day 30 is essentially identical to that seen in adult animals. Therefore, the development of reliable, spatially specific place cell activity parallels the developmental time course of spatial navigational ability, but head directional firing appears before full maturation of Page 39 Place cell references the hippocampus.

•Martin, P.D. & O'Keefe, J. (1998). Place field dynamics and directionality in a spatial memory task. Brain Research 783(2): 249-261. In previous studies place fields have been shown to be governed by one or more polarizing stimuli such that rotation of the stimuli caused concomitant rotation of the fields. Place fields have also been observed to persist after removal of stimulus cues. In the present study we confirm the previous findings and report two new responses. Hippocampal place fields were observed to decrease or cease place specific firing after the removal of the polarizing cues. Others increased or initiated place specific firing after cue removal. Thus in these instances place field location was dependent on the orientation of the polarizing cues but place field magnitude was governed by their presence or absence. A subset of the place fields recorded in the present study were found to display directionality. Place field directionality was found to be governed by the polarizing cues such that cue rotation produced concomitant rotation in the direction of maximal firing. However directionally specific firing was unaffected by cue removal. These results suggest that place field directionality is initially set up by the polarizing cues but is subsequently independent of them.

•Masters, J.J. & Skaggs, W.E. (2001). Effects of hippocampal place cell remapping on a goal directed navigational task. Society for Neuroscience Abstracts 31(643.9): 329. Hippocampal place cells have been hypothesized to play a role in navigation, but there is currently little direct evidence linking place cell maps and behavior. In this experiment, rats are being recorded from while performing a task that combines random searching with goal directed navigation, in order to determine what effect shifting or remapping of place fields have on task-related behavior. Rats are trained to navigate a 76cm cylindrical arena containing a salient cue card and a small unmarked goal area away from the walls, defined only by its relations with the wall and cue card, much like the hidden platform in a Morris water maze. The rats receive randomly scattered food reward for waiting within the goal location for varying lengths of time. Therefore the rats alternate between waiting in the goal location for food delivery and random foraging for food. [Rossier et al. Behav. Neurosci. 114, 273-84, 2000] Cue card manipulations include rotation of the cue card, duplication of the cue card, and replacement of a white card with a black card, which sometimes produces remapping. Place cells from the CA1 layer of the hippocampus are recorded using an array of twelve tetrodes, allowing ensembles of 50 or more cells to be recorded. If hippocampal place field maps control behavior, we would expect rotations of these maps to yield a rotation in where the rats wait Page 40 Place cell references for food rewards. In the case of remapping, we would expect to see an absence of task behavior. Simultaneous observation of hippocampal place cell map behavior and task performance will help to clarify the significance of place cell remapping. Supported by: U. Pittsburgh and the Center for the Neural Basis of Cognition

•Matthews, D.B., Simson, P.E. & Best, P.J. (1996). Ethanol alters spatial processing of hippocampal place cells: a mechanism for impaired navigation when intoxicated. Alcoholism, Clinical & Experimental Research 20: 404-407. This study describes a new mechanism by which ethanol alters brain function and may impair performance on tasks requiring spatial navigation. Recording electrophysiological activity from single neurons in the awake, freely behaving animal, the present study shows that ethanol impairs the ability of place cells in the hippocampus to process spatial information. The impairment by ethanol in spatial processing of place cells was remarkably similar to the impairment produced by lesions of afferents to the hippocampus, except that the effect of ethanol was reversible. Since lesions to hippocampal afferents that alter spatial processing of place cells concomitantly impair spatial navigation, the present results suggest that ethanol similarly impairs spatial navigation by altering spatial processing of place cells. The present results have implications for the observation that ethanol impairs performance on navigational tasks that require spatial processing, such as automobile driving.

•McNaughton, N., Flanagan, D., Young, B. & Kirk, I.J. (2001). Theta phase of hippocampal cells in DRL. Society for Neuroscience Abstracts 31(85.8): 76. Rat hippocampal cells often discharge preferentially in circumscribed locations ("place fields"). They discharge late on the positive phase of hippocampal theta initially and progressively earlier as the rat moves through the field (phase precession). They also have non-spatial receptive fields in non-spatial tasks. So, we studied theta phase relationships of hippocampal cells in a non-spatial task, differential reinforcement of low rates of response (DRL). Data from 89 cells with abrupt firing rate transitions were analysed. There were 40 "brief burst cells" that abruptly increased their discharge rate for brief periods and 49 "brief pause cells" that abruptly ceased firing for brief periods. Using spike duration and firing rate, brief burst cells were divided into complex spike cells and non-complex spike cells and brief pause cells into theta cells and 3 other groups. Phase was assessed on the resumption of firing for all cells. No cell had a highly consistent phase pattern within or between firing episodes; including a complex spike cell with firing tightly locked to lever pressing. However, the circular average across firing episodes was consistent for each cell. "Brief burst" cells as a group showed typical phase Page 41 Place cell references precession. Theta cells showed as clear phase precession as complex spike cells. Other "brief pause" cells showed precession or progressive phase lag. Theta phase shift is, thus, general to non-spatial as well as spatial processing. Phase precession is unlikely to be solely an index of location within a place field. Supported by: Health Research Council 97/90

•Mehta, M.R., Barnes, C.A. & McNaughton, B.L. (1997). Experience-dependent, asymmetric expansion of hippocampal place fields. Proceedings of the National Academy of Sciences of the United States of America 94(16): 8918-21. Theories of sequence learning based on temporally asymmetric, Hebbian long-term potentiation predict that during route learning the spatial firing distributions of hippocampal neurons should enlarge in a direction opposite to the animal's movement. On a route AB, increased synaptic drive from cells representing A would cause cells representing B to fire earlier and more robustly. These effects appeared within a few laps in rats running on closed tracks. This provides indirect evidence for Hebbian synaptic plasticity and a functional explanation for why place cells become directionally selective during route following, namely, to preserve the synaptic asymmetry necessary to encode the sequence direction.

•Mizumori, S.J. & Kalyani, A. (1997). Age and experience-dependent representational reorganization during spatial learning. Neurobiology of Aging 18: 651-659. Previously, we found that aged rats showed a significant enhancement of hippocampal CA1 place cell spatial specificity, as well as a reduction of hilar place cell spatial specificity, during asymptote performance of a spatial memory task. Because such an age effect was not observed when animals performed a nonspatial task, the present study tested the hypothesis that the different patterns of spatial selectivity observed in memory and nonmemory tests reflected a redistribution of spatial representations that occurred in response to changing task demands. In the present experiment, after animals became familiar with the test environment and motor demands of performance on a radial maze, CA1 and hilar place cells were recorded as they learned a spatial memory task. CA1 place cells recorded from unimpaired old, but not impaired old or young, animals became more spatially selective as animals learned the task. Hilar spatial selectivity for both age groups was not significantly related to choice accuracy. These data support the hypothesis that at least a subpopulation of aged rats may benefit from reorganization of spatial representations in such a way that the normal age-related spatial learning deficit is attenuated.

Page 42 Place cell references •Mizumori, S.J. & Leutgeb, S. (2001). Directing place representation in the hippocampus. Reviews in Neuroscience 12(4): 347-363. Theoretical models of rodent navigation consider location information and directional heading to be essential. Indeed, the existence of location-selective 'place cells' and orientation- selective 'head direction cells' is well documented. Different models suggest different forms of interaction between information about location and heading direction. However, until recently, there were no clear empirical data that could be used to distinguish the different models in terms of the nature of the integration of location and directional heading information. Recently, Leutgeb et al. provided evidence that head direction and place signals coexist within the CA1 region of hippocampus, and that the head direction signals are likely to be generated by a subpopulation of interneurons. This finding opens up new possibilities for clarifying current models and for developing biologically plausible theories of synaptic interactions between location and head direction codes. In this paper, we first present the issue concerning the nature of the interaction between location and head direction signals, followed by a selective review of place and head direction cell research. The finding of Leutgeb et al. is then summarized, and its implications for current models are discussed. Finally, a view is presented that considers place fields to be a product not only of (external and internal) sensory input, but also of non-spatial variables such as motivation and responses. The finding of Leutgeb et al. and many earlier anatomical studies suggest that hippocampal head direction, motivation and response information may be represented by the interneuron population. Thus, these factors may have strong impact on the location codes of hippocampal pyramidal neurons. Their influence may further define the behavioral context of the current spatial environment.

•Molden, S., Fyhn, M., Hollup, S.A., Moser, M.B. & Moser, E.I. (2001). Place correlates of complex spikes in CA1 pyramidal cells. Society for Neuroscience Abstracts 31(643.4): 329. To determine whether complex spikes in CA1 pyramidal cells have specific memory functions, we compared the behavioral correlates of complex and single spikes as trained rats swam in a corridor- constrained version of the Morris water-maze. Complex spikes were identified on the basis of inter-spike interval (ISI) statistics. Consecutive spikes were assigned as members of a complex spike if their interval were less than a preset threshold. The data were analyzed using three different thresholds (6, 15 and 25 ms). All pyramidal cells fired complex spikes, but the proportion of complex spike events ranged from 10 to 90%. Complex spikes were studied across different behavioral conditions (water-corridor and dry open-field, learning trials and retrieval trials) Page 43 Place cell references to clarify whether their abundance was determined by the behavioral condition. Preliminary results show that there is strong between-cell variability and that this variability is maintained across conditions. Place fields of complex spikes and single spikes were co-localized in space. Place fields of complex spikes were sharper and less dispersed, as demonstrated by a higher selectivity and a lower sparsity of firing (Skaggs et al., 1996). Cross-correlation of single spikes and complex spikes showed a temporal asymmetry, suggesting that the temporal ordering of bursts and single spikes is not random. These results show that bursts can contain more precise information about the rats spatial location than single spikes, and may therefore be relevant for spatial learning and the development of precise navigation.

•Moser, E.I. & Paulsen, O. (2001). New excitement in cognitive space: between place cells and spatial memory. Review. Current Opinions in Neurobiology 11(6): 745-751. Hippocampal principal neurons-'place cells'-exhibit location-specific firing. Recent work addresses the link between place cell activity and hippocampal memory function. New tasks that challenge spatial memory allow recording from single neurons, as well as ensembles of neurons, during memory computations, and insights into the cellular mechanisms of spatial memory are beginning to emerge.

•Moser, E.I., Hollup, S.A., Tuvnes, F.A. & Moser, M.B. (2001). Functional diversity among hippocampal pyramidal cells with firing fields at the goal location. Society for Neuroscience Abstracts 31(643.1): 329. To identify memory- related activity patterns in the hippocampus, we recorded spikes from pyramidal cells in CA1 while rats searched for a hidden escape platform in an annular watermaze. When the platform location was constant, a larger number of cells had firing fields at the expected goal location than elsewhere (Hollup et al., 2001). These platform-associated cells may represent allocentric position just like cells with fields at other places, or they may also be involved in recognition or recall processes that happen specifically at the goal location. To isolate goal-related memory processes, we trained rats to swim freely in the corridor (> 40 trials) and then compared pyramidal cell activity before and after introduction of the platform at a specific position in the corridor. Stable place fields were recorded in all parts of the corridor during free swimming. These place cells generally maintained their firing fields when the platform was introduced. In addition, several cells that were silent or had scattered fields during free swimming started to fire at the platform location. Some of them fired as the rat passed the platform position; others fired only after the rat had escaped. When the platform was finally moved to a new Page 44 Place cell references position, a small number of the cells with activity around the platform developed a second field at the new target location, but many cells continued to fire exclusively at the original location. These findings suggest that the place cell population is heterogeneous and that a subset of the cells with fields at the goal location fire during selective stages of the memory task. Supported by: Eur. Commission (QLG3- CT-1999-00192) and Norw. Res. Council

•Muir, G.M. & Bilkey, D.K. (2000). Lesions centered on the perirhinal cortex alter theta- and movement-related firing of hippocampal place cells. Society for Neuroscience Abstracts 30. Theta rhythm is a large amplitude, rhythmical slow wave that can be recorded from the hippocampus (HPC) and parahippocampal region. Theta rhythm is associated with locomotion and has been proposed to have a mnemonic function. The perirhinal cortex (PRC) also appears to play a key role in memory and has a large number of reciprocal connections to both cortical and subcortical structures, in particular, to CA1 in the HPC both directly and via entorhinal cortex. The purpose of the present study was to investigate the contribution of the PRC to the theta-related and movement-related firing of hippocampal complex-spike ('place') cells. The firing characteristics of dorsal CA1 place cells were examined in freely moving rats with either bilateral ibotenic acid lesions centered on the PRC or control surgeries. The phase of firing (where 0° represents the positive peak of the reference CA1 theta rhythm) for 31 theta- modulated place cells recorded from 4 perirhinal Lesion animals was significantly earlier during the theta rhythm cycle (266.27°) than for 22 theta-modulated place cells recorded from 5 Controls (315.00°; Watson-Williams test, F1,30 = 5.215, p < 0.05). The proportion of velocity-modulated place cells (Lesion = 13 of 31; Control = 23 of 31; c2 = 6.624, p < 0.05) recorded was also significantly lower in perirhinal Lesion animals than in Controls. These data indicate that the PRC has a role in the locomotion-related modulation of the firing of HPC CA1 place cells. This may be a factor in our recent finding that PRC lesions destabilize HPC place cell activity and may have important implications for spatial navigation processes (supported by the Marsden Fund and University of Otago).

•Muir, G.M. & Bilkey, D.K. (2001). Instability in the place field location of hippocampal place cells after lesions centered on the perirhinal cortex. Journal of Neurophysiology 21(11): 4016-4025. The perirhinal cortex appears to play a key role in memory, and the neighboring hippocampus is critically involved in spatial processing. The possibility exists, therefore, that perirhinal-hippocampal interactions are important for spatial memory processes. The purpose of the Page 45 Place cell references present study was to investigate the contribution of the perirhinal cortex to the location-specific firing ("place field") of hippocampal complex-spike ("place") cells. The firing characteristics of dorsal CA1 place cells were examined in rats with bilateral ibotenic acid lesions centered on the perirhinal cortex (n = 4) or control surgeries (n = 5) as they foraged in a rectangular environment. The activity of individual place cells was also monitored after a delay period of either 2 min, or 1 or 24 hr, during which time the animal was removed from the environment. Although the perirhinal cortex lesion did not affect the place field size or place cell firing characteristics during a recording session, it was determined that the location of the place field shifted position across the delay period in 36% (10 of 28) of the cells recorded from lesioned animals. In contrast, none of the place cells (0 of 29) recorded from control animals were unstable by this measure. These data indicate that although the initial formation of place fields in the hippocampus is not dependent on perirhinal cortex, the maintenance of this stability over time is disrupted by perirhinal lesions. This instability may represent an erroneous "re- mapping" of the environment and suggests a role for the perirhinal cortex in spatial memory processing.

•Muller, R.U. & Stead, M. (1996). Hippocampal place cells connected by Hebbian synapses can solve spatial problems. Hippocampus 6: 709-719.

•O'Keefe, J. (1993). Hippocampus, theta, and spatial memory. Review. Current Opinion in Neurobiology 3(6): 917-924. The past 18 months have witnessed interesting developments in several areas of hippocampal research. First, the mechanisms of hippocampal theta are becoming clear, as is its role in spatial coding; each theta cycle appears to act as a clock mechanism against which the firing of the place cells can be timed. Second, there has been a continued strengthening in the support for the spatial theory of hippocampal function from single unit and lesion experiments; particularly important is the finding that the deficit in (non-spatial) delayed non-match to sample memory experiments in the monkey following medial temporal lobe damage stems from the part of the cortex which surrounds the hippocampus, and not from the hippocampus itself. Third, in contrast, it is proving more difficult than originally thought to show a causal relationship between long- term potentiation at the synaptic level and place learning-induced changes in hippocampal synapses.

•Muller, R.U., Bostock, E., Ranck, J.B., Jr. & Kubie, J.L. (1994). On the directional firing properties of hippocampal place cells. Journal of Neuroscience Page 46 Place cell references 14: 7235-7251. Using a two-spot tracking system that allowed measurements of the direction of a rat's head in the environment as well as the position of the rat's head, we investigated whether hippocampal place cells show true direction-specific as well as location-specific firing. Significant modulations of firing rate by head direction were seen for most cells while rats chased food pellets in a cylindrical apparatus. It was possible, however, to account quantitatively for directional modulation with a simple scheme that we refer to as the "distributive hypothesis." This hypothesis assumes that firing is ideally location specific, and that all directional firing modulations are due to differences in the time that the rat spends in different portions of the firing field of the place cell in different head direction sectors. When the distributive hypothesis is put into numeric form, the directional firing profiles that it predicts are extremely similar to the observed directional firing profiles, strongly suggesting that there is no intrinsic directional specificity of place cell firing in the cylinder. Additional recordings made while rats ran on an eight-arm maze reveal that many firing fields on the arms are polarized; the cell discharges more rapidly when the rat runs in one direction than the other on the maze. This result provides an independent confirmation of the findings of McNaughton et al. (1983). For fields that appear to be polarized by inspecting firing rate maps of the raw data, the magnitude of directional firing variations is greater than predicted by the distributive hypothesis. By comparison with postsubicular head direction cells, it is shown that the distributive prediction of weaker-than- observed directional firing is expected if there is a true directional firing component. A major conclusion reached from recording in both environments is that the directional firing properties of hippocampal place cells are variable and not fixed; this is true of individual units as well as of the population.

•Muller, R.U., Ranck, J.B., Jr. & Taube, J.S. (1996). Head direction cells: Properties and functional significance. Current Opinion in Neurobiology 6: 196-206. The strong signal carried by head direction cells in the postsubiculum complements the positional signal carried by hippocampal place cells; together, the directional and positional signals provide the information necessary to permit rats to generate and carry out intelligent, efficient solutions to spatial problems. Our opinion is that the hippocampal positional system acts as a cognitive map and that the role of the directional system is to put the map into register with the environment. In this way, paths found using the map can be properly executed. Head direction cells have recently been discovered in parts of the thalamus reciprocally connected with the postsubiculum; such cells provide important clues to the organization of the directional system. [References: 40] Page 47 Place cell references

•Muller, R.U., Stead, M. & Pach, J. (1996). The hippocampus as a cognitive graph. Journal of General Physiology 107: 663-694. A theory of cognitive mapping is developed that depends only on accepted properties of hippocampal function, namely, long-term potentiation, the place cell phenomenon, and the associative or recurrent connections made among CA3 pyramidal cells. It is proposed that the distance between the firing fields of connected pairs of CA3 place cells is encoded as synaptic resistance (reciprocal synaptic strength). The encoding occurs because pairs of cells with coincident or overlapping fields will tend to fire together in time, thereby causing a decrease in synaptic resistance via long-term potentiation; in contrast, cells with widely separated fields will tend never to fire together, causing no change or perhaps (via long-term depression) an increase in synaptic resistance. A network whose connection pattern mimics that of CA3 and whose connection weights are proportional to synaptic resistance can be formally treated as a weighted, directed graph. In such a graph, a "node" is assigned to each CA3 cell and two nodes are connected by a "directed edge" if and only if the two corresponding cells are connected by a synapse. Weighted, directed graphs can be searched for an optimal path between any pair of nodes with standard algorithms. Here, we are interested in finding the path along which the sum of the synaptic resistances from one cell to another is minimal. Since each cell is a place cell, such a path also corresponds to a path in two-dimensional space. Our basic finding is that minimizing the sum of the synaptic resistances along a path in neural space yields the shortest (optimal) path in unobstructed two-dimensional space, so long as the connectivity of the network is great enough. In addition to being able to find geodesics in unobstructed space, the same network enables solutions to the "detour" and "shortcut" problems, in which it is necessary to find an optimal path around a newly introduced barrier and to take a shorter path through a hole opened up in a preexisting barrier, respectively. We argue that the ability to solve such problems qualifies the proposed hippocampal object as a cognitive map. Graph theory thus provides a sort of existence proof demonstrating that the hippocampus contains the necessary information to function as a map, in the sense postulated by others (O'Keefe, J., and L. Nadel. 1978. The Hippocampus as a Cognitive Map. Clarendon Press, Oxford, UK). It is also possible that the cognitive mapping functions of the hippocampus are carried out by parallel graph searching algorithms implemented as neural processes. This possibility has the great attraction that the hippocampus could then operate in much the same way to find paths in general problem space; it would only be necessary for pyramidal cells to exhibit a strong nonpositional firing correlate. [References: 108] Page 48 Place cell references

•Nakazawa, K., Quirk, M.C., Wilson, M.A. & Tonegawa, S. (2001). Place cell analysis of CA3 NMDA receptor knockout mice. Society for Neuroscience Abstracts 31(744.2): 383. We have analyzed genetically engineered mice in which NMDA receptor subunit 1 (NR1) is ablated only in hippocampal CA3 pyramidal cells (Nakazawa et al., 2000, SFN abstr. 564.3). In the hidden platform version of the Morris water maze task, memory acquisition and retrieval of a fixed platform position were normal in the CA3 NR knockout (mutant) mice. However, the memory retrieval was impaired when the extramaze cues were partially eliminated, suggesting that CA3 NRs are involved in spatial pattern completion. In a delayed matching-to-place (DMP) version, in which the platform position was changed day by day, the mutants showed deficits, suggesting a role for CA3 NRs in hippocampal working memory. To explore the neural mechanisms underlying these deficits in the mutants, we measured CA1 place cell activity of freely exploring animals using in vivo tetrode recording techniques. Preliminary results comparing mutants and NR1-floxed (control) mice showed that place field size and peak firing rate of CA1 place cells in mutants are dramatically decreased when allocentric cues are partially eliminated in a familiar open field, while those in controls are not changed. These results suggest that CA1 place cells in mutants are vulnerable to perturbation of current spatial context, which may be involved in the impaired pattern completion.Supported by: NIH grant RO1 NS32925

•Nitz, D.A. (2001). Spatially-modulated discharge of single units of parietal cortex in rats running multiple routes in a labyrinth: Evidence for path segmentation. Society for Neuroscience Abstracts 31(744.3): 383. Single unit recordings from the parietal cortex and hippocampus of 4 Sprague-Dawley rats were made using moveable stereotrodes. Single unit activity of hippocampal and parietal cortical (N=27) neurons was recorded as rats ran multiple routes between the same two food reward sites in a labyrinth. Barriers blocked some pathways in the labyrinth and determined a single direct route by which rats could shuttle between food sites. For a given recording, spatially-modulated discharge of single units was assessed for 2-3 different routes having partial overlap. Hippocampal complex-spike cells (N=30) exhibited activity specific to one or two regions (fields) of the environment and such fields remained constant even when the field bordered the divergence of 2 routes. Nevertheless, the extent to which field-specific discharge was modulated by the animal's direction of movement through the field differed, in a few cases, with respect to route. Parietal cortical cells exhibited a number of different patterns of discharge across the environment. Most cells discharged with Page 49 Place cell references relation to multiple behaviors such as 180-degree turns, nearing a food site, and traversal of some segments of the labyrinth. Typically, the subset of behaviors or labyrinth segments to which such activity could be correlated tended to be arranged non-contiguously and in alternation. The findings suggest that unit activity in parietal cortex is segmented according to the spatial context of action. Supported by: Neurosciences Research Foundation.

•O'Keefe, J. & Burgess, N. (1996). Geometric determinants of the place fields of hippocampal neurons. Nature 381(6581): 425-428. The human hippocampus has been implicated in memory, in particular episodic or declarative memory. In rats, hippocampal lesions cause selective spatial deficits, and hippocampal complex spike cells (place cells) exhibit spatially localized firing, suggesting a role in spatial memory, although broader functions have also been suggested. Here we report the identification of the environmental features controlling the location and shape of the receptive fields (place fields) of the place cells. This was done by recording from the same cell in four rectangular boxes that differed solely in the length of one or both sides. Most of our results are explained by a model in which the place field is formed by the summation of gaussian tuning curves, each oriented perpendicular to a box wall and peaked at a fixed distance from it.

•O'Keefe, J. & Recce, M.L. (1993). Phase relationship between hippocampal place units and the EEG theta rhythm. Hippocampus 3(3): 317-330. Many complex spike cells in the hippocampus of the freely moving rat have as their primary correlate the animal's location in an environment (place cells). In contrast, the hippocampal electroencephalograph theta pattern of rhythmical waves (7-12 Hz) is better correlated with a class of movements that change the rat's location in an environment. During movement through the place field, the complex spike cells often fire in a bursting pattern with an interburst frequency in the same range as the concurrent electroencephalograph theta. The present study examined the phase of the at which the place cells fired. It was found that firing consistently began at a particular phase as the rat entered the field but then shifted in a systematic way during traversal of the field, moving progressively forward on each theta cycle. This precession of the phase ranged from 100 degrees to 355 degrees in different cells. The effect appeared to be due to the fact that individual cells had a higher interburst rate than the theta frequency. The phase was highly correlated with spatial location and less well correlated with temporal aspects of behavior, such as the time after place field entry. These results have implications for several aspects of hippocampal function. First, by using the phase relationship as well as Page 50 Place cell references the firing rate, place cells can improve the accuracy of place coding. Second, the characteristics of the phase shift constrain the models that define the construction of place fields. Third, the results restrict the temporal and spatial circumstances under which synapses in the hippocampus could be modified.

•O'Keefe, J. (1999). Do hippocampal pyramidal cells signal non-spatial as well as spatial information? Review. Hippocampus 9(4): 352-364. It is generally agreed that the rat hippocampus is involved in spatial memory. Whether this is its sole or primary function, or merely one component of a broader function, is still debated. It has been suggested, for example, that the hippocampus stores information about flexible relations between stimuli, both spatial and non-spatial. In this paper, I reiterate the basic tenet of the cognitive map theory that the processing and storage of spatial information is the primary and perhaps the exclusive role of the hippocampus in the rat, and that data that appear to contradict this have been misinterpreted. These data are found in reports of non-spatial correlates of unit activity recorded in the awake animals and reports of deficits on non-spatial tasks following hippocampal lesions. In this paper, I examine both claims and suggest alternative explanations of the data. The first part of the paper contains a review of some of the properties of hippocampal place cells, which might be misinterpreted as non-spatial in "non-spatial" tasks. For example, if an animal is trained to carry out a sequence of stereotyped actions in different parts of an environment, there will be a strong correlation between the performance of each behaviour and the animal's location, and it is necessary to rule out the locational correlate as the cause of the firing pattern. The second part of the paper looks at the results of experiments on conditioning and non-spatial discrimination tasks and concludes that the results are less supportive of a more general relational theory of hippocampal function than has been suggested. Furthermore, there is often a discrepancy between the correlates of unit firing in non-spatial tasks and the absence of an effect of hippocampal damage on these same or similar tasks. It is concluded that, contrary to the claims of its detractors, the cognitive map theory is still the theory of hippocampal function that is most clearly specified, makes the most testable predictions, and for which there is the strongest experimental support.

•O'Keefe, J., Burgess, N., Donnett, J.G., Jeffery, K.J. & Maguire, E.A. (1998). Place cells, navigational accuracy, and the human hippocampus. Philosophical Transactions of the Royal Society of London - Series B: Biological Sciences 353(1373): 1333-1340. The hippocampal formation in both rats and humans is involved in spatial navigation. In the rat, cells coding for places, directions, and Page 51 Place cell references speed of movement have been recorded from the hippocampus proper and/or the neighbouring subicular complex. Place fields of a group of the hippocampal pyramidal cells cover the surface of an environment but do not appear to do so in any systematic fashion. That is, there is no topographical relation between the anatomical location of the cells within the hippocampus and the place fields of these cells in an environment. Recent work shows that place cells are responding to the summation of two or more Gaussian curves, each of which is fixed at a given distance to two or more walls in the environment. The walls themselves are probably identified by their allocentric direction relative to the rat and this information may be provided by the head direction cells. The right human hippocampus retains its role in spatial mapping as demonstrated by its activation during accurate navigation in imagined and virtual reality environments. In addition, it may have taken on wider memory functions, perhaps by the incorporation of a linear time tag which allows for the storage of the times of visits to particular locations. This extended system would serve as the basis for a spatio-temporal event or episodic memory system.

•O'Mara, S.M., Commins, S. & Anderson, M.I. (2000). Synaptic plasticity in the hippocampal area CA1-subiculum projection: Implications for theories of memory. Hippocampus 10(4): 447-456. This paper reviews investigations of synaptic plasticity in the major, and underexplored, pathway from hippocampal area CA1 to the subiculum. This brain area is the major synaptic relay for the majority of hippocampal area CA1 neurons, making the subiculum the last relay of the hippocampal formation prior to the cortex. The subiculum thus has a very major role in mediating hippocampal-cortical interactions. We demonstrate that the projection from hippocampal area CA1 to the subiculum sustains plasticity on a number of levels. We show that this pathway is capable of undergoing both long-term potentiation (LTP) and paired-pulse facilitation (PPF, a short-term plastic effect). Although we failed to induce long-term depression (LTD) of this pathway with low- frequency stimulation (LFS) and two-pulse stimulation (TPS), both protocols can induce a late-developing potentiation of synaptic transmission. We further demonstrate that baseline synaptic transmission can be dissociated from paired- pulse stimulation of the same pathway; we also show that it is possible, using appropriate protocols, to change PPF to paired-pulse depression, thus revealing subtle and previously undescribed mechanisms which regulate short-term synaptic plasticity. Finally, we successfully recorded from individual subicular units in the freely-moving animal, and provide a description of the characteristics of such neurons in a pellet-chasing task. We discuss the implications of these findings in relation to theories of the biological consolidation of memory. Page 52 Place cell references

•Oler, J.A. & Markus, E.J. (2000). Age-related deficits in the ability to encode contextual change: A place cell analysis. Hippocampus 10(3): 338-350. Aging is known to impair the formation of episodic memory, a process dependent upon the integrity of the hippocampal region. To investigate this issue, hippocampal place cells were recorded from middle-aged and old F-344 male rats while running on a figure-8 track. The top and bottom arcs of the track were removed, converting it into a plus maze, and the animals were required to conduct a working memory task. Following this change in task, the arcs were replaced and the animals again ran the figure-8 task. Analysis of place fields across the recording session demonstrated that both middle-aged and old rats had reliable representations of the figure-8 task. A comparison of place fields between different behavioral tasks (figure-8 and plus maze) demonstrated a change in the hippocampal representation of the environment in both age groups, despite the fact that the animals remained on the maze throughout the recording session. Notably, place cells in old animals were less affected by the change in task than those in middle-aged animals. The results suggest that hippocampal neurons reflect significant behavioral events within a given environment. Furthermore, the data indicate that age-related episodic memory deficits may result from decreased sensitivity of the hippocampal network to respond to meaningful changes in the environment.

•Oler, J.A. & Markus, E.J. (2000). Age-related deficits on the radial maze and in fear conditioning: Hippocampal processing and consolidation. Hippocampus 10(1): 131. Aging is known to impair the formation of episodic memory, a process dependent upon the integrity of the hippocampal region. To investigate this issue, hippocampal place cells were recorded from middle-aged and old F-344 male rats while running on a figure-8 track. The top and bottom arcs of the track were removed, converting it into a plus maze, and the animals were required to conduct a working memory task. Following this change in task, the arcs were replaced and the animals again ran the figure-8 task. Analysis of place fields across the recording session demonstrated that both middle-aged and old rats had reliable representations of the figure-8 task. A comparison of place fields between different behavioral tasks (figure-8 and plus maze) demonstrated a change in the hippocampal representation of the environment in both age groups, despite the fact that the animals remained on the maze throughout the recording session. Notably, place cells in old animals were less affected by the change in task than those in middle-aged animals. The results suggest that hippocampal neurons reflect significant behavioral events within a given environment. Furthermore, the data indicate that age-related episodic memory Page 53 Place cell references deficits may result from decreased sensitivity of the hippocampal network to respond to meaningful changes in the environment.

•Pennartz, C.M.A., Geurtsen, A.M.S., Lipa, P., Barnes, C.A. & McNaughton, B.L. (2001). Reactivation of neuronal ensembles in the nucleus accumbens during sleep. Society for Neuroscience Abstracts 31(189.6). Communication between the hippocampus and neocortex is believed to be essential for memory retrieval and consolidation. However, the hippocampus also projects extensively to subcortical structures such as the nucleus accumbens (ACB) and we asked whether this nucleus may also be implicated in these processes. Specifically, we examined whether groups of neurons in ACB reactivate during sleep, which is apparent as a recurrence of correlations in firing patterns that were generated during prior behavioral experience. Three male Fischer 344 rats were trained on a T-maze task. Multiple tetrodes were implanted unilaterally in ACB. Each rat was subjected to a protocol consisting of (i) a first sleep phase (SLEEP1); (ii) a phase of reward-searching behavior on the maze (BEHAVIOR) and (iii) a second sleep phase (SLEEP2). Spike trains from 15-25 well-isolated units could be stably recorded in parallel. For each cell pair we calculated a correlation coefficient reflecting covariation of firing rates on a time scale of 50 msec. We next examined to what extent the correlation pattern during SLEEP2 resembled the pattern during BEHAVIOR, correcting for SLEEP1, using an Explained Variance measure (EV; Kudrimoti et al., J. Neurosci. 19: 4090-4101, 1999). The EV across 8 sessions from the 3 rats (mean + sem: 9.2 + 3.3 %) was significantly larger than the control value (1.7 + 0.6 %; p < 0.02). These results indicate a significant reactivation of correlated firing patterns in ACB during post-experiential sleep. Supported by: NATO Grant CRG 972196 and PHS grant MH46823.

•Poucet, B. (1993). Spatial cognitive maps in animals--new hypotheses on their structure and neural mechanisms. Psychological Review 100: 163-182. •Poucet, B., Thinus-Blanc, C. & Muller, R.U. (1994). Place cells in the ventral hippocampus of rats. Neuroreport 5: 2045-2048. Many cells recorded from the dorsal hippocampus of freely moving rats are intensely active only when the rat's head is in a particular part of its environment. For this reason, such units are called 'place cells'. We have investigated whether place cells are also found in the ventral hippocampus. Recordings were made from ventral hippocampal units while rats chased food pellets in a cylindrical arena. The rat's position was simultaneously recorded by tracking a light on the rat's head. Our data show the existence of cells in the ventral hippocampus whose positional firing patterns and Page 54 Place cell references electrophysiological properties are very similar to those of dorsal hippocampal place cells.

•Poucet, B., Cressant, A., Lenck-Santini, P.P. & Save, E. (2001). [Neural basis for spatial memory in animals: what do hippocampal neurons tell us?] Review. French. Journale Societie Biologie 195(4): 355-361. Recent studies relying on the recording of neuronal unit activity in freely moving rats show the existence of two populations of neurons signalling the animal's location or head direction: place cells found primarily in the hippocampus and head direction cells found in brain areas anatomically and functionally related to the hippocampus. The properties of these two neuronal populations suggest that their activity strongly depends upon information cues stemming from the spatial environment, and also suggest their involvement in spatial memory. Place cells and head direction cells would jointly participate in a neural network allowing the animal to orient in space and to store spatial locations in memory. This network would also be operating in humans, in particular for encoding specific events in episodic memory.

•Ragozzino, K.E., Leutgeb, S. & Mizumori, S.J. (2001). Dorsal striatal head direction and hippocampal place representations during spatial navigation. Experimental Brain Research 139(3): 372-376. Several theories of basal ganglia function describe a striatal contribution to learning that is independent of hippocampal function. This study examined the question of whether the striatum should be regarded as functioning independently of or acting in concert with limbic structures. Dorsal striatal head direction cells and hippocampal place cells were recorded in parallel while rats performed a hippocampal-dependent radial maze task. Changes in the directional preference of head direction cells and the location of place fields were compared following alterations of the sensory environment. When familiar visual cues were presented in new spatial arrangements, or when new visual cues were placed in a familiar environment, rotations of directional preferences were consistent with the mean place-field response. When familiar visual and nonvisual cues were presented in conflict, or when rats were exposed to novel environments, the responses of the two cell types were inconsistent relative to each other. This pattern suggests that current perceptions and expectations of familiar spatial contexts may dynamically modulate the relationship between hippocampus and dorsal striatum.

•Rao, G., Knierim, J.J. & Lazott, L. (2000). Place field properties following apparatus translations and distal cue rotations. Society for Neuroscience Page 55 Place cell references Abstracts 30. The relative contributions of distal and local cues in controlling place cells were explored with lateral translations of an apparatus from the center of a room that had controlled distal cues on the curtains and floor. Place cells were recorded from 4 rats running on a circular track (30" diam.) or on a rectangle (18" x 24") for randomly placed food reward; the surfaces of each track were uniform, with no intentionally placed cues. Of the 59 cells with place fields on the tracks, 77% stayed in the same position on the track after the eastward (15-19") translation of the apparatus, while 23% either ceased firing or developed a new place field. (Cells from CA1, CA3, and FD are combined as no subfield differences were evident). 80% of place cells fired in the same position on the track following a translation (30- 34") from east to west, and firing remained strongly bound to the track when the apparatus was returned to the central position. Thus, the large majority of place fields were insensitive to translations of the apparatus within the controlled cue environment, even though the translations from east to west placed the tracks in completely nonoverlapping regions of the room. For the 3 rats tested on the circular track in the center of the room, a control test was performed in which the distal cues were rotated in 2 increments of 45°, and a majority of cells (78% and 65% for each rotation) followed the rotation of the distal cues. Thus, the role of distal visual landmarks may be limited to controlling the overall orientation of place cells (presumably by controlling head direction [HD] cell input), and the primary determinants of place fields may be local apparatus, behavioral, or self-motion cues combined with the HD input. Supported by: NS39456.

•Redish, A.D., Battaglia, F.P., Ekstrom, A.D., Gerrard, J.L., Lipa, P., Rosenzweig, E.S., McNaughton, B.L. & Barnes, C.A. (2000). Hippocampal pyramidal cells located near each other anatomically do not show related spatial firing correlates. Society for Neuroscience Abstracts 30. In many neocortical areas, local clusters of neurons frequently exhibit correlated encoding properties. Hippocampal neuronal ensembles recorded in unrestrained rats, however, can exhibit independent (i.e., uncorrelated) population encoding patterns (e.g., in different environments; within the same environment when salient cues, behavioral context, or some other internal variable are changed; after a salient event; in animals with deficient plasticity mechanisms). These results are incompatible with a large-scale tendency for anatomically neighboring neurons to exhibit correlated firing. We examined the relation between the anatomical location of hippocampal pyramidal cells and their spatial firing correlates by performing a meta-analysis on cell ensembles recorded with multiple tetrodes at a lattice spacing of 350 mm. 3074 spike trains were recorded from 933 tetrodes in 28 rats over 165 sessions under Page 56 Place cell references four different experimental conditions. Each experimental condition was analyzed separately. First, the place field for each cell was determined. Then, the correlation between the two fields from each pair of cells recorded from each tetrode was calculated. The resulting distribution was compared to a Monte Carlo distribution calculated from the entire database of all cells recorded from that experimental condition. The distributions of within-tetrode correlation followed the expected distributions very closely and was not measurably different over the four experimental conditions (Kolomogorov-Smirnov two-sample test, P>0.5). Supported by: MH01565, AG12609, AG05805, NSF IGERT, HFSP, ARCS, JST CREST

•Rivard, B., Poucet, B. & Muller, R.U. (2000). The effect of removing a barrier on the firing of hippocampal place cells. Society for Neuroscience Abstracts 30. Roughly half of the pyramidal neurons of the CA1/CA3 regions of the rat hippocampus act as place cells in a given environment. A place cell fires preferentially when the head is in a cell-specific portion (firing field) of a familiar environment, largely independent of behavior and head direction. Thus, place cells together signal head location and may form a map-like representation used during spatial learning and navigation. Previous work showed that forcing the rat to use detours by putting a novel barrier into the environment usually suppresses the activity of place cells local to the barrier. Here we report how place cells are affected by removing a familiar barrier, a situation that allows shortcut behavior. Rats were trained to forage for food randomly dropped into a 76 cm diameter cylindrical chamber in which a 24 cm long barrier was set along a fixed radius starting 14 cm from the center. We recorded from 27 place cells with 30 fields in 2 rats. Each cell was assessed in three consecutive 16 min sessions with the barrier present (baseline), absent (removal) and present again (baseline 2). Fields were classified as adjacent (a field edge directly abutted the barrier) or not adjacent to the barrier. Of 30 fields, 13 were categorized as adjacent. By inspection, removal had no effect on 3 of 13 fields (23%), caused firing to virtually cease in 6 of 13 fields (46%) and caused 4 of 13 (31%) fields to markedly expand. In contrast, 15 of 17 non-adjacent fields (88%) were unchanged by barrier removal; one of the other fields expanded while the second was suppressed. These results are in line with studies reporting "partial remapping" in which only a fraction of the fields of place cells are affected by a manipulation of the environment. This suggests that the population of place cells can adapt to a small change in the environment without forming a completely new representation. The multiple outcomes for barrier- adjacent fields may reflect the existence of a variety of field subtypes formed in the vicinity of a barrier, but in any case the partial remapping was mainly local to Page 57 Place cell references the barrier. Supported by: RO1-NS37150, a scholarship from FCAR, Québec, Canada to BR and CNRS, France.

•Rosenzweig, E.S., Ekstrom, A.D., Redish, A.D., McNaughton, B.L. & Barnes, C.A. (2000). Phase precession as an experience-dependent process: Hippocampal pyramidal cell phase precession in a novel environment and under NMDA-receptor blockade. Society for Neuroscience Abstracts 30. Hippocampal pyramidal cells in rats fire spikes at earlier and earlier phases of the theta rhythm as the animals pass through the place field of the cell (phase precession, O’Keefe and Recce, 1993). Some models of this phenomenon suggest that phase precession should only be observed after significant experience in a given environment, and that it must also depend on processes such as long-term potentiation (LTP). To test these predictions, the activities of ensembles of hippocampal pyramidal cells were recorded in six Fischer-344 rats on two experiments. In the first experiment, five rats ran in a novel environment. In all five rats, cells showed robust phase precession within the first five laps. In addition, phase precession on the first lap alone was measured as the phase shift between spikes fired on the first two theta cycles within a place field. A majority of fields within each animal showed phase precession on the first lap in the environment. In the second experiment, one rat was recorded both under NMDA-receptor blockade with CPP (7.5 mg/kg, sufficient to block spatial memory and place field expansion, Ekstrom et al., 1999), and under a control condition with saline. This rat showed phase precession both with and without NMDA-receptor blockade. These results suggest that phase precession is a phenomenon intrinsic to hippocampal pyramidal cells and/or the hippocampal network, even though phase precession might be modulated by experience and LTP-like processes. Supported by: MH01565, NS20331, AG12609, AG05805, NSF IGERT, JST CREST

•Routenberg, A., Mayford, M., Hawkins, R.D., Kandel, E.R. & Muller, R.U. (1996). Mice expressing activated CaMKII lack low frequency LTP and do not form stable place cells in the CA1 region of the hippocampus. Cell 87: 1351-1361. To relate different forms of synaptic plasticity to the formation and maintenance of place cells in the hippocampus, we have recorded place cells in freely behaving, transgenic mice that express a mutated Ca2+-independent form of CaM Kinase II. These mice have normal long-term potentiation (LTP) at 100 Hz, but they lack LTP in response to stimulation at 5-10 Hz and are impaired on spatial memory tasks. In these transgenic mice, the place cells in the CA1 region have three important differences from those of wild types: they are less common, less precise, and less stable. These findings suggest that LTP in the 5-10 Hz range may be important for Page 58 Place cell references the maintenance of place-field stability and that this stability may be essential for the storage of spatial memory.

•Russell, N.A., Horii, A., Liu, P., Smith, P.F., Darlington, C.L. & Bilkey, D.K. (2000). Hippocampal place fields have decreased stability in rats with bilateral vestibular labyrinthectomies. Society for Neuroscience Abstracts 30. Previous research has shown that temporary inactivation of the vestibular labyrinth by bilateral intratympanic injections of tetrodotoxin disrupts place fields, decreasing their spatial coherence and information content (Stackman and Taube, Soc. Neurosci. Abstr., Vol 22, p 1873, 1996). It is unclear, however, whether this is a transient or permanent effect. It is also possible that vestibular compensation, in which spontaneous recovery from oculomotor symptoms occurs, will allow for the recovery of place fields over time. In order to resolve these issues Sprague Dawley rats received bilateral labyrinthectomies. Using a retro-auricular approach the vestibular labyrinth was destroyed by drilling into the oval window and horizontal/anterior canal ampullae, aspirating and perfusing with 0.1 ml 100% ethanol. Movable multichannel microelectrodes were then implanted into the CA1 field of the hippocampus for single unit recording. Complex burst cells were recorded, several months post lesion, as rats foraged in a cylindrical environment. Preliminary results show that rats with vestibular lesions can form place fields but that these fields have significantly reduced stability as compared to controls. Thus although rats with vestibular lesions are able to generate place fields, an intact vestibular input is necessary to maintain their stability. Furthermore, vestibular compensation does not return place field properties to their pre-lesion state. Supported by: The Marsden Fund and The Neurological Foundation of New Zealand

•Save, E., Lenck-Santini, P.P. & Poucet, B. (2000). Relationships between hippocampal place cell firing and rats' spatial performance. Society for Neuroscience Abstracts 30. Most studies on hippocampal place cells have concentrated on their sensory properties but little is known about their actual contribution to the animal's spatial performance. To address this issue, place cells were recorded while rats solved a continuous spatial alternation task. They had to alternate between the 2 arms of a Y-maze to get a food reward at the end of the third (goal) arm. At symptotic performance, successive sessions were recorded with the only available cue (a white cue card) being rotated or removed between the sessions. Some of these manipulations were expected to result in an inconsistent placement of the firing fields relative to the goal arm. The aim was to see whether inconsistent position of the firing fields would be correlated with diminished Page 59 Place cell references behavioral performance. Forty-seven place cells were recorded from 8 rats. The analysis of pairs of sessions comprising a reference session and a test session (effect of cue manipulations) allowed to consider two categories : " inconsistent " pairs (fields out of register with the goal) and " consistent " pairs (fields in register with the goal). 68 % of the session pairs were found to be consistent after cue rotation and 94 % after cue removal. Analysis of the behavioral performance in each category showed that the total number of errors increased between the reference and the test sessions for inconsistent pairs but not for consistent pairs. These results suggest that the inconsistent field placements are accompanied by disorganized spatial behavior, thus providing direct evidence that there is a relationship between the firing patterns of place cells and the observable spatial behavior of the animal. Supported by: CNRS and MENRT

•Save, E., Nerad, L. & Poucet, B. (2000). Contribution of multiple sensory information to place field stability in hippocampal place cells. Hippocampus 10(1): 64-76. Hippocampal place cells in rats display spatially selective firing in relation to both external and internal cues. In the present study, we assessed the effects of removing visual and/or olfactory cues on place field stability. Place cell activity was recorded as rats searched for randomly scattered food in a cylinder. During an initial recording session, the lights were on and the only available cue was a single white cue card. Following this session, three sessions were run in a row with the cue card removed. In addition, the lights were either turned off or left on and the floor was either cleaned or left unchanged, thus creating four conditions: dark/cleaning, dark/no cleaning, light/cleaning, and light/no cleaning. A fifth session was run with the cue card back on the cylinder wall and the lights turned on. The rat remained in the cylinder during all sessions without being removed at any time. In the dark/cleaning and light/cleaning conditions, most place fields were not stable (i.e., abruptly shifted position). In addition, half of the cells stopped firing in the dark/cleaning condition. In contrast, in the dark/no cleaning and light/no cleaning conditions, most place fields remained stable across sessions. These results suggest that 1) rats are not able to rely on only movement-related information to maintain a stable place representation, 2) visual input is necessary for the firing of a large number of cells, and 3) olfactory information can be used to compensate for the lack of visuospatial information.

•Shapiro, M. (2001). Plasticity, hippocampal place cells, and cognitive maps. Review. Archives of Neurology 58(6): 874-881. Memory of even the briefest event can last a lifetime. Thus, learning and memory require neuronal mechanisms that allow rapid, Page 60 Place cell references yet persistent, changes to brain circuits. Hippocampal neuropsychology, synaptic and cellular electrophysiology, pharmacology, and molecular genetics converge and begin to reveal these mechanisms. Lesions of the hippocampus profoundly impair memory for recent events in humans and rodents. Circuits within the hippocampus are remarkably plastic, and this plasticity is mediated in part through changes in synaptic strength and revealed by long-term potentiation (LTP) and long-term depression (LTD). N-methyl D-aspartate (NMDA) receptors, a subtype of , are crucial for inducing these plastic changes, and blocking these receptors reduces plasticity and impairs learning in tasks that require the hippocampus. Molecular genetic alterations that disrupt signaling mechanisms downstream of the NMDA receptor also prevent LTP induction and impair hippocampus-dependent learning. N-methyl D-aspartate receptor mechanisms have also been linked to information coding by hippocampal neurons. Hippocampal cells fire selectively in specific and restricted locations (place fields) as rodents move through open environments. Place fields form within minutes and persist for months. N-methyl D-aspartate receptor antagonists prevent the establishment of stable place fields. The same molecular genetic manipulations that interfere with hippocampal NMDA receptor function, prevent LTP induction, and impair spatial learning also disrupt the formation of stable hippocampal place fields. Finally, learning has been improved in mice with genetically modified NMDA receptors that enhance LTP induction. Thus, hippocampal cells "learn" to encode the salient features of experience through NMDA receptor-dependent synaptic plasticity mechanisms, and this rapid and persistent neuronal encoding is a crucial step toward the formation of long-term memory. Disruption of these plasticity mechanisms may underlie age-related memory deficits.

•Shen, J., Barnes, C.A., McNaughton, B.L., Skaggs, W.E. & Weaver, K.L. (1997). The effect of aging on experience-dependent plasticity of hippocampal place cells. Journal of Neuroscience 17(17): 6769-82. The firing characteristics of 1437 CA1 pyramidal neurons were studied in relation to both spatial location and the phase of the theta rhythm in healthy young and old rats performing a simple spatial task on a rectangular track. The old rats had previously been found to be deficient on the Morris spatial learning task. Age effects on the theta rhythm per se were minimal. Theta amplitude and frequency during rapid eye movement sleep were virtually identical. During behavior, theta frequency was slightly reduced with age. In both groups, cell firing occurred at progressively earlier phases of the theta rhythm as the rat traversed the place field of the cell (i. e., there was "phase precession," as reported by others). The net phase shift did not differ between age Page 61 Place cell references groups. The main finding of the study was a loss of experience-dependent plasticity in the place fields of old rats. During the first lap around the track on each day, the initial sizes of the place fields were the same between ages; however, place fields of young rats, but not old, expanded significantly during the first few laps around the track in a given recording session. As the place fields expanded, the rate of change of firing with phase slowed accordingly, that the net phase change remained constant. Thus changes in field size and phase precession are coupled. A deficit in plasticity of place fields in old rats may lead to a less accurate population code for spatial location.

•Silva, A.J., Giese, K.P., Fedorov, N.B., Frankland, P.W. & Kogan, J.H. (1998). Molecular, cellular, and neuroanatomical substrates of place learning. Neurobiology of Learning & Memory 70: 44-61.

•Skaggs, W.E. & McNaughton, B.L. (1998). Spatial firing properties of hippocampal CA1 populations in an environment containing two visually identical regions. Journal of Neuroscience 18(20): 8455-8466. Populations of 10-39 CA1 pyramidal cells were recorded from four rats foraging for food reward in an environment consisting of two nearly identical boxes connected by a corridor. For each rat, a higher-than-chance fraction of cells had similarly shaped spatial firing fields in both boxes, but other cells had completely different fields in the two boxes. The level of correlation of fields in the two boxes differed greatly across rats and, for three of the four rats, across recording sessions. Thus, the factors controlling the level of correlation are likely to be subtle. Two control manipulations were performed. First, the two boxes were physically interchanged. In no case did firing fields move along with the boxes. Second, on the final session of recording, the rat was started in the south box, after having been started in the north box for every previous session. For at least two of the four rats, the north fields from the previous session were instantiated in the south during the first visit of the second session, but thereafter reverted. Thus neither differences between the physical boxes nor sensory input from outside the apparatus could account for the differences in firing fields: most likely they were caused by a combination of learned expectations and a neural mechanism for remembering movements. These findings could be explained either by hypothesizing a more sophisticated attractor-map architecture than has been proposed previously, or by hypothesizing that the hippocampus conjunctively encodes both map information and some other type of information.

Page 62 Place cell references •Smulders, T.V., Deadwyler, S.A. & Hampson, R.E. (2000). Interaction between landmark configuration and foraging pattern on spatial information coding in the rat hippocampus. Society for Neuroscience Abstracts 30. During a random foraging task hippocampal neurons predominantly fire relative to the rat's location in the arena. Changing the relevance of certain locations in the environment can alter the spatial firing patterns (Breese et al.,1989), as can changing the rat's movement pattern in the same environment (Markus et al.,1995). Rats were trained to forage for randomly distributed food-pellets in a large cylinder. The landmarks were one moveable cue card and two fixed-location pellet-dispensers, symmetrically positioned at the wall of the cylinder. When first changed from random to fixed-location food delivery, about half of the place cells changed their spatial firing patterns. Subsequent 10-min alternations between the two patterns of food delivery, however, did not influence the newly established firing patterns, perhaps due to the fact that even during random foraging, the rats frequently investigated the fixed-delivery locations. When the cue card was rotated 90° relative to the fixed cues, most place cells changed their firing fields. The altered fields looked the same during random foraging as during fixed delivery. The amount of spatial information contained in the firing patterns after card rotation (as measured with a Canonical Correlation) did not change during random foraging, but it decreased during fixed-delivery. This may reflect the greater importance placed on the landmark configuration during fixed- location foraging. There clearly is an interaction between landmark configuration and foraging pattern on the encoding of spatial information in the rat hippocampus. Supported by: MH12306(TVS),DA03502,DA00119(SAD),DA08549(REH)

•Spiers, H.J., Burgess, N., Hartley, T., Vargha-Khadem, F. & O'Keefe, J. (2001). Bilateral hippocampal pathology impairs topographical and episodic memory but not visual pattern matching. Hippocampus 11(6): 715-725. A virtual reality environment was used to test memory performance for simulated real-world spatial and episodic information in a 22-year-old male, Jon, who has selective bilateral hippocampal pathology caused by perinatal anoxia. He was allowed to explore a large- scale virtual reality town and was then tested on his memory for spatial layout and for episodes experienced. Topographical memory was tested by assessing his ability to navigate, recognize previously visited locations, and draw maps of the town. Episodic memory was assessed by testing the retrieval of simulated events which consisted of collecting objects from characters while following a route through the virtual town. Memory for the identity of objects, as well as for where they were collected, from whom, and in what order, was also tested. While the first task tapped simple recognition memory, the latter three tested memory for context. Jon Page 63 Place cell references was impaired on all topographical tasks and on his recall of the context-dependent questions. However, his recognition of objects from the virtual town, and of topographical scenes (as evaluated by standard neuropsychological tests), was not impaired. These findings are consistent with the view that the hippocampus is involved in navigation, recall of long term allocentric spatial information and context-dependent episodic memory, but not visual pattern matching.

•Spiers, H.J., Burgess, N., Maguire, E.A., Baxendale, S.A., Hartley, T., Thompson, P.J. & O'Keefe, J. (2001). Unilateral temporal lobectomy patients show lateralized topographical and episodic memory deficits in a virtual town. Brain 124(Pt 12): 2476-2489. A large-scale virtual reality town was used to test the topographical and episodic memory of patients with unilateral temporal lobe damage. Seventeen right and 13 left temporal lobectomy patients were compared with 16 healthy matched control subjects. After they had explored the town, subjects' topographical memory was tested by requiring them to navigate to specific locations in the town. The ability to recognize scenes from and draw maps of the virtual town was also assessed. Following the topographical memory tests, subjects followed a route around the same town but now collected objects from two different characters in two different locations. Episodic memory for various aspects of these events was then assessed by paired forced-choice recognition tests. The results showed an interaction between laterality and test type such that the right temporal lobectomy (RTL) patients were worse on tests of topographical memory, and the left temporal lobectomy (LTL) patients worse on tests of context-dependent episodic memory. Specifically, the RTL group was impaired on navigation, scene recognition and map drawing relative to control subjects. They were also impaired on recognition of objects in the episodic memory task. The LTL group was impaired relative to control subjects on their memory for contextual aspects of the events, such as who gave them the objects, the order in which objects were received and the locations in which they received them. They were also mildly impaired on topographical memory, but less so than the RTL group. These results suggest that topographical memory is predominately mediated by structures in the right medial temporal lobe, whereas the context-dependent aspects of episodic memory in this non-verbal test are more dependent on the left medial temporal lobe.

•Stackman, R.W., Clark, A.S. & Taube, J.S. (2002). Hippocampal spatial representations require vestibular input. Hippocampus 12(3): 291-303. The hippocampal formation participates in learning and memory, particularly that of a spatial nature. In adult rats, individual CA1 pyramidal neurons only fire when the Page 64 Place cell references animal visits specific locations in an environment, the place field of the neuron. Other structures (postsubiculum, thalamus, cingulum) contain neurons that code for the animal's instantaneous head direction. Previous work has shown that the rat hippocampal formation undergoes anatomical and neurophysiological maturation during the first 2 months of life and that rats <40 days of age are impaired in spatial navigation tasks. Here we show that the locational firing of CA1 pyramidal neurons is both less specific and less stable in animals aged <50 days. However, preliminary results indicate that head directional firing recorded around day 30 is essentially identical to that seen in adult animals. Therefore, the development of reliable, spatially specific place cell activity parallels the developmental time course of spatial navigational ability, but head directional firing appears before full maturation of the hippocampus.

•Tabuchi, E.T., Mulder, A.B. & Wiener, S.I. (2000). Position and behavioral modulation of synchronization of hippocampal and accumbens neuronal discharges in freely moving rats. Hippocampus 10(6): 717-728! To understand how hippocampal signals are processed by downstream neurons, we analyzed the relative timing between neuronal discharges in simultaneous recordings in the hippocampus and nucleus accumbens of rats performing in a plus maze. In all, 154 pairs of cells (composed of 65 hippocampal and 56 accumbens neurons) were examined during the 1 s period prior to reward delivery. Cross-correlation analyses over a ±300-ms window with 10-ms bins revealed that 108 pairs had at least one significant histogram bin (P < 0.01). The most frequently occurring peaks of hippocampal firing prior to accumbens discharges appeared at latencies from -30-0 ms, corresponding to published values of the latency of the hippocampal pathway to the nucleus accumbens. Other peaks appeared most often at latencies multiples of about 110 ms prior to and after this, corresponding to theta rhythmicity. Since firing synchronization can result from several types of connectivity patterns (such as common inputs), a group of 18 hippocampus-accumbens pairs was selected as those most likely to have monosynaptic connections. The criterion was the presence of at least one highly significant peak (P < 0.001) at latencies corresponding to field potentials evoked in the accumbens by hippocampal stimulation. A significant peak occurred on all four maze arms for only one of these cell pairs, indicating positional modulation for the others. In addition, behavior dependence of the synchrony between these nucleus accumbens and hippocampus neurons was examined by studying data in relation to three different synchronization points: reward box arrival, box departure, and arrival at the center of the maze. This indicates that the functional connectivity between hippocampal and accumbens neurons was stronger when the rat Page 65 Place cell references was near reward areas. Ten of the hippocampal neurons in these 18 cell pairs showed 9-Hz (theta) rhythmic activity in autocorrelation analyses. Of these 10 cells, cross- correlograms from eight hippocampal-accumbens pairs also showed theta rhythmicity. Overall, these results indicate that the synchrony between hippocampus and nucleus accumbens neurons is modulated by spatial position and behavior, and theta rhythm may play an important role for this synchronization.

•Tanila, H. (1999). Hippocampal place cells can develop distinct representations of two visually identical environments. Hippocampus 9(9): 235-246.

•Taube, J.S. (1999). Some thoughts on place cells and the hippocampus. Hippocampus 9: 452-457.

•Tsodyks, M.V., Skaggs, W.E., Sejnowski, T.J. & McNaughton, B.L. (1996). Population dynamics and theta rhythm phase precession of hippocampal place cell firing: A spiking neuron model. Hippocampus 6: 271-280. O'Keefe and Recce ([1993] Hippocampus 3:317-330) have observed that the spatially selective firing of pyramidal cells in the CA1 field of the rat hippocampus tends to advance to earlier phases of the electroencephalogram theta rhythm as a rat passes through the place field of a cell. We present here a neural network model based on integrate- and-fire neurons that accounts for this effect. In this model, place selectivity in the hippocampus is a consequence of synaptic interactions between pyramidal neurons together with weakly selective external input. The phase shift of neuronal spiking arises in the model as result of asymmetric spread of activation through the network, caused by asymmetry in the synaptic interactions. Several experimentally observed properties of the phase shift effect follow naturally from the model, including 1) the observation that the first spikes a cell fires appear near the theta phase corresponding to minimal population activity, 2) the overall advance is less than 360 degrees, and 3) the location of the rat within the place field of the cell is the primary correlate of the firing phase, not the time the rat has been in the field. The model makes several predictions concerning the emergence of place fields during the earliest stages of exploration in a novel environment. It also suggests new experiments that could provide further constraints on a possible explanation of the phase precession effect.

•Tanila, H. (2001). Noradrenergic regulation of hippocampal place cells. Hippocampus 11(6): 793-808. The influence of noradrenergic input to the hippocampus was assessed by recording hippocampal place cells and by modulating the Page 66 Place cell references noradrenergic tone with a selective agonist and antagonist of the alpha2- autoreceptors. The rats received intraperitoneal injection of 5 microg/kg of dexmedetomidine (DEX), an alpha2-agonist, 0.2 mg/kg of atipamezole (ATI), an alpha2-antagonist, or saline. Hippocampal place cells were recorded in a familiar rectangular environment and in three types of new environments (rectangle, square, and cylinder). Recordings in the familiar environment were conducted in two phases, either before (early phase) or after (late phase) the exposure to new environments. In the familiar environment, DEX significantly increased the mean firing rate of hippocampal interneurons, while ATI increased the mean firing rate of pyramidal cells. Only ATI in the early phase of the experiment impaired spatial selectivity. Both drugs induced field rotations in the early phase of the study, but in the late phase DEX decreased, while ATI increased field stability in the familiar environment. The drug effects in the new environment were dependent on degree of novelty. No difference between treatments was observed in the new rectangle, but in the square and cylinder, ATI increased the mean firing rate, number of fields, and field area compared to other treatments. Stability of the original firing fields in the familiar rectangle was dependent on type of interfering environment and drug treatment. Exposure to another rectangle had the smallest impact, and exposure to a square the largest impact, on the original field pattern. ATI impaired stability of the original field after exposure to a rectangular and cylinder, while the impairing effect of DEX was only observed after exposure to a cylinder. In conclusion, increased noradrenergic tone increases the firing rate of hippocampal place cells, especially when the experimental situation and environment are new, but this increase is spatially nonselective. Furthermore, manipulation of the noradrenergic tone in either direction leads to instability of firing fields.

•Terrazas, A., Krause, M., Bohne, K.M., Poneta, K.M., Dees, J.A., McNaughton, B.L. & Barnes, C.A. (2001). The contributions of vestibular and optical flow information to location specific firing of rat hippocampal pyramidal cells. Society for Neuroscience Abstracts 31(643.14): 329. Rodents can navigate by path integration, and hippocampal pyramidal cells can maintain accurate spatial selectivity using only self-motion cues. Vestibular lesions are known to disrupt spatial tuning of hippocampal cells. McNaughton et al. (1996) proposed that self-motion information from optic flow, vestibular inputs and motor efference copy may be a primary means of updating hippocampal spatial tuning and that associations with visual and other landmarks may be secondary. To examine the influence of optic flow and vestibular signals on place-specific firing, in the absence of motor efference copy, multiple CA1 pyramidal cells were recorded from 3 rats trained to Page 67 Place cell references drive a small car between goal locations on a circular platform, to which was attached a cylindrical wall containing distinct visual cues. The car and platform were attached to separate motor-driven axes, enabling independent rotation of CAR (optic flow and vestibular) and WORLD (optic flow only). CA1 pyramidal cells fired robustly during both conditions, but with very low spatial selectivity during WORLD movement (i.e., in the absence of vestibular input). In contrast, during movement of the CAR, spatial selectivity was comparable to that normally observed during natural locomotion. Spatial information per spike differed significantly between conditions (CAR 1.4 bits/spike, WORLD 0.55 bits/spike, p < .001). Theta appeared normal under both conditions (Dees et al., this session). Thus, vestibular information appears to be necessary for hippocampal cells to show robust spatial selectivity. Supported by: AG12609, DFG & MH01565

•Thorsnes, E. & Srebro, B. (2000). The emergence and stability of the hippocampal place cells activity in a new environment. Society for Neuroscience Abstracts 30. We have analysed the development of activity and stability of place cells (complex-spike neurons) of the CA1 field of the rodent hippocampus in a new environment. Long-Evans male rats were implanted with a movable bundle of 10 microelectrodes. After the recovery period recording electrodes were slowly advanced towards the pyramidal cell layer of the CA1 field. Animals were housed individually. Single units activity and location of the animal were recorded in a home cage surrounded by black walls 50 cm high. Exposure to a new environment was started only after complex spike neurons were recorded during 2 consecutive sessions. All sessions were videotaped. Off-line clustering and inter-session identification was based on principal-components, template matching and inter-spike intervals. Activity of the theta cells was used as a measure of stability across repeated sessions. Home cage recordings revealed the presence of distinct place cells, which retained for some time their firing fields after the home cage was placed in a new environment. Repeated exposures to an open field containing 4 small objects resulted in a gradual emergence of new firing fields. Place cells responses were variable for some time in the new environment and only after several sessions attained relative stability. Our preliminary conclusion is that, in contrast to a familiar environment (home cage), the population of place cells in unfamiliar environment appears to be unstable both in regard to their firing fields, and the number of active place cells. It appears that establishing of the place encoding properties (firing fields) requires repeated exposures to the new environment. Supported by: University of Bergen

Page 68 Place cell references •Touretzky, D.S., Weisman, W.E., Fuhs, M.C., Skaggs, W.E., Fenton, A.A. & Muller, R.U. (2001). Attactor model of hippocampal map deformation. Society for Neuroscience Abstracts 31(643.8): 329. To investigate conjoint stimulus control over place cells, Fenton et al. (2000a) recorded while rats foraged in a cylinder with 45o white and black cue cards on the wall whose centers were 135o apart. In probe trials the cards were rotated together or apart by 25o. Firing field centers shifted during these trials, stretching and shrinking the cognitive map. Fenton et al. (2000b) described this deformation using an ad hoc vector field equation. We present two other models of map deformation. In a maximum likelihood formulation, the rat's location is estimated by a conjoint probability density function. Card edges serve as landmarks. Each spot in the arena has a unique set of distances to landmarks, or of bearing differences between landmark pairs. These features are treated as independent, gaussian-distributed evidence sources. In an attractor neural network model, recurrent connections produce a movable bump of activity over a 2D array of cells. Visual feature detector units tuned to distances or bearing differences make excitatory projections onto the attractor network, putting bump location under cue card control. The two approaches yield similar results, supporting previous conjectures that maximum likelihood may be an appropriate framework for describing hippocampal attractor dynamics. Models based on either distances or bearing differences produced deformation anomalies that disagreed with data and the vector field equation. But these anomalies were complementary, and were eliminated by combining the two types of landmark features. Supported by: NSF IIS-9978403

•Twum-Danso, N. & Brockett, R. (2001). Trajectory estimation from place cell data. Review. Neural Networks 14(6-7): 835-844. We consider the problem of propagating the conditional probability density associated with the movement parameters (position, heading, velocity, etc.) of an animal, given the responses of an ensemble of place cells. While we are not the first to look at this question, ours seems to be the first treatment that incorporates a general Markov process model for the motion parameters and a general observation model postulating place cells centered in a lower dimensional 'measurement space' formed from combinations of the Markovian variables. An important part of our analysis involves the determination of a suitable set of sufficient statistics for propagating the conditional density in this context. Making use of these results we are led to approximations which greatly simplify the estimation problem and various aspects of its neuroscientific interpretation.

Page 69 Place cell references •Vazdarjanova, A.I., McNaughton, B.L., Barnes, C.A., Worley, P.F. & Guzowski, J.F. (2001). Neural activity mapping with temporal and cellular resolution using double fluorescence in situ hybridization to the immediate-early genes Arc and Homer 1a. Society for Neuroscience Abstracts 31(316.1).The subcellular localization of Arc RNA, as revealed by FISH and confocal microscopy, can be used to determine the activity history of brain neurons: Cells activated by exploration of a novel environment ~2-15 min before sacrifice show intranuclear foci (INF), which are the sites of allelic transcription, and cells active ~20-40 min earlier show prominent cytoplasmic labeling (Guzowski et al., Nature Neurosci. 2:1120-1124, 1999). Such behavioral exploration also induces transcription of another IEG, Homer 1a (H1a). H1a is a splice variant of the Homer 1 gene that has a unique 3' UTR located ~50 kbp downstream of the start site. Hybridization to this region as evidenced by H1a INF is not seen until ~25 min after cell activation. We report that in rats sacrificed 30 min after exploration of a novel environment, 39% of CA1 neurons and 45% of parietal cortical neurons show both H1a INF and Arc cytoplasmic labeling. The correspondence of cells double labeled for H1a INF and Arc cytoplasmic staining is 95% in CA1 and 93% in parietal cortex. Thus, experience-dependent transcription of these two genes is coordinately regulated. This finding enables a powerful new brain imaging approach Arc INF indicate cells active 2-15 min before sacrifice, whereas H1a INF indicate cells active 25-40 min earlier. Because all measurements are made within defined nuclei, the Arc/H1a INF analysis will be more amenable to computer automation than the Arc cytoplasmic/nuclear analysis. Supported by: MH60123, AG09219, AG18230 & MH01565

•Wiener, S.I. (1993). Spatial and behavioral correlates of striatal neurons in rats performing a Self-Initiated navigation task. Journal of Neuroscience 13(9): 3802- 3817.

•Wilson, M.A. & McNaughton, B.L. (1994). Reactivation of hippocampal ensemble memories during sleep [see comments]. Science 265: 676-679. Simultaneous recordings were made from large ensembles of hippocampal "place cells" in three rats during spatial behavioral tasks and in slow-wave sleep preceding and following these behaviors. Cells that fired together when the animal occupied particular locations in the environment exhibited an increased tendency to fire together during subsequent sleep, in comparison to sleep episodes preceding the behavioral tasks. Cells that were inactive during behavior, or that were active but had non- overlapping spatial firing, did not show this increase. This effect, which declined Page 70 Place cell references gradually during each post-behavior sleep session, may result from synaptic modification during waking experience. Information acquired during active behavior is thus re-expressed in hippocampal circuits during sleep, as postulated by some theories of memory consolidation.

•Wood, E.R., Dudchenko, P.A. & Eichenbaum, H. (1999). The global record of memory in hippocampal neuronal activity. Nature 397(6720): 613-616. In humans the hippocampal region of the brain is crucial for declarative or episodic memory for a broad range of materials. In contrast, there has been controversy over whether the hippocampus mediates a similarly general memory function in other species, or whether it is dedicated to spatial memory processing. Evidence for the spatial view is derived principally from the observations of 'place cells'-hippocampal neurons that fire whenever the animal is in a particular location in its environment, or when it perceives a specific stimulus or performs a specific behaviour in a particular place. We trained rats to perform the same recognition memory task in several distinct locations in a rich spatial environment and found that the activity of many hippocampal neurons was related consistently to perceptual, behavioural or cognitive events, regardless of the location where these events occurred. These results indicate that nonspatial events are fundamental elements of hippocampal representation, and support the view that, across species, the hippocampus has a broad role in information processing associated with memory.

•Wood, E.R., Dudchenko, P.A., Robitsek, R.J. & Eichenbaum, H. (2000). Hippocampal neurons encode information about different types of memory episodes occurring in the same location. Neuron 27: 623-633.

•Yamaguchi, Y., Gothard, K.M. & McNaughton, B.L. (2000). Hippocampal phase coding and information dynamics. Society for Neuroscience Abstracts 30. Hippocampal neurons exhibit changes in firing phase relative to the theta rhythm as the rat traverses their place fields. The change is more complex than a simple linear phase shift. Based on previous ensemble neural recording data (Skaggs et al., 1996; Hoffman et al., 1998) we propose that the phase change involves two separate components: 1) a late-phase component (in CA1 and DG) involving a gradual, linear phase shift during the initial firing in the place field and 2) a more complex, early- phase component (in CA1 but not DG) that occurs in the latter part of the field. If these two components are indeed mechanistically distinct, it is reasonable to suggest that the late-phase component originates in entorhinal cortex (ECII) whereas the early phase component results from intrinsic dynamics of CA3 or CA1. Page 71 Place cell references The late-phase component in a population of cells represents the compressed temporal sequence, while the early phase component may involve more complex effects. We propose a hypothesis of information dynamics in the closed circuit. 1) Units in ECII are activated by behavior dependent input and exhibit stimulus dependent intrinsic oscillations whose frequencies increase with time after stimulus onset. Mutual interactions result in global oscillation in which the cells with higher intrinsic frequencies fire at earlier phase. 2) The EC pattern is inherited by CA3, where temporal sequences are stored by asymmetric LTP. A neural network model based on the hypothesis reconstructs the complexity of theta phase precession and shows that temporal sequence can be coded to phase and stored in the network of CA3. Supported by: JST CREST, MH01565

•Yan, J., Zhang, Y., Jia, Z., Taverna, F.A., McDonald, R.J., Muller, R.U. & Roder, J.C. (2002). Place-cell impairment in glutamate receptor 2 mutant mice. Journal of Neuroscience 22(3): RC204.There is a strong correlation between Hebbian, NMDA receptor-dependent long-term potentiation (LTP), place-cell firing, and learning and memory. We made glutamate receptor 2 (GluR2) null mutant mice that show enhanced non-Hebbian LTP in hippocampal CA1 neurons and impaired performance in a spatial learning task. We concluded that in vivo hippocampal place cells of GluR2 mutant mice were functionally impaired because (1) only 22.6% of CA1 neurons showed place fields in GluR2 mutant mice, which was significantly lower than that (43.8%) in wild-type mice; (2) GluR2 mutant place fields were much less precise; and (3) GluR2 mutant place fields were extremely unstable. Our data suggest that place cells of GluR2 knock-out mice did not form robust place fields, and that enhanced non-Hebbian LTP might play a negative role in their formation.

•Zhang, K., Bower, M.R., McNaughton, B.L. & Sejnowski, T.J. (2001). Tracking head location, direction, tilt and roll for determining place cell egocenter in three dimensions. Society for Neuroscience Abstracts 31(643.19): 330. The activity of a hippocampal place cell depends on where the head of an animal is located in the environment, but the point for representing head location has been chosen arbitrarily. For example, when two light-emitting diodes are used for video tracking a rat, any point in the sagittal plane of the head may be chosen as the representing point, and for a typical place cell, a unique point in the plane yields the most compact place field (Soc. Neurosci. Abst. 24:932, 1998): this point is called the egocenter for that place cell. However, with only two diodes there is an ambiguity in the roll angle (left ear up vs. right ear up). In order to define an egocenter in 3-D space, we sought to determine head location, direction, tilt and roll from the video Page 72 Place cell references images of a head-stage with 11 light-emitting diodes after taking into account geometric distortion, light smearing and blockage effects to suitably place and orient a rigid geometric model. The accuracy of the method was calibrated on a video with known direction, tilt, and roll angles. In a preliminary analysis of several place cells, each place field had only a single compactness minimum in the 3-D space around the rat's head, which suggests that the egocenter can be defined in 3-D space and raises further questions about the stability of the egocenter and its relation to phase precession and the theta rhythm.Supported by: Howard Hughes Medical Institute, NS20331 & MH01565

•Zhang, Y., Jan, J., Jia, Z., Taverna, F., McDonald, R., Muller, R.U. & Roder, J. (2000). Impaired spatial representation of hippocampal place cells in GluR2 mutant mice. Society for Neuroscience Abstracts 30. GluR2 plays an important role in the assembly of AMPARs and the flux of Ca2+ across the channel. Hippocampal slices from our GluR2 gene KO mice showed greatly (3-9 fold) enhanced LTP. One would expect this non-Hebbian enhancement to block learning and memory and impair the spatial representation of hippocampal place cells. We implanted electrodes and recorded CA1 cells of mice freely running in a cylinder arena. We found that the place cells of GluR2 mutant mice did not form robust place fields. Only 15/59 (25.4%) cells had place field but 28/57 (49.1%) in wildtypes. The average field size in mutants was significantly larger than that in wildtypes. We also measured the spatial coding rate (SCR, indicating the contrast of in-field firing with the background firing). The place cells of mutants showed much lower SCR than wildtypes, but their in-field firing were not significantly higher. Place fields rotated following the rotation of cue card in 5/15 cells in mutants but 18/28 in wildtypes. The fields of other cells either appeared elsewhere or disappeared. The place cells of mutants also showed unstable place fields. Our results indicate that the spatial representation in the CA1 place cells of mice lacking the GluR2 was impaired. Other data that we have shown elsewhere suggested that GluR2 mutant mice have lower spatial learning and memory. This is being confirmed in GluR2 Cre KO mice. This data suggests that saturated, non Hebbian LTP in the hippocampus leads to impaired spatial representation in the hippocampus. The first two authors have made an equal contribution. Supported by: MRC of Canada, the Ontario Mental Health Foundation and NIH

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