View metadata, citation and similar papers at core.ac.uk brought to you by CORE

provided by Frontiers - Publisher Connector REVIEW ARTICLE published: 20 February 2012 NEURAL CIRCUITS doi: 10.3389/fncir.2012.00005 Possible role of in regulating spatial novelty effects on theta rhythm and grid cells

Caswell Barry 1,2*, James G. Heys 1 and Michael E. Hasselmo 1*

1 Department of Psychology, Center for Memory and Brain, Boston University, Boston, MA, USA 2 Institute of Neurology, University College London, London, UK

Edited by: Existing pharmacological and lesion data indicate that acetylcholine plays an important Lisa M. Giocomo, Norwegian role in memory formation. For example, increased levels of acetylcholine in the University of Science and are known to be associated with successful encoding while Technology, Norway disruption of the cholinergic system leads to impairments on a range of mnemonic Reviewed by: Dori Derdikman, Technion, Israel tasks. However, cholinergic signaling from the medial septum also plays a central role James Ainge, University of in generating and pacing theta-band oscillations throughout the hippocampal formation. St Andrews, UK Recent experimental results suggest a potential link between these distinct phenomena. *Correspondence: Environmental novelty, a condition associated with strong cholinergic drive, has been Caswell Barry, ICN, Alexandra shown to induce an expansion in the firing pattern of entorhinal grid cells and a reduction House, 17 Queen Square, WC1N 3AR, London, UK. in the frequency of theta measured from the LFP. Computational modeling suggests the e-mail: [email protected] spatial activity of grid cells is produced by interference between neuronal oscillators; Michael E. Hasselmo, Department scale being determined by theta-band oscillations impinging on entorhinal stellate cells, of Psychology, Center for Memory the frequency of which is modulated by acetylcholine. Here we propose that increased and Brain, Boston University, cholinergic signaling in response to environmental novelty triggers grid expansion by Boston, 02215 MA, USA. e-mail: [email protected] reducing the frequency of the oscillations. Furthermore, we argue that cholinergic induced grid expansion may enhance, or even induce, encoding by producing a mismatch between expanded grid cells and other spatial inputs to the , such as boundary vector cells. Indeed, a further source of mismatch is likely to occur between grid cells of different native scales which may expand by different relative amounts.

Keywords: grid cell, , acetylcholine, theta, stellate cell

INTRODUCTION levels of acetylcholine, promotes a constant theta state in the LFP Compelling evidence from several fields indicates that of anesthetized animals (Yoder and Pang, 2005). acetylcholine enhances the dynamics of memory encoding. The significance of this dual role exhibited by acetylcholine Pharmacological studies in humans, primates, and other ani- remains unclear; to what extent are common systems involved mals show that blockade of cholinergic receptors compromises and what role might modulation of theta-band oscillations have memory formation whereas cholinergic agonists can promote in memory encoding? A recent theory linking theta-band fre- mnemonic function. In particular, impairment of the parahip- quencies of intrinsic oscillations in entorhinal stellate cells with pocampal cholinergic system produces deficits in recognition, the generation of spatial firing produced by grid cells provides spatial, and working memory apparently limited to encoding a potential resolution. Briefly, the scale of the grid firing pat- but not retrieval (Aigner and Mishkin, 1986; Tang et al., 1997). tern is believed to depend on the relative frequency of theta-band Electrophysiological investigations suggest this enhancement is neuronal oscillators in the (Burgess et al., due to several factors including an augmentation of long-term 2007), which are subject to cholinergic modulation. In response potentiation (LTP) as well as suppression of feedback connectiv- to environmental novelty, a condition known to increase intra- ity, which may reduce interference between existing memories hippocampal acetylcholine, the frequency of the theta-band net- and incoming stimuli (Hasselmo et al., 1995; Hasselmo, 2006). work oscillations is seen to decrease (Jeewajee et al., 2008b)and However, a parallel body of work implicates acetylcholine in is matched by an increase in grid scale (Barry et al., Soc. Neurosci. the generation and pacing of theta-band oscillations observed Abstr. 101.25, 2009). We anticipate the expansion of the grid fir- in the local field potential (LFP) throughout the hippocampal ing pattern will likely lead to a mismatch between grids and other formation. For example, disruption of cholinergic transmission spatial inputs to the hippocampus [see also, (Burgess et al., 2007; from the medial septum to the hippocampus severely attenuates Burgess, 2008)] and potentially also between grids of different theta power (Lee et al., 1994), impairs spatial learning (Rogers native scales (Monaco and Abbott, 2011). It is likely then that this and Kesner, 2003; Elvander et al., 2004)[butalsoseeBaxter orthogonalized input promotes the formation of spatial memo- et al. (1995)], and reduces the spatial specificity of hippocampal ries in the form of distinct, stable place cell representations. In place cells (Shapiro et al., 1989; Brazhnik et al., 2003). Conversely this document we first describe how acetylcholine has been pro- systemic application of physostigmine, which leads to elevated posed to modulate learning in the hippocampal formation before

Frontiers in Neural Circuits www.frontiersin.org February 2012 | Volume 6 | Article 5 | 1 Barry et al. Acetylcholine, theta, and grid cells

focusing on its role in the generation of theta. Finally, we argue cholinergic lesions appear to impair the increased exploration by that the reduction in theta frequency observed in response to rats encountering novel objects (Winters and Bussey, 2005)or environmental novelty is mediated by acetylcholine and drives novel associations of locations and context (Easton et al., 2011) hippocampal remapping. though surprisingly not more complex episodic associations. In summary, the studies of local infusion effects and selective cholin- ACETYLCHOLINE AND ITS ROLE IN THE MODULATION ergic lesions suggest a role for acetylcholine in the hippocampus OF LEARNING and parahippocampal cortex for encoding of new memories. Extensive data indicates a role of acetylcholine in encoding of Further understanding of these behavioral effects can be obtained new memories. Multiple studies have shown impairments of by considering the cellular effects of acetylcholine on encoding after systemic injections of scopolamine, an antagonist within these cortical structures. at muscarinic acetylcholine receptors. Subjects that encoded a list of words under the influence of scopolamine showed severe CHOLINERGIC MODULATION OF SYNAPTIC AND reductions in subsequent free recall of the word list (Ghoneim CELLULAR MECHANISMS FOR ENCODING and Mewaldt, 1975; Peterson, 1977).Thesamesubjectsunder Acetylcholine could enhance encoding through a number of the influence of scopolamine did not show impaired retrieval direct effects on the physiology of cortical principal cells. of words encoded before the injection. Scopolamine injections Acetylcholine directly enhances the induction of LTP in corti- also impair performance in an n-back working memory task cal regions including the hippocampus (Blitzer et al., 1990), the (Green et al., 2005). In monkeys, the encoding of visual stimuli entorhinal cortex (Yun et al., 2000), and other structures includ- for subsequent recognition is impaired by systemic injections of ing piriform cortex (Patil et al., 1998)andprimaryvisualcortex scopolamine (Aigner and Mishkin, 1986), and in rats systemic (Brocher et al., 1992). The induction of Hebbian synaptic mod- injections of muscarinic antagonists impair performance on the ification could also be enhanced by muscarinic enhancement of Morris water maze (Whishaw, 1985; Buresova et al., 1986)and postsynaptic spiking activity due to direct depolarization of corti- eight-arm radial maze (McGurk et al., 1988). cal pyramidal cells (Cole and Nicoll, 1984; Barkai and Hasselmo, 1994) as well as suppression of spike frequency accommodation CHOLINERGIC MODULATION IN THE HIPPOCAMPAL (Madison and Nicoll, 1984; Madison et al., 1987; Barkai and FORMATION Hasselmo, 1994). Localized infusions suggest that these effects of acetylcholine Acetylcholine may also enhance encoding by augmenting the receptor blockade are due to effects in the hippocampus and influence of external afferent input relative to the internal spread regions of parahippocampal cortex. Encoding for recognition of activity within cortical structures (see Figure 1). Acetylcholine memory in monkeys is impaired by local infusions of scopo- causes direct nicotinic enhancement of afferent fiber synap- lamine into the perirhinal cortex but not the dentate gyrus tic transmission at thalamocortical synapses (Gil et al., 1997). (Tang et al., 1997). In rats, local infusions of scopolamine into Acetylcholine also enhances the response of the dentate gyrus to the perirhinal cortex impair encoding of stimuli for subsequent afferent input (Foster and Deadwyler, 1992), and these responses recognition (Winters et al., 2006), and local infusions of cholin- also increase during behavioral states associated with increased ergic antagonists impair encoding of the association between acetylcholine such as REM sleep (Winson and Abzug, 1977). tone stimuli and shock in a trace conditioning paradigm (Bang At the same time as it enhances input, acetylcholine reduces and Brown, 2009; Esclassan et al., 2009). Encoding of platform the synaptic transmission at excitatory glutamatergic recur- location in the Morris water maze is impaired by infusions of rent feedback synapses within cortical structures. For example, scopolamine in the hippocampus (Blokland et al., 1992)andthe medial septum (Elvander et al., 2004). Encoding for subsequent recognition is also impaired by selective lesions of the cholin- ergic fibers in rats that innervate entorhinal cortex (McGaughy et al., 2005) and perirhinal cortex (Winters and Bussey, 2005) and recognition performance is also impaired by selective lesions of cholinergic fibers innervating perirhinal cortex in monkeys (Turchi et al., 2005). The role of acetylcholine in the encoding of new informa- tion appears consistent with microdialysis studies of levels of acetylcholine in the hippocampus, which increase in novel envi- ronments (Acquas et al., 1996). Acetylcholine levels in the hip- pocampus and neocortex also increase during active exploration FIGURE 1 | Effect of acetylcholine on cortical processing. High of the environment (Marrosu et al., 1995). Active exploration is acetylcholine (ACh) enhances encoding by increasing the efficacy of also associated with theta rhythm oscillations in the hippocam- afferent input to the cortex via the action of nicotinic receptors. At the same pus, and theta rhythm oscillations are associated with increases in time high acetylcholine suppresses transmission at glutamatergic recurrent acetylcholine levels measured with microdialysis (Monmaur et al., feedback synapses within cortical regions. Conversely, lower acetylcholine favors the retrieval of stored memories by enhancing the influence of 1997)andamperometry(Zhang et al., 2010). The increase of recurrent connections relative to afferent input. acetylcholine during novelty is consistent with the evidence that

Frontiers in Neural Circuits www.frontiersin.org February 2012 | Volume 6 | Article 5 | 2 Barry et al. Acetylcholine, theta, and grid cells

acetylcholine suppresses excitatory feedback synapses in the Though less obvious, theta is also present in the hippocampal LFP piriform cortex (Hasselmo and Bower, 1992, 1993), in neocortical of other animals including bats, rabbits, and humans (Winson, structures (Gil et al., 1997; Kimura and Baughman, 1997)and 1976; Kahana et al., 1999; Cantero et al., 2003; Ulanovsky and in region CA3 of the hippocampal formation (Hasselmo et al., Moss, 2007). Work conducted in the 1960s and 1970s revealed 1995; Vogt and Regehr, 2001; Kremin and Hasselmo, 2007). that theta has distinct behavioral correlates which vary between Computational models of cortical structures show that this selec- animal species, as does the frequency and amplitude of the oscil- tive muscarinic presynaptic inhibition of glutamatergic synaptic lation (Whishaw and Vanderwolf, 1973; Vanderwolf, 2001). These transmission prevents retrieval of previously encoded memories correlates are most clearly defined for the rat in which, based on from interfering with the encoding of new memories in the hip- behavioral and pharmacological grounds, two distinct forms of pocampus (Hasselmo et al., 1992; Hasselmo and Schnell, 1994), theta have been identified (Kramis et al., 1975; Vanderwolf et al., while the cholinergic enhancement of input and LTP can enhance 1977). Type 1 theta, sometimes referred to as translational theta encoding. or t-theta, is apparent during voluntary movement, specifically In contrast, cortical circuits have different dynamics dur- any behavior that causes the animal’s head to move through space ing slow wave sleep, when levels of acetylcholine in the hip- (e.g., running, swimming, grooming) (Whishaw and Vanderwolf, pocampus and neocortex drop to less than 1/3 of waking levels 1973; O’Keefe and Nadel, 1978). In contrast, type 2 or attentional (Marrosu et al., 1995). Slow wave sleep has been proposed to theta, can be identified during highly aroused states when the ani- provide dynamics for consolidation of previously encoded infor- mal is immobile (e.g., in the presence of a predator or during fear mation (Buzsaki, 1989; Wilson and McNaughton, 1994). The conditioning) (Whishaw, 1972; Sainsbury et al., 1987). lower levels of acetylcholine mean less presynaptic inhibition of While several subcortical nuclei are implicated in the pacing glutamatergic transmission, allowing the spread of activity at of theta, the medial septum-diagonal band of Broca seems par- feedback synapses within the hippocampus and from hippocam- ticularly important and is necessary for the generation of both pus back to neocortical structures (Hasselmo, 1999). Consistent forms of theta; inactivation or lesion of the medial septum abol- with this, scopolamine blockade of acetylcholine enhances con- ishes all theta (Rawlins et al., 1979; Mitchell et al., 1982; Mizumori solidation (Rasch et al., 2006) whereas cholinergic agonists et al., 1989). Pharmacological manipulation of the medial septum impair consolidation in rats (Bunce et al., 2004) and humans has revealed distinct neuromodulatory mechanisms supporting (Gais and Born, 2004). the two forms (Bland, 1986; Mizumori et al., 1990b). Hence, type 2 theta appears to be acetylcholine dependent, so intrasep- MAINTENANCE OF BISTABLE PERSISTENT SPIKING tal infusion of anti-cholinergic drugs, such as atropine, eliminate AT THE LEVEL OF INPUTS TO HIPPOCAMPUS it but spare the acetylcholine independent type 1 theta (Kramis In addition to enhancing dynamics for encoding, acetylcholine et al., 1975). Conversely, application of carbachol, a choliner- also appears to be important for the maintenance of working gic agonist, to the septum promotes a constant type 2 theta memory (Green et al., 2005). This is consistent with cellular state (Bunce et al., 2004). In turn, movement-related type 1 effects of acetylcholine that enhance the maintenance of pre- theta depends upon the entorhinal cortex as entorhinal lesions sented activity by enhancing bistable persistent spiking or plateau spare only type 2 theta (Kramis et al., 1975). In particular the potentials (Klink and Alonso, 1997) that allows depolarization to glutamatergic layer II/III entorhinal afferents to the hippocam- persist after the end of an input stimulus. In addition to enhanc- pus seem to be a necessary component of the circuit generating ing mechanisms of working memory, these effects may also favor movement-related theta; application of the NMDAR antagonist long-term encoding by prolonging specific input patterns to the ketamine abolishes type 1 theta and coupled with scopolamine hippocampus, acting as a buffer to hold recently presented novel removes all theta (Buzsaki, 2002). Electrophysiological investiga- information during encoding (Hasselmo, 2006; Hasselmo and tion of the medial septum revealed populations of GABAergic Stern, 2006). and cholinergic neurons, which exhibit phase locking to hip- The effects described above provide a coherent framework pocampal theta, and project to interneurons in CA3 and CA1 for understanding the enhancement of encoding. However, they (Freund and Antal, 1988; Stewart and Fox, 1990; King et al., focus on a static view of the role of acetylcholine in the hippocam- 1998). Destruction of the cholinergic projections alone attenu- pal formation, as if the representations for working memory and ates but does not eliminate theta during movement and as such long-term encoding were all stable fixed-point attractors. To fully is the complement of septal infusion of cholinergic antagonists understandtheroleofacetylcholine,wemustaddressthefull (Lee et al., 1994). It is tempting then to simply equate these range of dynamics, including transient activity and oscillations. two cell types with the two forms of theta (Stewart and Fox, Acetylcholine also has a well-defined role in the generation and 1990). However, subsequent work has complicated the picture. pacing of theta, which is itself linked to memory formation. For example, while the GABAergic septal cells are highly active and show strong theta phase locking, the cholinergic cells are less HIPPOCAMPAL THETA active and do not exhibit rhythmic activity (Simon et al., 2006). Theta-band modulations of the LFP are among the most dis- Furthermore, work in slices shows the application of cholinergic tinct and easily visualized electrophysiological phenomena in the agonists to the hippocampus, in particular CA3, is sufficient to brain. In the moving rat theta is evident in the hippocampus promote spontaneous oscillations (Fischer et al., 1999). Similarly, as a large amplitude (exceeding 1 mV) 6–12 Hz sinusoidal oscil- in the intact rat, non-phasic activation of acetylcholine recep- lation (Vanderwolf, 1969, 1971; Buzsaki, 2002)(seeFigure 2A). tors in the hippocampus and medial septum increases theta

Frontiers in Neural Circuits www.frontiersin.org February 2012 | Volume 6 | Article 5 | 3 Barry et al. Acetylcholine, theta, and grid cells

A B

C D

E

FIGURE 2 | Theta-band oscillations play an important role in structuring oscillation (blue) with a constant frequency in the theta-band (fb) and; spatial activity in the hippocampus and entorhinal cortex. (A) Theta A velocity controlled component (red) the frequency (fd)ofwhich recorded from the entorhinal LFP of a moving rat. Black trace, raw LFP, increases proportionate to the animal’s velocity in a preferred direction (ϕi). mean normalized showing 1s of data. 8 Hz theta modulation is clearly visible, (D) Interference pattern generated between the components described in C. higher frequency gamma oscillations are also present. Red trace, same Spikes are emitted at the peaks of the carrier (black) which has a frequency signal band pass filtered in 6–12 Hz range. (B) in a CA1 equal to the mean of fb and fd. Grid scale is determined by the envelope place cell, the phase, and location of individual spikes is shown as (green) which has a frequency equal to the difference between fb and fd. follows: X-axis indicates the animal’s progress across the place field, (E) Multiple velocity controlled components with preferred firing moving left to right. Y-axis indicates the phase of each spike relative to theta directions at increments of 60◦ are required to produce a grid interference measured from the cell layer, two cycles are shown for completeness. Red pattern. A single baseline oscillator and velocity controlled component line indicates best fit to data for linear-circular regression. (C) Schematic of will produce a spatially stable stripped pattern similar to a sine the basic oscillatory interference model showing two components: a baseline grating. power (Siok et al., 2006). A more accurate view then is that the What then is the function of hippocampal theta? In addition GABAergic septal cells probably do function as a pacemaker, and to the behavioral correlates outlined above, manipulations that so entrain oscillators in the EC and hippocampus. In contrast, attenuate or abolish theta in vivo point to a role in learning and the cholinergic projection has a permissive modulatory role memory. Lesions made to the fornix or septum, which reduce (Buzsaki, 2002). theta power but also cholinergic drive to the hippocampus, impair

Frontiers in Neural Circuits www.frontiersin.org February 2012 | Volume 6 | Article 5 | 4 Barry et al. Acetylcholine, theta, and grid cells

performance on a wide range of memory tasks including goal advances through the field spikes are emitted at progressive earlier directed navigation (Winson, 1978; Hagan et al., 1988), delayed phases, typically moving forwards by about 180◦ during a single non-match to position (Markowska et al., 1989), and spatial alter- run to be fired near the trough of theta as it exits the place field nation (Givens and Olton, 1990). More specifically, reversible (O’Keefe and Recce, 1993)(seeFigure 2B). This effect, known medial septal inactivations show that the deficit is specific to as phase precession, is equivalent to the spike train of the place the encoding and retrieval phases of a spatial alternation task, cell being modulated at a frequency slightly greater than theta thus theta was not required for maintenance of a recent memory measured from the LFP (as measured in autocorrelations); this (Mizumori et al., 1990a). Similarly, theta power was found to cor- modulation is referred to as the intrinsic firing frequency of the relate with performance on a non-spatial working memory task cell. Because spike phase is linked to the proportion of the field but not on a reference memory task, indicating a role in encod- traversed, cells with large place fields tend to have lower frequency ing of information (Givens and Olton, 1994). This behavioral link modulation than those with smaller fields and similarly faster between theta and learning is supported by physiological stud- running is matched by higher firing frequencies (Huxter et al., ies that point to a modulation in the efficacy of hippocampal 2003; Geisler et al., 2007). Phase precession is clearest for runs LTP with theta phase. As such, tetanic stimuli arriving at the made on a linear track, in such conditions the phase of spikes peak of theta measured in the stratum radiatum (correspond- relative to theta convey more information about the animal’s ing to trough of theta at the fissure), are more likely to result in position than the firing rate (Jensen and Lisman, 2000; Huxter potentiation, those arriving during the opposite phase produce et al., 2003). Phase precession is, however, evident in data col- depression (Huerta and Lisman, 1995; Holscher et al., 1997; Orr lected during open field foraging (Burgess et al., 1994; Skaggs et al., 2001; Hyman et al., 2003). Theta can also provide a mech- et al., 1996). anism during which synaptic potentiation or synaptic depression Recently a second class of spatial cells, grid cells, have been can occur depending upon relative timing of the presynaptic reported in the medial entorhinal cortex of rodents and humans, input and separate modulatory input (Kwag and Paulsen, 2009). as well as in the pre and parasubiculum (Fyhn et al., 2004; Hafting In this study, CA1 Schaeffer collaterals were stimulated relative to et al., 2005; Boccara et al., 2010; Doeller et al., 2010). Grid cells, an induced theta input at the cell body. Either LTP or LTD could like place cells, have spatially stable fields but differ in that each be induced in the Schaeffer collaterals depending upon which grid cell has multiple circular firing fields arranged in a hexagonal phase of theta the stimulation occurred and the relative timing lattice. Grid cells that neighbor each other in the brain typi- of secondary stimulation of the tempero-ammonic pathway. This cally exhibit a lattice of similar scale but a topographical gradient work highlights the fact that the hippocampus and entorhinal exists so those at more ventral locations tend to be of a larger circuit must work in concert with theta to produce consistent scale, increasing in increments that possibly have a fixed ratio learning rules. (Hafting et al., 2005; Barry et al., 2007; Stensland et al., 2010). The lattice of grids in each hemisphere, and possibly those in THETA-BAND MODULATION OF SPATIAL FIRING IN different hemispheres, appear to have the same orientation such THE HIPPOCAMPUS: PLACE CELLS AND GRID CELLS that the hexagonal arrangement of their firing fields share the Perhaps the clearest evidence for the functional role of theta same three axes, albeit with some localized distortions (Hafting comes from studies of the spatially modulated cell types found in et al., 2005; Barry et al., 2007; Stensland et al., 2010). Significantly the hippocampus and surrounding regions; in these areas at least, grid cells also exhibit phase precession, the effect being clearest in theta-band oscillations seem to have an important role in struc- cells recorded from layer II of medial entorhinal cortex where all turing spatial activity. Working in the early 1970s O’Keefe and grids precess. In deeper layers a subset of grid cells phase precess, Dostrovsky (1971) first reported place cells, hippocampal pyra- the others being phase locked or simply firing with no apparent midal cells that exhibit spatially stable firing. Place cells seem to relationship to theta phase (Hafting et al., 2008). be a common feature of the mammalian hippocampus and have subsequently been found in bats, monkeys, humans, and even THE OSCILLATORY INTERFERENCE MODEL OF GRID pigeons (Ekstrom et al., 2003; Hori et al., 2003; Bingman et al., CELL FIRING 2006; Ulanovsky and Moss, 2007). In a familiar environment the The regular firing of grid cells is particularly amenable to com- firing field (place field) of a place cell is typically stable between putational modeling and a number of ideas have been presented visits to a location, even if those visits are separated by several to account for the lattice-like activity of these cells. With a few days (Muller et al., 1987). However, if an animal is moved to a exceptions [see Kropff and Treves (2008)] most of the models novel environment place cells change their relative firing positions describe grid firing in terms of self-motion; updating an ani- and rates such that a new stable population code is generated, this mal’s representation of its location based on movement cues. effect is known as remapping and is considered to be part of the Broadly, the models fall into two schools, those in which grid fir- process by which the hippocampus encodes a new spatial mem- ing is a product of attractor dynamics (Fuhs and Touretzky, 2006; ory (O’Keefe and Nadel, 1978; Muller and Kubie, 1987; Bostock McNaughton et al., 2006; Burak and Fiete, 2009; Navratilova et al., et al., 1991). The timing of spikes emitted by place cells show an 2011) and those which see grid activity as resulting from inter- interesting relationship relative to the current phase of theta mea- ference between multiple de-tuned neuronal oscillators (O’Keefe sured from the LFP, as follows: when an animal first enters the and Burgess, 2005; Blair et al., 2007; Burgess et al., 2007; Hasselmo firing field of a cell, action potentials are emitted around the peak et al., 2007; Giocomo and Hasselmo, 2008a; Welday et al., 2011; of theta (measured from the pyramidal cell layer). As the animal Hasselmo and Brandon, 2012,thisissue).Attractorbasedmodels

Frontiers in Neural Circuits www.frontiersin.org February 2012 | Volume 6 | Article 5 | 5 Barry et al. Acetylcholine, theta, and grid cells

provide a good account of some of the properties of grid cells, for medial entorhinal cortex (Giocomo et al., 2007). This gradient example, the incremental steps in scale and apparently fixed phase mirrors grid scale which increases along the same axis (Hafting offset between neighboring cells (Barry et al., 2007; Fyhn et al., et al., 2005; Barry et al., 2007); this relationship is predicted by 2007). This class of model requires a precise pattern of recurrent the model. MPO and resonance frequency is partly determined by connectivity which would presumably have to be learnt in early the composition of the HCN channel, the HCN1 subunit being life, and has yet to be identified in the medial entorhinal cor- differentially expressed along the dorsal-ventral axis (Giocomo tex. It is possible though that the necessary connectivity may be and Hasselmo, 2008b). Mice with the HCN1 subunit knocked located in other brain regions, potentially the pre or parasubicu- out exhibit a reduction in the frequency of the MPOs as well as lum. Alternatively it may be spatially localized, for example, being a flattening of the frequency gradient (Giocomo and Hasselmo, limited to the dense entorhinal cell islands (Burgalossi et al., 2011) 2009). Significantly, grids recorded from these mice are of a larger and thus be hard to detect. For a detailed review of the relative scale than those found in wild type mice, indicating a causal link merits of recurrent models of grid cell formation and oscillatory between the intrinsic frequency of neurons and the spatial firing interference models see Giocomo et al. (2011b). of grid cells (Giocomo et al., 2011a). However, the relationship The oscillatory interference framework was first proposed as may be more complex than initially assumed because the dorsal- model of place cell activity with a place field described as the ventral gradient in grid scale was not flattened in the same way envelope of an interference pattern generated between two neu- the frequency gradient was. Third, the model requires VCOs that ronal oscillators (O’Keefe and Recce, 1993; Lengyel et al., 2003). track an animal’s velocity, their firing frequency being modu- The lower frequency component oscillates at theta frequency and lated in the theta-band but increasing with the speed of travel the higher frequency component increases in frequency above this along a preferred firing direction. Bursting theta cells with these proportionate with the animal’s running speed (see Figure 2C). properties, specifically a cosine-like directional tuning and speed Spikes are emitted at the peaks of the carrier which is the com- modulation, have been found in the medial septum as well as the binedactivityofthetwooscillatorsandhasthemeanfrequencyof hippocampus and anterior thalamus (Welday et al., 2011). Finally, the two component waves. Thus, spikes exhibit phase precession the model explicitly requires theta-band oscillations to generate relative to the slower frequency theta oscillation (see Figure 2D). grid firing, though once established firing may be maintained Though intended as a model of place cell activity, grid cells pro- by sensory input from environmental cues, such as boundaries vide a more natural target for this type of model, the multiple (Hartley et al., 2000; Burgess et al., 2007; Solstad et al., 2008). regular fields of the grid lattice arising as the oscillators move Accordingly, inactivation of the medial septum, which abolishes repeatedly into and out of phase. Extension of the model to grid theta-band modulation in the entorhinal cortex, caused grid cells cells requires the addition of one or more velocity controlled to temporarily lose their spatial firing, the grid lattice being rein- oscillators (VCOs), the frequency of which tracks the animal’s stated when theta returns (Brandon et al., 2011; Koenig et al., velocity in a preferred direction. So, the model consists of a single 2011). baseline oscillator and multiple (between two and six) VCOs with A possible criticism of the model is that the level of temporal preferred directions that lie at increments of 60◦ to each other precision necessary to maintain stable spatial firing is beyond (O’Keefe and Burgess, 2005; Burgess et al., 2007)(seeFigure 2E). that which can be expected of a biological system (Burak and The scale of grids generated by the model is determined by the Fiete, 2009; Zilli et al., 2009). Simulations suggest this is not difference in frequency between the baseline oscillator and the the case, while independent realistically noisy oscillators would higher frequency VCOs; a large difference resulting in smaller quickly decohere, a population of coupled oscillators would not spacing between firing fields of grid cells and vice versa. Early ver- (Zilli and Hasselmo, 2010; Welday et al., 2011). Furthermore, sions of the model supposed that the multiple oscillators required work by Fernandez and White (Soc. Neurosci. Abstr. 766.19, 2011) to form a grid might be present within individual stellate cells demonstrates that correlated excitatory and inhibitory synaptic (Burgess et al., 2007).However,modelingshowsthisisunlikelyas background noise increases firing rate modulation to sinusoidal oscillators arranged in this way would quickly entrain each other input which could help to maintain stable firing of grid cells. (Remme et al., 2010), subsequent formulations of the model place Recently, recordings from the medial entorhinal cortex of crawl- the VCOs in individual cells upstream of the grid cells (Zilli and ing fruit bats have added to the debate. These animals exhibit Hasselmo, 2010). grid-like spatial firing in the absence of theta-band modulation The interference model has found support from a number of of the cells’ spike trains or of the hippocampal and entorhinal directions. In the first instance, entorhinal layer II stellate cells LFP (Yartsev et al., 2011). It remains to be seen if species specific exhibit sub-threshold membrane potential oscillations (MPOs) differences, the unnatural nature of the foraging task, or possibly with frequencies in the theta-band (Alonso and Klink, 1993) the low firing rate of the bat grid cells themselves might account and have been proposed as one of the components of the model for this discrepancy with the rodent data. (O’Keefe and Burgess, 2005; Burgess et al., 2007). These cells have been labeled after juxtacellular recording in moving rats, con- GRID EXPANSION, THETA RHYTHM, AND firming that stellate cells do exhibit grid-like firing and are likely ENVIRONMENTAL NOVELTY to be the layer II grid cells previously recorded with extracel- It has been known for some time that when an animal enters a lular electrodes (Burgalossi et al., 2011). Second, a gradient in novel environment place cells remap; place fields change their rel- the frequency of the MPOs as well as the resonance of stellate ative positions and rates (Muller and Kubie, 1987; Bostock et al., cells has been shown to exist along the dorsal-ventral axis of the 1991; Karlsson and Frank, 2008). Conditions that provoke place

Frontiers in Neural Circuits www.frontiersin.org February 2012 | Volume 6 | Article 5 | 6 Barry et al. Acetylcholine, theta, and grid cells

cell remapping also cause grid firing to shift and rotate relative This decrease in resonance frequency could underlie the decrease to the environment but not relative to grids of the same scale in the intrinsic frequency of theta modulation of grid cells in (Fyhn et al., 2007). Now, several new studies suggest a poten- novel environments (Barry et al., Soc. Neurosci. Abstr. 101.25, tial link between these phenomena and cholinergic signaling of 2009). In addition to the decrease in the intrinsic resonance fre- novelty (Acquas et al., 1996; Thiel et al., 1998; Giovannini et al., quency, application of carbachol also decreased the resonance 2001). Entorhinal recordings show that when a rat first enters a strength in stellate cells, which is consistent with reports from novel environment the regular grid lattice expands and becomes Barry et al. (Soc. Neurosci. Abstr. 101.25, 2009) demonstrating a less regular (Barry et al., Soc. Neurosci. Abstr. 101.25, 2009), these decrease in the theta-band modulation of the grids’ spike train. effects occur in addition to the previously reported realignment. The reduction of intrinsic frequency could also contribute to the Individual fields increase in size and move further apart, at the reduction in network theta frequency in the LFP. Cholinergic same time becoming less circular and conform less well to a modulation of other cellular properties could also contribute to hexagonal structure. With repeated exposure to the environment the change in network oscillations, as cholinergic modulation the grid returns to the scale seen in a familiar environment, has been shown to induce oscillations in the hippocampus in becoming more regular at the same time. The initial expansion, interneurons in lacunosum-moleculare (Chapman and Lacaille, which is typically about 40% of the familiar scale, attenuates at a 1999) as well as interneurons in stratum oriens that synapse decreasing rate so that the “novel” grids come to resemble “famil- in lacunosum-moleculare (Lawrence et al., 2006). Cholinergic iar” grids after about four hours of experience. Environmental modulation also regulates rhythmicity in GABAergic cells of the novelty is known to reduce theta frequency measured from the medial septum projecting to the hippocampus (Alreja et al., hippocampal LFP, which exhibits a similar recovery time course 2000). (Jeewajee et al., 2008b). Similarly, the theta-band modulation of What then is the utility of reduced theta frequency and why expanded grids’ spike trains were found to reduce in the novel should this occur in response to environmental novelty? One pro- environment, as did theta measured from the entorhinal LFP posed function of the theta rhythm is to provide a distinction (Barry et al., Soc. Neurosci. Abstr. 101.25, 2009). More specifi- between the circuit dynamics of encoding and retrieval (Hasselmo cally, the reduction in intrinsic firing frequency was found to et al., 2002); reducing interference between patterns being learnt inversely correlate with the increase in scale, indicating a causal and those already stored (see Figure 3). In this model, the encod- link between entorhinal oscillations and grid firing, as posited by ing of new information involves a strong influence of external the oscillatory interference model. afferent input on cortical structures including the hippocampus Increased cholinergic drive, such as that resulting from envi- and entorhinal cortex as well as neocortical regions (Hasselmo ronmental novelty (Acquas et al., 1996; Thiel et al., 1998; et al., 2002). In the hippocampus, this is consistent with the strong Giovannini et al., 2001), reduces hippocampal theta frequency current sinks in stratum lacunosum-moleculare during the peak (Givens and Olton, 1995). Might cholinergic modulation con- of theta recorded in the cell body layer (Brankack et al., 1993). tribute to the reduction in entorhinal theta and concomitant Furthermore, studies of LTP show that stimulation delivered at grid expansion? The potential link between increases in acetyl- this same phase are most effective at producing potentiation choline level and decreases in oscillation frequencies is supported (Huerta and Lisman, 1995; Holscher et al., 1997; Orr et al., 2001; by cellular data on the effects of acetylcholine on stellate cell Hyman et al., 2003). In contrast, the opposite phase of theta is resonance frequency. As noted above, intracellular recording from stellate cells in medial entorhinal cortex allows measure- ment of their intrinsic frequency. In particular, the resonance frequency of these neurons can be measured by delivering a current injection with a sinusoid oscillation that progressively increases in frequency from 0 Hz to 20 Hz over 20 s (Haas and White, 2002; Erchova et al., 2004; Heys et al., 2010). Stellate cells in medial entorhinal cortex show a clear change in amplitude of their membrane potential response to this current injection, increasing amplitude as frequency increases to theta frequen- cies, and then decreasing thereafter. In contrast, neurons in the lateral entorhinal cortex show a decrease in oscillation ampli- tude across the full range of frequencies (Shay et al., 2011). In recent experiments, the resonance frequency of stellate cells was measured before and during application of the cholinergic ago- nist carbachol (Heys et al., 2010). These experiments showed FIGURE 3 | Theta phase is proposed to segment retrieval and encoding a clear decrease in the resonance frequency of stellate cells in phases of mnemonic processing in the hippocampus. Encoding (left) the presence of carbachol. This decrease in resonance frequency occurs around the peak of theta (measured from the cell-layer) when strong appears to arise from a cholinergic reduction in the magnitude current sinks are evident in the lacunosum-moleculare where entorhinal of the hyperpolarization activated cation current (h current), as inputs terminate. Retrieval (right) occurs during the trough of theta when internal connectivity within the hippocampus is more active, producing a shown by voltage clamp studies with carbachol in these same strong current sink in the stratum radiatum. cells (Heys and Hasselmo, Soc. Neurosci. Abstr. 730.09, 2011).

Frontiers in Neural Circuits www.frontiersin.org February 2012 | Volume 6 | Article 5 | 7 Barry et al. Acetylcholine, theta, and grid cells

proposed to play a role in retrieval. In this phase, the internal environments. Grid expansion is likely to induce a mismatch connections of the hippocampus cause a stronger current sink between the expanded firing pattern of grid cells and the more in stratum radiatum (Brankack et al., 1993), and stimulation on stable activity of other sensory inputs to the hippocampus, such as this phase (the trough of theta in stratum pyramidale) causes entorhinal boundary vector cells, which do not remap or expand long-term depression instead of LTP. Thus, this model proposes in novel environments (Solstad et al., 2008; Lever et al., 2009), see a rapid transition between encoding and retrieval during individ- also (Burgess et al., 2007; Burgess, 2008). Additionally, because ual cycles of theta (Hasselmo et al., 2002),butatthesametime grids of different native scales appear to expand by differing slower changes in acetylcholine levels may shift the overall tone of amounts (Barry et al., Soc. Neurosci. Abstr. 101.25, 2009) they may the network more toward encoding. Such a shift is consistent with also produce a mismatch relative to one another (see Figure 4). unit recording studies that have shown a change in the phase of This differential expansion may occur if populations of grid cell spiking with novel stimuli (Manns et al., 2007) or in novel envi- or VCOs exhibit different sensitivity to acetylcholine [e.g., Shulz ronments (Lever et al., 2010). In fact, a possible mechanism for et al. (2000)], alternatively it might simply be a product of local theshiftmaybeanincreaseinthedurationoftheencodingphase variations in the concentration of extracellular acetylcholine. A of the theta cycle, which would allow more effective encoding further source of mismatch may be the realignment of different and arise from the decrease in theta frequency observed in novel scaled grids which occurs between distinct environments (Fyhn environments (Jeewajee et al., 2008a,b; Barry et al., Soc. Neurosci. et al., 2007). Together these effects would result in a significant Abstr. 101.25, 2009). change in the medial entorhinal input to the hippocampus, essen- In addition to moving the network toward a state that favors tially orthogonalizing the pattern of activity being presented to encoding, increased cholinergic modulation may, as we have CA3 and CA1. It seems possible then that this change would described, provoke the increase in grid scale seen in novel drive remapping of the hippocampal place cells, causing a new

FIGURE 4 | Grid expansion as a source of mismatch. Top row, cartoon small and large grid do not shift relative to one another. The pattern of showing the spatial activity of two idealized grid cells in a square overlap is expanded (by 50%) relative to the first row but is otherwise environment, a small-scale grid is shown in red and larger scale grid unchanged; the area of largest overlap (red cross) is shifted only slightly (1.7x larger than the small grid) in blue. Panel to the right shows areas relative to the unexpanded situation. Bottom row, an uneven expansion where the firing of the two grids overlap (gray), the red cross indicates the (small grid expands by 75% but large by only 25%, again focus is center area of largest overlap. Middle row, grid activity from the first row with a 50% of environment) causes fields from the two grids to move relative to the expansion applied to both the small and large grid (expansion focused on the environment but also relative to one another, producing an additional center of the environment). Fields from both grids are translocated relative to source of mismatch. The pattern of overlap shown in gray is dissimilar to the environment and will likely “mismatch” with spatial inputs, such as the previous rows and the site of maximum overlap is completely boundary vector cells that do not expand or remap. However, the fields of the changed.

Frontiers in Neural Circuits www.frontiersin.org February 2012 | Volume 6 | Article 5 | 8 Barry et al. Acetylcholine, theta, and grid cells

representation to be formed for the current environment. This entorhinal cortex and hippocampus is augmented (Acquas et al., view is supported by a recent computational study showing that 1996). Increased cholinergic tone causes a reduction in the fre- distinct patterns of hippocampal activity could be generated by quency of theta-band oscillations in the hippocampal formation shiftedorexpandedgridinputs(Monaco and Abbott, 2011). As (Givens and Olton, 1995), a state which may favor encoding well as initiating hippocampal remapping, the orthogonalized and likely contributes to the expansion and reorganization of input would also enhance the dynamics of encoding: Because the grid firing seen in novel environments (Fyhn et al., 2007;Barry expanded pattern of entorhinal activity is distinct from stored et al., Soc. Neurosci. Abstr. 101.25, 2009). In turn, this imme- patterns encoding familiar environments interference produced diate and pronounced change in grid cell activity is expected by inappropriate retrieval would be reduced further (Hasselmo to push the entorhinal input to the hippocampus away from et al., 2002; Hasselmo, 2005). After the initial expansion, subse- previously learnt states, instigating remapping, and supporting quent exposure to a novel environment produces an incremental accurate encoding (Hasselmo et al., 2002). This dynamic mech- reduction in grid scale until, after several days, grids are the anism is consistent with the established view of acetylcholine as same size as those in a familiar environment (Barry et al., Soc. an important controller of mnemonic function and fits with the Neurosci. Abstr. 101.25, 2009). This contraction is accompanied mechanisms that have already been proposed to support this role, by a gradual increase in theta frequency from the LFP and grid for example, the enhancement of LTP (Blitzer et al., 1990; Huerta spike trains (Jeewajee et al., 2008b; Barry et al., Soc. Neurosci. and Lisman, 1995; Patil et al., 1998; Adams et al., 2004), eleva- Abstr. 101.25, 2009), and presumably is mediated by a reduc- tion of feedforward over feedback connectivity (Hasselmo and tion in cholinergic drive from the medial septum, which also Bower, 1992; Gil et al., 1997), and maintenance of input pat- attenuates with familiarity (Thiel et al., 1998). Unlike the sud- terns (Hasselmo and Stern, 2006). Similarly, existing research den increase in scale provoked by environmental novelty, the (Huerta and Lisman, 1995; Holscher et al., 1997; Hyman et al., gradual reversion to a native scale does not cause hippocampal 2003), in particular computational modeling (Hasselmo et al., remapping, although place fields do exhibit a slight reduction in 2002), suggests a role for hippocampal theta in the segmenta- scale with experience (Karlsson and Frank, 2008; Barry et al., Soc. tion of encoding and retrieval. The mechanism proposed here Neurosci. Abstr. 101.25, 2009). It seems likely that the slower rate builds on those existing ideas and demonstrates how they may be of change in the latter case does not generate a mismatch signal, tailored to an animal’s current conditions, for example, biasing possibly providing time for slow plastic processes to update the the efficacy of encoding when confronted with a new or changed mapping between entorhinal grids and hippocampal place cells environment. (Lever et al., 2002). We have described a circuit for the detection and encod- ACKNOWLEDGMENTS ing of novelty, in particular environmental novelty, in which This work was supported by ONR MURI award N000141010936 cholinergic modulation of theta frequency both triggers and aug- and NIH R01 MH61492 and R01 MH60013, USA. Caswell ments the formation of new memories. In response to novel Barry additionally supported by the Wellcome Trust and EU stimuli, cholinergic signaling from the medial septum to the SPACEBRAIN.

REFERENCES impulse flow in the septohippocam- spatial cognition: properties of a lat- Moser, E. I., and Moser, M. B. Acquas, E., Wilson, C., and Fibiger, H. pal GABA but not cholinergic path- eralized homing pigeon hippocam- (2010). Grid cells in pre- and C. (1996). Conditioned and uncon- way: implications for learning and pus. Rev. Neurosci. 17, 17–28. parasubiculum. Nat. Neurosci. 13, ditioned stimuli increase frontal memory. J. Neurosci. 20, 8103–8110. Blair, H. T., Welday, A. C., and Zhang, 987–994. cortical and hippocampal acetyl- Bang, S. J., and Brown, T. H. (2009). K. (2007). Scale-invariant memory Bostock, E., Muller, R. U., and Kubie, choline release: effects of novelty, Muscarinic receptors in perirhinal representations emerge from moire J. L. (1991). Experience-dependent habituation, and fear. J. Neurosci. cortex control trace conditioning. interference between grid fields that modifications of hippocampal place 16, 3089–3096. J. Neurosci. 29, 4346–4350. produce theta oscillations: a com- cell firing. Hippocampus 1, 193–206. Adams, S. V., Winterer, J., and Muller, Barkai, E., and Hasselmo, M. E. (1994). putational model. J. Neurosci. 27, Brandon, M. P., Bogaard, A. R., Libby, W. (2004). Muscarinic signaling is Modulation of the input/output 3211–3229. C.P.,Connerney,M.A.,Gupta, required for spike-pairing induc- function of rat piriform cortex pyra- Bland, B. H. (1986). The physiology K., and Hasselmo, M. E. (2011). tion of long-term potentiation at midal cells. J. Neurophysiol. 72, and pharmacology of hippocampal- Reduction of theta rhythm dis- rat Schaffer collateral-CA1 synapses. 644–658. formation theta rhythms. Prog. sociates grid cell spatial periodic- Hippocampus 14, 413–416. Barry, C., Hayman, R., Burgess, N., Neurobiol. 26, 1–54. ity from directional tuning. Science Aigner, T. G., and Mishkin, M. (1986). and Jeffery, K. J. (2007). Experience- Blitzer, R. D., Gil, O., and Landau, E. 332, 595–599. The effects of physostigmine and dependent rescaling of entorhinal M. (1990). Cholinergic stimulation Brankack, J., Stewart, M., and Fox, S. scopolamine on recognition mem- grids. Nat. Neurosci. 10, 682–684. enhances long-term potentiation in E. (1993). Current source density ory in monkeys. Behav. Neurosci. 45, Baxter, M. G., Bucci, D. J., Gorman, the CA1 region of rat hippocampus. analysis of the hippocampal theta 81–87. L.K.,Wiley,R.G.,andGallagher, Neurosci. Lett. 119, 207–210. rhythm: associated sustained poten- Alonso, A., and Klink, R. (1993). M. (1995). Selective immunotoxic Blokland, A., Honig, W., and tials and candidate synaptic genera- Differential electroresponsiveness of lesions of basal forebrain cholin- Raaijmakers, W. G. M. (1992). tors. Brain Res. 615, 310–327. stellate and pyramidal-like cells of ergic cells: effects on learning and Effects of intra-hippocampal scopo- Brazhnik, E. S., Muller, R. U., and Fox, medial entorhinal cortex layer II. memory in rats. Behav. Neurosci. lamine injections in a repeated S. E. (2003). Muscarinic blockade J. Neurophysiol. 70, 128–143. 109, 714–722. spatial acquisition task in the rat. slows and degrades the location- Alreja, M., Wu, M., Liu, W., Atkins, J. Bingman, V. P., Siegel, J. J., Gagliardo, Psychopharmacology 109, 373–376. specific firing of hippocampal B., Leranth, C., and Shanabrough, A., and Erichsen, J. T. (2006). Boccara, C. N., Sargolini, F., Thoresen, pyramidal cells. J. Neurosci. 23, M. (2000). Muscarinic tone sustains Representing the richness of avian V. H., Solstad, T., Witter, M. P., 611–621.

Frontiers in Neural Circuits www.frontiersin.org February 2012 | Volume 6 | Article 5 | 9 Barry et al. Acetylcholine, theta, and grid cells

Brocher, S., Artola, A., and Singer, pyramidal cells. J. Physiol. 352, Gais, S., and Born, J. (2004). Low scopolamine-induced working W. (1992). Agonists of cholinergic 173–188. acetylcholine during slow-wave memory impairment by muscarinic and noradrenergic receptors facili- Doeller, C. F., Barry, C., and Burgess, sleep is critical for declarative mem- activation of the medial septal tate synergistically the induction of N. (2010). Evidence for grid cells in ory consolidation. Proc. Natl. Acad. area. Neurobiol. Learn. Mem. 63, long-term potentiation in slices of a human memory network. Nature Sci. U.S.A. 101, 2140–2144. 269–276. rat visual cortex. Brain Res. 573, 463, 657–661. Geisler, C., Robbe, D., Zugaro, M., Givens, B. S., and Olton, D. S. (1990). 27–36. Easton, A., Fitchett, A. E., Eacott, M. Sirota, A., and Buzsaki, G. (2007). Cholinergic and GABAergic mod- Bunce, J. G., Sabolek, H. R., and J., and Baxter, M. G. (2011). Medial Hippocampal place cell assemblies ulation of the medial septal area: Chrobak, J. J. (2004). Intraseptal septal cholinergic neurons are are speed-controlled oscillators. effect on working memory. Behav. infusion of the cholinergic agonist necessary for context-place memory Proc. Natl. Acad. Sci. U.S.A. 104, Neurosci. 104, 849–855. carbachol impairs delayed-non- but not episodic-like memory. 8149–8154. Green, A., Ellis, K. A., Ellis, J., match-to-sample radial arm Hippocampus 21, 1021–1027. Ghoneim, M. M., and Mewaldt, S. P. Bartholomeusz, C. F., Ilic, S., maze performance in the rat. Ekstrom, A. D., Kahana, M. J., Caplan, (1975). Effects of diazepam and Croft, R. J., Luan Phan, K., and Hippocampus 14, 450–459. J.B.,Fields,T.A.,Isham,E. scopolamine on storage, retrieval Nathan, P. J. (2005). Muscarinic Burak, Y., and Fiete, I. R. (2009). A., Newman, E. L., and Fried, I. and organizational processes in and nicotinic receptor modula- Accurate in con- (2003). Cellular networks under- memory. Psychopharmacologia 44, tion of object and spatial n-back tinuous attractor network mod- lying human spatial navigation. 257–262. working memory in humans. els of grid cells. PLoS Comput. Nature 425, 184–188. Gil,Z.,Conners,B.W.,andAmitai, Pharmacol. Biochem. Behav. 81, Biol. 5, e1000291. doi: 10.1371/jour- Elvander, E., Schott, P. A., Sandin, J., Y. (1997). Differential regulation 575–584. nal.pcbi.1000291 Bjelke, B., Kehr, J., Yoshitake, T., of neocortical synapses by neuro- Haas, J. S., and White, J. A. (2002). Buresova, O., Bolhuis, J. J., and Bures, and Ogren, S. O. (2004). Intraseptal modulators and activity. 19, Frequency selectivity of layer II stel- J. (1986). Differential effects of muscarinic ligands and galanin: 679–686. late cells in the medial entorhi- cholinergic blockade on perfor- influence on hippocampal acetyl- Giocomo, L. M., and Hasselmo, M. nal cortex. J. Neurophysiol. 88, mance of rats in the water tank choline and cognition. Neuroscience E. (2008a). Computation by oscilla- 2422–2429. navigation task and in a radial 126, 541–557. tions: implications of experimental Hafting, T., Fyhn, M., Bonnevie, T., water maze. Behav. Neurosci. 100, Erchova, I., Kreck, G., Heinemann, U., data for theoretical models of grid Moser, M. B., and Moser, E. I. 476–482. and Herz, A. V. (2004). Dynamics of cells. Hippocampus 18, 1186–1199. (2008). Hippocampus-independent Burgalossi, A., Herfst, L., von rat entorhinal cortex layer II and III Giocomo, L. M., and Hasselmo, M. E. phase precession in entorhinal grid Heimendahl, M., Forste, H., cells: characteristics of membrane (2008b). Time constants of h cur- cells. Nature 453, 1248–1252. Haskic,K.,andSchmidt,M.B.M. potential resonance at rest predict rent in layer II stellate cells dif- Hafting, T., Fyhn, M., Molden, S., (2011). Microcircuits of function- oscillation properties near thresh- fer along the dorsal to ventral axis Moser, M. B., and Moser, E. I. ally identified neurons in the rat old. J. Physiol. 560, 89–110. of medial entorhinal cortex. J. (2005). Microstructure of a spa- medial entorhinal cortex. Neuron Esclassan, F., Coutureau, E., Di Scala, Neurosci. 28, 9414–9425. tial map in the entorhinal cortex. 70, 773–786. G., and Marchand, A. R. (2009). Giocomo, L. M., and Hasselmo, Nature 436, 801–806. Burgess, N. (2008). Grid cells and theta A cholinergic-dependent role for M. E. (2009). Knock-out of Hagan, J. J., Salamone, J. D., Simpson, as oscillatory interference: theory the entorhinal cortex in trace HCN1 subunit flattens dorsal- J.,Iversen,S.D.,andMorris,R. and predictions. Hippocampus 18, fear conditioning. J. Neurosci. 29, ventral frequency gradient of G. M. (1988). Place navigation in 1157–1174. 8087–8093. medial entorhinal neurons in adult rats is impaired by lesions of medial Burgess, N., Barry, C., and O’Keefe, Fischer, Y., Gahwiler, B. H., and mice. J. Neurosci. 29, 7625–7630. septum and diagonal band but J. (2007). An oscillatory interfer- Thompson, S. M. (1999). Activation Giocomo, L. M., Hussaini, S. A., Zheng, not nucleus basalis magnocellularis. ence model of grid cell firing. of intrinsic hippocampal theta F.,Kandel,E.R.,Moser,M.B.,and Behav. Brain Res. 27, 9–20. Hippocampus 17, 801–812. oscillations by acetylcholine in Moser, E. I. (2011a). Grid cells use Hartley, T., Burgess, N., Lever, C., Burgess, N., Recce, M., and O’Keefe, rat septo-hippocampal cocultures. HCN1 channels for spatial scaling. Cacucci, F., and O’Keefe, J. (2000). J. (1994). A model of hippocam- J. Physiol. 519(Pt 2), 405–413. Cell 147, 1159–1170. Modeling place fields in terms of the pal function. Neural Netw. 7, Foster, T. C., and Deadwyler, S. A. Giocomo, L. M., Moser, M. B., and cortical inputs to the hippocampus. 1065–1081. (1992). Acetylcholine modulates Moser, E. I. (2011b). Computational Hippocampus 10, 369–379. Buzsaki, G. (1989). Two-stage model of averaged sensory evoked responses models of grid cells. Neuron 71, Hasselmo, M. E. (1999). Neuro- memory trace formation: a role for and perforant path evoked field 589–603. modulation: acetylcholine and “noisy” brain states. Neuroscience potentials in the rat dentate gyrus. Giocomo,L.M.,Zilli,E.A.,Fransen, memory consolidation. Trends 31, 551–570. Brain Res. 587, 95–101. E., and Hasselmo, M. E. (2007). Cogn. Sci. 3, 351–359. Buzsaki, G. (2002). Theta oscillations Freund, T. F., and Antal, M. (1988). Temporal frequency of subthreshold Hasselmo, M. E. (2005). What is the in the hippocampus. Neuron 33, GABA-containing neurons in the oscillations scales with entorhinal function of hippocampal theta 325–340. septum control inhibitory interneu- grid cell field spacing. Science 315, rhythm? – Linking behavioral Cantero, J. L., Atienza, M., Stickgold, rons in the hippocampus. Nature 1719–1722. data to phasic properties of field R., Kahana, M. J., Madsen, J. 336, 170–173. Giovannini, M. G., Rakovska, A., potential and unit recording data. R., and Kocsis, B. (2003). Sleep- Fuhs, M. C., and Touretzky, D. S. Benton, R. S., Pazzagli, M., Bianchi, Hippocampus 15, 936–949. dependent theta oscillations in the (2006). A spin glass model of path L., and Pepeu, G. (2001). Effects of Hasselmo, M. E. (2006). The role human hippocampus and neocor- integration in rat medial entorhinal novelty and habituation on acetyl- of acetylcholine in learning and tex. J. Neurosci. 23, 10897–10903. cortex. J. Neurosci. 26, 4266–4276. choline, GABA, and glutamate memory. Curr. Opin. Neurobiol. 16, Chapman, C. A., and Lacaille, J. C. Fyhn, M., Hafting, T., Treves, A., Moser, release from the frontal cortex and 710–715. (1999). Cholinergic induction of M. B., and Moser, E. I. (2007). hippocampus of freely moving rats. Hasselmo, M. E., Anderson, B. P., and theta-frequency oscillations in hip- Hippocampal remapping and grid Neuroscience 106, 43–53. Bower, J. M. (1992). Cholinergic pocampal inhibitory interneurons realignment in the entorhinal cor- Givens, B., and Olton, D. S. (1994). modulation of cortical associative and pacing of pyramidal cell firing. tex. Nature 446, 190–194. Local modulation of basal fore- memory function. J. Neurophysiol. J. Neurosci. 19, 8637–8645. Fyhn,M.,Molden,S.,Witter,M.P., brain: effects on working and ref- 67, 1230–1246. Cole, A. E., and Nicoll, R. A. (1984). Moser, E. I., and Moser, M. B. erence memory. J. Neurosci. 14, Hasselmo, M. E., Bodelon, C., and Characterization of a slow choliner- (2004). Spatial representation in 3578–3587. Wyble, B. P. (2002). A proposed gic postsynaptic potential recorded the entorhinal cortex. Science 305, Givens, B., and Olton, D. S. (1995). function for hippocampal theta in vitro from rat hippocampal 1258–1264. Bidirectional modulation of rhythm: separate phases of encoding

Frontiers in Neural Circuits www.frontiersin.org February 2012 | Volume 6 | Article 5 | 10 Barry et al. Acetylcholine, theta, and grid cells

and retrieval enhance reversal of Huxter, J., Burgess, N., and O’Keefe, Kramis,R.,Vanderwolf,C.H.,and Manns,J.R.,Zilli,E.A.,Ong,K.C., prior learning. Neural Comput. 14, J. (2003). Independent rate and Bland, B. H. (1975). Two types of Hasselmo, M. E., and Eichenbaum, 793–817. temporal coding in hippocam- hippocampal rhythmical slow activ- H. (2007). Hippocampal CA1 spik- Hasselmo, M. E., and Bower, J. M. pal pyramidal cells. Nature 425, ity in both the rabbit and the rat: ing during encoding and retrieval: (1992). Cholinergic suppression 828–832. relations to behavior and effects relation to theta phase. Neurobiol. specific to intrinsic not afferent Hyman,J.M.,Wyble,B.P.,Goyal,V., of atropine, diethyl ether, urethane, Learn. Mem. 87, 9–20. fiber synapses in rat piriform (olfac- Rossi, C. A., and Hasselmo, M. E. and pentobarbital. Exp. Neurol. 49, Markowska, A. L., Olton, D. S., Murray, tory) cortex. J. Neurophysiol. 67, (2003). Stimulation in hippocam- 58–85. E. A., and Gaffan, D. (1989). A com- 1222–1229. pal region CA1 in behaving rats Kremin, T., and Hasselmo, M. E. parative analysis of the role of fornix Hasselmo, M. E., and Bower, J. M. yields long-term potentiation when (2007). Cholinergic suppression of and cingulate cortex in memory: (1993). Acetylcholine and memory. delivered to the peak of theta and glutamatergic synaptic transmission rats. Exp. Brain Res. 74, 187–201. Trends Neurosci. 6, 218–222. long-term depression when deliv- in hippocampal region CA3 exhibits Marrosu, F., Portas, C., Mascia, M. S., Hasselmo, M. E., and Brandon, M. P. ered to the trough. J. Neurosci. 23, laminar selectivity: implication for Casu, M. A., Fa, M., Giagheddu, (2012). A model combining phase 11725–11731. hippocampal network dynamics. M.,Imperato,A.,andGessa,G.L. coding and continuous attractors Jeewajee, A., Barry, C., O’Keefe, J., Neuroscience 149, 760–767. (1995). Microdialysis measurement for generation of grid cell firing. and Burgess, N. (2008a). Grid cells Kropff, E., and Treves, A. (2008). of cortical and hippocampal acetyl- Front. Neural Circuits, this issue. and theta as oscillatory interfer- The emergence of grid cells: intel- choline release during sleep-wake Hasselmo, M. E., Giocomo, L. M., and ence: electrophysiological data from ligent design or just adaptation? cycle in freely moving cats. Brain Zilli, E. A. (2007). Grid cell fir- freely moving rats. Hippocampus 18, Hippocampus 18, 1256–1269. Res. 671, 329–332. ing may arise from interference of 1175–1185. Kwag, J., and Paulsen, O. (2009). The McGaughy, J., Koene, R. A., theta frequency membrane poten- Jeewajee, A., Lever, C., Burton, S., timing of external input controls the Eichenbaum, H., and Hasselmo, tial oscillations in single neurons. O’Keefe, J., and Burgess, N. (2008b). sign of plasticity at local synapses. M. E. (2005). Cholinergic deaf- Hippocampus 17, 1252–1271. Environmental novelty is signaled Nat. Neurosci. 12, 1219–1221. ferentation of the entorhinal Hasselmo, M. E., and Schnell, E. by reduction of the hippocampal Lawrence,J.J.,Grinspan,Z.M., cortex in rats impairs encoding of (1994). Laminar selectivity of the theta frequency. Hippocampus 18, Statland, J. M., and McBain, C. novel but not familiar stimuli in a cholinergic suppression of synap- 340–348. J. (2006). Muscarinic receptor delayed nonmatch-to-sample task. tic transmission in rat hippocampal Jensen, O., and Lisman, J. E. (2000). activation tunes mouse stratum J. Neurosci. 25, 10273–10281. region CA1: computational model- Position reconstruction from oriens interneurones to amplify McGurk,S.R.,Levin,E.D.,and ing and brain slice physiology. J. an ensemble of hippocampal spike reliability. J. Physiol. 571, Butcher, L. L. (1988). Cholinergic- Neurosci. 14, 3898–3914. place cells: contribution of theta 555–562. dopaminergic interactions in Hasselmo, M. E., Schnell, E., and phase coding. J. Neurophysiol. 83, Lee, M. G., Chrobak, J. J., Sik, A., radial-arm maze performance. Barkai, E. (1995). Dynamics of 2602–2609. Wiley, R. G., and Buzsaki, G. (1994). Behav. Neural Biol. 49, 234–239. learning and recall at excitatory Kahana, M. J., Sekuler, R., Caplan, J. Hippocampal theta activity follow- McNaughton, B. L., Battaglia, F. P., recurrent synapses and choliner- B., Kirschen, M., and Madsen, J. ing selective lesion of the septal Jensen, O., Moser, E. I., and Moser, gic modulation in rat hippocam- R. (1999). Human theta oscillations cholinergic system. Neuroscience 62, M. B. (2006). Path integration and pal region CA3. J. Neurosci. 15, exhibit task dependence during vir- 1033–1047. the neural basis of the “cogni- 5249–5262. tual maze navigation. Nature 399, Lengyel, M., Szatmary, Z., and Erdi, tive map”. Nat. Rev. Neurosci. 7, Hasselmo, M. E., and Stern, C. E. 781–784. P. (2003). Dynamically detuned 663–678. (2006). Mechanisms underly- Karlsson, M. P., and Frank, L. M. oscillations account for the cou- Mitchell, S. J., Rawlins, J. N., Steward, ing working memory for novel (2008). Network dynamics under- pled rate and temporal code of O., and Olton, D. S. (1982). Medial information. Trends Cogn. Sci. 10, lying the formation of sparse, place cell firing. Hippocampus 13, septal area lesions disrupt theta 487–493. informative representations in 700–714. rhythm and cholinergic staining in Heys,J.G.,Giocomo,L.M., the hippocampus. J. Neurosci. 28, Lever, C., Burton, S., Jeewajee, A., medial entorhinal cortex and pro- and Hasselmo, M. E. (2010). 14271–14281. O’Keefe, J., and Burgess, N. (2009). duce impaired radial arm maze Cholinergic modulation of the Kimura, F., and Baughman, R. W. Boundary vector cells in the subicu- behavior in rats. J. Neurosci. 2, resonance properties of stellate (1997). Distinct muscarinic recep- lum of the hippocampal formation. 292–302. cells in layer II of medial entorhi- tor subtypes suppress excitatory and J. Neurosci. 29, 9771–9777. Mizumori, S. J., Perez, G. M., nal cortex. J. Neurophysiol. 104, inhibitory synaptic responses in cor- Lever, C., Burton, S., Jeewajee, A., Wills, Alvarado, M. C., Barnes, C. A., 258–270. tical neurons. J. Neurophysiol. 77, T.J.,Cacucci,F.,Burgess,N.,and and McNaughton, B. L. (1990a). Holscher, C., Anwyl, R., and Rowan, 709–716. O’Keefe, J. (2010). Environmental Reversible inactivation of the M. J. (1997). Stimulation on the King, C., Reece, M., and O’Keefe, J. novelty elicits a later theta phase of medial septum differentially affects positive phase of hippocampal theta (1998). The rhythmicity of cells of firing in CA1 but not subiculum. two forms of learning in rats. Brain rhythm induces long-term potenti- the medial septum/diagonal band Hippocampus 20, 229–234. Res. 528, 12–20. ation that can be depotentiated by of Broca in the awake freely mov- Lever, C., Wills, T., Cacucci, F., Burgess, Mizumori,S.J.Y.,Barnes,C.A., stimulation on the negative phase ing rat: relationships with behaviour N., and O’Keefe, J. (2002). Long- and Mcnaughton, B. L. (1989). in area CA1 in vivo. J. Neurosci. 17, and hippocampal theta. Eur. J. term plasticity in hippocampal Reversible inactivation of the 6470–6477. Neurosci. 10, 464–477. place-cell representation of envi- medial septum-selective effects on Hori,E.,Tabuchi,E.,Matsumura,N., Klink, R., and Alonso, A. (1997). ronmental geometry. Nature 416, the spontaneous unit-activity of Tamura, R., Eifuku, S., Endo, S., Muscarinic modulation of the oscil- 90–94. different hippocampal cell-types. Nishijo, H., and Ono, T. (2003). latory and repetitive firing prop- Madison, D. V., Lancaster, B., and Brain Res. 500, 99–106. Representation of place by monkey erties of entorhinal cortex layer Nicoll, R. A. (1987). Voltage clamp Mizumori,S.J.Y.,Barnes,C.A., hippocampal neurons in real and II neurons. J. Neurophysiol. 77, analysis of cholinergic action in and Mcnaughton, B. L. (1990b). virtual translocation. Hippocampus 1813–1828. the hippocampus. J. Neurosci. 7, Behavioral-correlates of theta-on 13, 190–196. Koenig, J., Linder, A. N., Leutgeb, J. 733–741. and theta-off cells recorded from Huerta, P. T., and Lisman, J. E. (1995). K., and Leutgeb, S. (2011). The Madison, D. V., and Nicoll, R. A. hippocampal-formation of mature Bidirectional synaptic plasticity spatial periodicity of grid cells (1984). Control of the repetitive young and aged rats. Exp. Brain Res. induced by a single burst during is not sustained during reduced discharge of rat CA 1 pyramidal 80, 365–373. cholinergic theta oscillation in CA1 theta oscillations. Science 332, neurones in vitro. J. Physiol. 354, Monaco, J. D., and Abbott, L. F. (2011). in vitro. Neuron 15, 1053–1063. 592–595. 319– 331. Modular realignment of entorhinal

Frontiers in Neural Circuits www.frontiersin.org February 2012 | Volume 6 | Article 5 | 11 Barry et al. Acetylcholine, theta, and grid cells

grid cell activity as a basis for hip- Rasch, B. H., Born, J., and Gais, Stensland, H., Kirkesola, T., Moser, immobility. Can. J. Psychol. 26, pocampal remapping. J. Neurosci. S. (2006). Combined blockade of M. B., and Moser, E. I. (2010). 219–239. 31, 9414–9425. cholinergic receptors shifts the brain Orientational geometry of entorhi- Whishaw, I. Q. (1985). Cholinergic Monmaur, P., Collet, A., Puma, C., from stimulus encoding to memory nal grid cells. Soc. Neurosci. Abstr. receptor blockade in the rat impairs Frankel-Kohn, L., and Sharif, A. consolidation. J. Cogn. Neurosci. 18, 36, 101.14. locale but not taxon strategies (1997). Relations between acetyl- 793–802. Stewart, M., and Fox, S. E. (1990). Do for place navigation in a swim- choline release and electrophys- Rawlins, J. N., Feldon, J., and Gray, J. septal neurons pace the hippocam- ming pool. Behav. Neurosci. 99, iological characteristics of theta A. (1979). Septo-hippocampal con- pal theta rhythm? Trends Neurosci. 979–1005. rhythm: a microdialysis study in nections and the hippocampal theta 13, 163–168. Whishaw, I. Q., and Vanderwolf, C. the urethane-anesthetized rat hip- rhythm. Exp. Brain Res. 37, 49–63. Tang, Y., Mishkin, M., and Aigner, H. (1973). Hippocampal EEG and pocampus. Brain Res. Bull. 42, Remme,M.W.,Lengyel,M.,and T. G. (1997). Effects of muscarinic behavior: changes in amplitude and 141–146. Gutkin, B. S. (2010). Democracy- blockade in perirhinal cortex during frequency of RSA (theta rhythm) Muller, R. U., and Kubie, J. L. (1987). independence trade-off in oscillat- visual recognition. Proc. Natl. Acad. associated with spontaneous The effects of changes in the envi- ing dendrites and its implications Sci. U.S.A. 94, 12667–12669. and learned movement patterns ronment on the spatial firing of for grid cells. Neuron 66, 429–437. Thiel, C. M., Huston, J. P., and in rats and cats. Behav. Biol. 8, hippocampal complex-spike cells. Rogers, J. L., and Kesner, R. P. (2003). Schwarting, R. K. (1998). 461–484. J. Neurosci. 7, 1951–1968. Cholinergic modulation of the hip- Hippocampal acetylcholine and Wilson,M.A.,andMcNaughton,B. Muller, R. U., Kubie, J. L., and Ranck, J. pocampus during encoding and habituation learning. Neuroscience L. (1994). Reactivation of hip- B. Jr. (1987). Spatial firing patterns retrieval. Neurobiol. Learn. Mem. 80, 85, 1253–1262. pocampal ensemble memories dur- of hippocampal complex-spike cells 332–342. Turchi,J.,Saunders,R.C.,andMishkin, ing sleep. Science 265, 676–679. in a fixed environment. J. Neurosci. Sainsbury,R.S.,Heynen,A.,and M. (2005). Effects of cholinergic Winson, J. (1976). Hippocampal theta 7, 1935–1950. Montoya, C. P. (1987). Behavioral deafferentation of the rhinal cor- rhythmn. II. Depth profiles in the Navratilova, Z., Giocomo, L. M., correlates of hippocampal type 2 tex on visual recognition memory freely moving rabbit. Brain Res. 103, Fellous, J. M., Hasselmo, M. E., theta in the rat. Physiol. Behav. 39, in monkeys. Proc. Natl. Acad. Sci. 71–79. and McNaughton, B. L. (2011). 513–519. U.S.A. 102, 2158–2161. Winson, J. (1978). Loss of hippocampal Phase precession and variable spa- Shapiro, M. L., Simon, D. K., Olton, Ulanovsky, N., and Moss, C. F. (2007). theta rhythm results in spatial mem- tial scaling in a periodic attractor D. S., Gage, F. H. 3rd., Nilsson, Hippocampal cellular network ory deficit in the rat. Science 201, map model of medial entorhinal O., and Bjorklund, A. (1989). activity in freely moving echolo- 160–163. grid cells with realistic after-spike Intrahippocampal grafts of fetal cating bats. Nat. Neurosci. 10, Winson, J., and Abzug, C. (1977). dynamics. Hippocampus [Epub basal forebrain tissue alter place 224–233. Gating of neuronal transmission in ahead of print]. fields in the hippocampus of Vanderwolf, C. H. (1969). the hippocampus: efficacy of trans- O’Keefe, J., and Burgess, N. (2005). rats with fimbria-fornix lesions. Hippocampal electrical activ- mission varies with behavioral state. Dual phase and rate coding in Neuroscience 32, 1–18. ity and voluntary movement in Science 196, 1223–1225. hippocampal place cells: theoreti- Shay, C. F., Boardman, I. S., James, N. the rat. Electroencephalogr. Clin. Winters, B. D., and Bussey, T. J. (2005). cal significance and relationship to M., and Hasselmo, M. E. (2011). Neurophysiol. 26, 407–418. Removal of cholinergic input to entorhinal grid cells. Hippocampus Comparison of resonance frequency Vanderwolf, C. H. (1971). Limbic- perirhinal cortex disrupts object 15, 853–866. at diffeent membrane potentials in diencephalic mechanisms of volun- recognition but not spatial working O’Keefe, J., and Dostrovsky, J. (1971). rat medial and lateral entorhinal tary movement. Psychol. Rev. 78, memory in the rat. Eur. J. Neurosci. The hippocampus as a spatial map. cortex. Soc. Neurosci. Abstr. 730.12. 83–113. 21, 2263–2270. Preliminary evidence from unit Shulz, D. E., Sosnik, R., Ego, V., Vanderwolf, C. H. (2001). The hip- Winters, B. D., Saksida, L. M., and activity in the freely-moving rat. Haidarliu, S., and Ahissar, E. pocampus as an olfacto-motor Bussey, T. J. (2006). Paradoxical Brain Res. 34, 171–175. (2000). A neuronal analogue of mechanism: were the classical facilitation of object recogni- O’Keefe, J., and Nadel, L. (1978). The state-dependent learning. Nature anatomists right after all? Behav. tion memory after infusion of Hippocampus as a . 403, 549–552. Brain Res. 127, 25–47. scopolamine into perirhinal cor- Oxford, UK: Oxford University Simon, A. P., Poindessous-Jazat, F., Vanderwolf, C. H., Kramis, R., tex: implications for cholinergic Press. Dutar, P., Epelbaum, J., and Bassant, and Robinson, T. E. (1977). system function. J. Neurosci. 26, O’Keefe, J., and Recce, M. L. (1993). M. (2006). Firing properties of Hippocampal electrical activity 9520–9529. Phase relationship between hip- anatomically identified neurons in during waking behaviour and sleep: Yartsev, M. M., Witter, M. P., and pocampal place units and the EEG the medial septum of anestheized analyses using centrally acting Ulanovsky, N. (2011). Grid cells theta rhythm. Hippocampus 3, and unanesthetized restrained rats. drugs. Ciba.Found.Symp.58, without theta oscillations in the 317–330. J. Neurosci. 26, 9038–9046. 199–226. entorhinal cortex of bats. Nature Orr, G., Rao, G., Houston, F. P., Siok,C.J.,Rogers,J.A.,Kocsis,B., Vogt, K. E., and Regehr, W. G. (2001). 479, 103–107. McNaughton, B. L., and Barnes, and Hajos, M. (2006). Activation Cholinergic modulation of excita- Yoder, R. M., and Pang, K. C. (2005). C. A. (2001). Hippocampal synap- of alpha7 acetylcholine receptors tory synaptic transmission in the Involvement of GABAergic and tic plasticity is modulated by augments stimulation-induced hip- CA3 area of the hippocampus. J. cholinergic medial septal neurons theta rhythm in the fascia den- pocampal theta oscillation. Eur. J. Neurosci. 21, 75–83. in hippocampal theta rhythm. tata of adult and aged freely Neurosci. 23, 570–574. Welday, A. C., Shlifer, I. G., Bloom, Hippocampus 15, 381–392. behaving rats. Hippocampus 11, Skaggs, W. E., McNaughton, B. L., M.L.,Zhang,K.,andBlair,H.T. Yun, S. H., Cheong, M. Y., Mook-Jung, 647–654. Wilson,M.A.,andBarnes,C. (2011). Cosine directional tuning I.,Huh,K.,Lee,C.,andJung,M. Patil, M. M., Linster, C., Lubenov, A. (1996). Theta phase precession of theta cell burst frequencies: evi- W. (2000). Cholinergic modulation E., and Hasselmo, M. E. (1998). in hippocampal neuronal popula- dence for spatial coding by oscil- of synaptic transmission and plas- Cholinergic agonist carbachol tions and the compression of tem- latory interference. J. Neurosci. 31, ticity in entorhinal cortex and hip- enables associative long-term poral sequences. Hippocampus 6, 16157–16176. pocampus of the rat. Neuroscience potentiation in piriform cor- 149–172. Whishaw, I. Q. (1972). Hippocampal 97, 671–676. tex slices. J. Neurophysiol. 80, Solstad,T.,Boccara,C.N.,Kropff, electroencephalographic activity Zhang,H.,Lin,S.C.,andNicolelis,M. 2467–2474. E.,Moser,M.B.,andMoser,E.I. in the Mongolian gerbil during A. (2010). Spatiotemporal coupling Peterson, R. C. (1977). Scopolamine- (2008). Representation of geomet- natural behaviours and wheel between hippocampal acetylcholine induced learning failures in man. ric borders in the entorhinal cortex. running and in the rat during release and theta oscillations in vivo. Psychopharmacologia 52, 283–289. Science 322, 1865–1868. wheel running and conditioned J. Neurosci. 30, 13431–13440.

Frontiers in Neural Circuits www.frontiersin.org February 2012 | Volume 6 | Article 5 | 12 Barry et al. Acetylcholine, theta, and grid cells

Zilli, E. A., and Hasselmo, M. E. (2010). and measured period variance of that could be construed as a potential cells. Front. Neural Circuits 6:5. doi: Coupled noisy spiking neurons as some biological oscillators. PLoS conflict of interest. 10.3389/fncir.2012.00005 velocity-controlled oscillators in a Comput. Biol. 5, e1000573. doi: Copyright © 2012 Barry, Heys and model of grid cell spatial firing. 10.1371/journal.pcbi.1000573 Received: 09 December 2011; accepted: Hasselmo. This is an open-access arti- J. Neurosci. 30, 13850–13860. 02 February 2012; published online: 20 cle distributed under the terms of the Zilli, E. A., Yoshida, M., Tahvildari, February 2012. Creative Commons Attribution Non B.,Giocomo,L.M.,andHasselmo, Conflict of Interest Statement: The Citation: Barry C, Heys JG and Commercial License, which permits non- M. E. (2009). Evaluation of the authors declare that the research Hasselmo ME (2012) Possible role commercial use, distribution, and repro- oscillatory interference model of was conducted in the absence of any of acetylcholine in regulating spatial duction in other forums, provided the grid cell firing through analysis commercial or financial relationships novelty effects on theta rhythm and grid original authors and source are credited.

Frontiers in Neural Circuits www.frontiersin.org February 2012 | Volume 6 | Article 5 | 13