The Hippocampus Via Subiculum Upon Exposure to Desiccation

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Where next for the study of Primer anhydrobiosis? Studies have largely Direct and relied on detecting gene upregulation The hippocampus via subiculum upon exposure to desiccation. CA1 This approach will fail to identify constitutively expresssed genes that James J. Knierim DG CA2 are important for anhydrobiotic survival but whose expression does not change The hippocampus is one of the most EC CA3 during desiccation and rehydration. thoroughly investigated structures in axons We still do not understand why some the brain. Ever since the 1957 report nematodes, for example, do not of the case study H.M., who famously survive desiccation, while others can lost the ability to form new, declarative Current Biology survive immediate exposure to extreme memories after surgical removal of the desiccation, and yet others require hippocampus and nearby temporal Figure 1. Coronal slice through the transverse axis of the hippocampus. preconditioning at a high relative lobe structures to treat intractable The black lines trace the classic ‘trisynaptic humidity. A comparative approach epilepsy, the hippocampus has been loop’. The red lines depict other important is likely to be informative, as has at the forefront of research into the pathways in the hippocampus, including the recently been published comparing neurobiological bases of memory. direct projections from entorhinal cortex (EC) to the genomes of P. vanderplanki and its This research led to the discovery all three CA fi elds, the feedback to the EC via desiccation-intolerant relative P. nubifer. in the hippocampus of long-term the subiculum, the recurrent collateral circuitry of CA3, and the feedback projection from CA3 potentiation, the pre-eminent model to DG. For simplicity, many other details of the Where can I fi nd out more? of the cellular basis of memory. connectivity of the hippocampus are omitted. Barrett, J. (1982). Metabolic responses to Furthermore, the discovery of place anabiosis in the fourth stage juveniles of Ditylenchus dipsaci (Nematoda). Proc. R. Soc. cells, head direction cells, and grid within the medial temporal lobe. Its Lond. B. 216, 159–177. cells in the rodent hippocampal resemblance in gross dissection to a Boschetti, C., Pouchkina-Stantcheva, N., formation established a fi rm seahorse inspired its naming after this Hoffmann, P., and Tunnacliffe, A. (2011). Foreign genes and novel hydrophilic protein foundation for the notion that the sea creature (genus Hippocampus). genes participate in the desiccation response hippocampus plays a critical role in In rodents, the hippocampus is a of the bdelloid rotifer Adineta ricciae. J. Exp. Biol. 214, 59–68. memory formation by providing the relatively large, cashew-shaped Crowe, J.H. (2014). Anhydrobiosis: an unsolved brain with a spatiotemporal framework structure lying just beneath the problem. Plant Cell Environ. 37, 1491–1493. within which the various sensory, neocortex. A cross-section of its long Erkut, C., and Kurzchalia, T.V. (2015). The C. elegans dauer larva as a paradigm to study emotional, and cognitive components axis reveals the classic, textbook metabolic suppression and desiccation of an experience are bound together. depiction of the hippocampal tolerance. Planta 242, 389–396. This framework allows the experience anatomical connectivity, the so-called Gusev, O., Suetsugu, Y., Cornette, R., Kawashima, T., Logacheva, M.D., Kondrashov, to be stored in such a way that it ‘trisynaptic loop’ (Figure 1). The A.S., Penin, A.A., Hatanaka, R., Kikuta, can be later retrieved as a conscious entorhinal cortex provides the major S., Shimura, S., et al. (2014). Comparative recollection of that experience. cortical input to the hippocampus, genome sequencing reveals genomic signature of extreme desiccation tolerance in the In this primer, I will fi rst review the with its strongest projections via the anhydrobiotic midge. Nat. Commun. 5, 4784. basic anatomy of the hippocampus, perforant path to the dentate gyrus Perry, R.N., and Wharton, D.A. (2011). Molecular and Physiological Basis of Nematode Survival giving a historical overview of early (DG) region (Synapse 1). The DG (CABI Publishing, Wallingford). conceptions of hippocampal circuitry projects to the CA3 region via the Potts, M., Slaughter, S.M., Hunneke, F.U., Garst, and describing modern fi ndings that mossy fi ber pathway (Synapse 2). J.F., and Helm, R.F. (2005). Desiccation tolerance of prokaryotes: Application of are the inspiration of much current CA3 projects to the CA1 region via the principles to human cells. Integr. Comp. Biol. work on hippocampal physiology Schaffer Collateral pathway (Synapse 45, 800–809. and function. Next, I will consider 3). Finally, CA1 projects back to the Tyson, T., O’Mahony Zamora, G., Wong, S., Skelton, M., Daly, B., Jones, J.T., human and animal lesion studies, the entorhinal cortex, completing the loop. Mulvihill, E.D., Elsworth, B., Phillips, M., results of which underlie our basic An important addition to the classic Blaxter, M., et al. (2012). A molecular analysis understanding that the hippocampus trisynaptic circuitry is that CA3 axons, of desiccation tolerance mechanisms in the anhydrobiotic nematode Panagrolaimus performs a critical function in the in addition to their projections to CA1, superbus using expressed sequence tags. brain’s ability to store and retrieve send collaterals that make synapses BMC Res. Notes 5, 68. Wang, C., Grohme, M.A., Mali, B., Schill, R.O., memories (particularly episodic onto other CA3 neurons. This and Frohme, M. (2014). Towards decrypting memories in humans). Finally, I will recurrent collateral pathway inspired a cryptobiosis - analyzing anhydrobiosis in review key aspects of hippocampal number of infl uential theories of CA3 the tardigrade Milnesium tardigradum using transcriptome sequencing. PLoS One 9, http:// behavioral neurophysiology and as an autoassociative memory system, dx.doi.org/10.1371/journal.pone.0092663. relate them to current theories of displaying attractor dynamics that are Wharton, D.A. (2002). Life at the Limits: Organisms hippocampal function. critical for supporting a distributed in Extreme Environments (Cambridge University Press, Cambridge). memory. Anatomy The unidirectional circuitry of Department of Zoology, University of Otago, Intrinsic circuitry the trisynaptic loop was originally P.O. Box 56, Dunedin, New Zealand. In humans, the hippocampus is an believed to be mainly contained *E-mail: [email protected] elongated structure buried deep within a cross-sectional slice (or

lamella) of the hippocampus. The input from LEC and the part of CA1 posterior orientation. The anterior ‘lamellar hypothesis’ proposed that close to CA2 receives input from hippocampus of primates corresponds the hippocampus was structured as MEC. The superfi cial layers of MEC to the ventral hippocampus of rodents, a stack of these lamellae, organized and LEC project to the hippocampus and the posterior hippocampus of as independent, functional modules (in general, layer II projects to DG primates corresponds to the dorsal along the longitudinal axis of the and CA3, whereas layer III projects hippocampus of rodents. In rodents, hippocampus. Modern anatomical to CA1 and subiculum). The deep the dorsal hippocampus and ventral tracing studies, however, have layers receive feedback from the hippocampus are differentially revealed widespread connectivity hippocampus. Connections from deep involved in spatial versus emotional along the longitudinal axis, showing to superfi cial layers, as well as the memory and cognition. Because most that transverse slices (cross- presence of basal dendrites of layer single unit recording studies and sections, as in Figure 1) through the II/III neurons in deep layers, form a many lesion studies in rodents are hippocampus are not functionally critical anatomical feedback loop that performed on dorsal hippocampus, independent. The connectivity within allows the hippocampal output to and many primate studies concentrate the transverse axis is also more directly affect the neural processing of on the anterior hippocampus (the complex, with multiple, parallel the hippocampal inputs. homolog of ventral hippocampus in processing circuits and feedback rodents), data that appear to show circuits. The entorhinal cortex projects Other cortical and subcortical species differences between rodents not only to DG, but also directly to the connections and primates may actually refl ect CA3 and CA1 regions. CA3 provides In addition to the major inputs differences between the computational a feedback projection to the DG, from the entorhinal cortex, the processes of dorsal (posterior) via the excitatory mossy cells of the hippocampus receives direct inputs hippocampus versus ventral (anterior) dentate hilus, thus violating the earlier from the perirhinal cortex and hippocampus. notion that hippocampal processing postrhinal cortex. It also receives is exclusively unidirectional. Finally, major subcortical inputs from the Hippocampal lesions recent experiments have fostered medial septum (related to the strong Human studies a new appreciation of the CA2 theta rhythm in the hippocampus), There is a rich literature on the region, which has traditionally been locus coeruleus, raphe nucleus, amnesic effects of hippocampal considered a transition zone between nucleus reuniens, and amygdala. damage in humans. The hippocampus CA1 and CA3: it is now clear that CA2 The CA3 and CA1 regions have a is highly susceptible to damage has its own functions and must be major output to the lateral septum from epilepsy, hypoxia, ischemia, regarded as a distinct computational via the fornix. CA1 also projects or encephalitis. The entorhinal unit on par with CA3 and CA1. to the nucleus accumbens (ventral cortex is typically the fi rst region of striatum), amygdala, and prefrontal the brain to show the plaques and Entorhinal inputs and outputs cortex. This list is incomplete, and is tangles of Alzheimer’s disease. Years The hippocampus receives major presented here as an indication that ago, a number of epilepsy patients, cortical input from the entorhinal the hippocampal anatomy is more including the famous H.M., had their cortex, which is composed of two complex than the classic trisynaptic hippocampus removed in an attempt distinct brain regions in rats. The circuit. The reader is referred to more to treat their debilitating seizures. medial entorhinal cortex (MEC), complete anatomy reviews mentioned Studies of these patient populations especially its most caudal regions, is in the Further Reading list. showed that a major function of the associated with spatial processing human hippocampus and its adjacent regions of the brain, such as Longitudinal axis brain regions is to support the the retrosplenial cortex and the As a fi nal point of anatomy, there creation of new, declarative memories dorsal presubiculum (also called are major differences in connectivity (memories that can be brought to the postsubiculum). The lateral patterns along the longitudinal axis conscious awareness and verbalized). entorhinal cortex (LEC) is associated of the hippocampus. In rodents, Declarative memory can be with high-order, item-recognition this axis is often referred to as the subdivided into two types: episodic areas, such as the perirhinal cortex. dorsal-ventral axis. The dorsal memory and semantic memory. Both regions receive input from hippocampus is the most rostral part Episodic memory refers to a the prefrontal cortex and olfactory of the hippocampus. At more caudal recollection about a specifi c event cortex, and they also send projections levels, the hippocampus curves in one’s past, tied to a specifi c time to each other. The MEC and LEC ventrally. The dorsal hippocampus and place — for example “This projections to DG and CA3 overlap, receives inputs from the parts of the morning, in my kitchen, I ate an egg appearing to target the same cells. MEC with the fi nest resolution spatial for breakfast”. Semantic memory Thus, DG and CA3 can combine cells. The ventral hippocampus is refers to one’s store of general the information conveyed by both highly connected with the prefrontal knowledge about the world — for inputs. In contrast, the projections cortex and the amygdala. In primates, example “Eggs come from chickens to CA1 are segregated along the the entire hippocampus is located and are a typical breakfast food”. transverse axis, such that the part of ventrally in the medial temporal lobe Many investigators believe that the CA1 close to the subiculum receives and is arranged primarily in an anterior- hippocampus proper is particularly

crucial for forming new episodic from its individual components a produce a conditioned response memories, whereas other parts of the mental narrative of an imagined in trace eyeblink and trace fear medial temporal lobe are more critical event may be related to the inability conditioning. In contrast, when the for forming new semantic memories. to reconstruct a mental narrative of unconditioned stimulus overlaps in In support of this distinction, some an actual autobiographical event time with the offset of the conditioned patients who sustained hippocampal (episodic memory amnesia). stimulus, called delay conditioning, damage early in life have defi cits in the hippocampus is not required. episodic memory, fi nding it diffi cult to Animal studies remember events of their daily lives, The literature on the effects of Physiology but seem to have an intact semantic hippocampal lesions in experimental A tremendous amount of information memory, being able to learn school animals is controversial. Much work in is known about the neurophysiology subjects such as languages and recent decades has centered largely of the hippocampus. Most of this work acquiring factual knowledge within a on the question of whether spatial has been done on rats, but research normal range. learning is the primary (exclusive) on mice is increasing at a fast pace. Patients with hippocampal damage defi cit that results from hippocampal Rather less work has been done on can retain memories of events that damage, or whether there might also other species, including rabbits, bats, occurred years prior to the onset be nonspatial defi cits. The dominant birds, monkeys, and humans, but of their brain damage. This sparing test for hippocampal damage has such research allows for important of remote memory has led to the been the Morris water maze. In the cross-species comparisons. notion of a consolidation gradient, basic version of this task, rats are whereby memories gradually become placed in a pool of opaque water and Place cells independent of the hippocampus as swim in search of a hidden escape The most famous and extensively they are consolidated in other brain platform, submerged just under the studied correlate of hippocampal regions (presumably neocortex). water surface, which is always located neural activity is the place cell (Figure Note that this phenomenon, called in a fi xed position. Because there are 2). Pyramidal cells of the CA1, CA2, ‘systems consolidation’, differs from no local cues available in the water, and CA3 regions, as well as granule a related concept, called ‘cellular and because the rats are started from cells of the DG, fi re selectively when consolidation’, in which memories a new location each trial, the rats rats occupy one or more specifi c become resistant to change over time cannot use surface cues or a simple locations in an environment, called due to changes in gene expression motor strategy to fi nd the platform; the ‘place fi eld’ or ‘fi ring fi eld’. The and protein synthesis in individual instead they are presumably forced discovery of these cells prompted the neurons. Some investigators question to rely on a spatial map strategy. Rats theory that the hippocampus forms whether the spared, remote memories with hippocampal lesions have severe a cognitive map of the environment. of hippocampal patients carry the defi cits in learning this task. Other Although many descriptions of place same richness of detail expected from tasks that are commonly used to test cells state that they are controlled a true episodic recall of the event, for for hippocampal spatial defi cits are primarily by distal landmarks, this example “I vividly recall my excitement the radial maze and contextual fear misconception has been overturned at receiving a bicycle on my 10th conditioning. by numerous studies showing that birthday”, as opposed to a more An early model of hippocampus- salient local cues can tightly control semanticized version of the event, dependent learning in primates was place fi elds, even overriding the such as “I know that I got a bicycle the delayed nonmatch-to-sample infl uence of distal landmark under on my 10th birthday”. This important task. In this task, monkeys are certain conditions. The spatial fi ring of question is still under intense debate. presented with a sample object; after place fi elds can also be infl uenced by A more recent twist was the a delay, they are required to choose local boundaries and by self-motion discovery that these amnesic patients between the sample object and a new cues, such as vestibular input, that also displayed a defi cit in their ability object in order to obtain a reward. support path integration. to imagine new experiences. When Subsequent work demonstrated that, It is increasingly clear that place asked to describe an imaginary under most conditions, the memory cells are a heterogeneous population scenario, such as a day at the beach, defi cit resulted primarily from damage with varying functional properties. hippocampal patients were able to to the entorhinal and perirhinal Under some circumstances, some mention the individual components cortex rather than the hippocampus place fi elds appear to encode associated with such an experience, proper. Other tasks that are not location primarily based on distances such as the presence of sand, waves, overtly spatial do appear to depend to boundaries or discrete object seagulls, and so on, but were less on the hippocampus. One example landmarks; other place fi elds able than control subjects to construct is Pavlovian trace conditioning, in apparently derive their spatial a detailed narrative, such as “I am which a temporal gap separates the specifi city from path integration lying on my back and feel the warmth offset of a conditioned stimulus, computations. Place cells in different of the sun on my face. I hear the such as a tone, and the onset of an parts of the hippocampus have sound of seagulls to my left. Behind unconditioned stimulus, such as a puff different properties, especially when me I hear a group of people playing of air to the eye. The hippocampus measured at the level of neural volleyball”. This inability to construct is required for a subject to learn to ensembles. Individual place fi elds

are larger in more ventral parts of the ABC hippocampus compared to dorsal parts, consistent with the anatomical and functional differences described above. Thus, place cells receive input from multiple sources, including self- motion, boundaries, objects, odors, and head-direction. They appear to combine these disparate sets of cues to create a map of spatial context that is used to underlie ﬂ exible learning and cognition (see below). D E

Grid cells and boundary cells Grid cells are not found in the hippocampus proper, but close by in the MEC and other extrahippocampal regions. Grid cells fi re in multiple locations in an environment, which are arranged in a precise, hexagonal grid. It is thought by many investigators Current Biology that grid cells are the fundamental unit for calculating a position signal based Figure 2. Behavioral correlates of hippocampal and medial entorhinal neurons. on self-motion, a process known as (A) Place fi eld recorded from a CA3 pyramidal cell (data provided by H. Lee). (B) Grid cell recorded from the MEC (data provided by F. Savelli). (C) Boundary cell recorded from the MEC (data pro- path integration. As MEC provides a vided by F. Savelli). (D) Object-vector cell recorded from CA1 (data provided by S. Deshmukh). The major input to the hippocampus, the three fi ring fi elds of this cell maintain a similar direction and distance from 3 of the 4 objects in the grid cells presumably play a major environment (white circles). (E) Illustration of theta phase precession. The top depicts a place fi eld role in the spatial computations of the (red) when a rat runs on a linear track. The bottom depicts eight cycles of the theta rhythm as the hippocampus. Early models assumed rat runs through the place fi eld. Red tick marks indicate spikes. The spikes occur at a late phase that grid cells provide the spatial input of the theta cycle as the rat enters the fi eld, and the spikes occur at increasingly earlier phases as the rat progresses through the place fi eld. that drives the spatial selectivity of place cells, but recent evidence shows that disruption of grid cells can leave cell is plotted as a function of time, a clock (time cells); if the periodic place cells largely intact. Moreover, some cells have a peak fi ring rate output is modulated by the animal’s inactivation of place cells causes shortly after the start of the epoch, speed of movement, it will function disruption of the MEC grid cells. It and other cells have peak fi ring rates as an odometer (distance cells); if is possible that boundary (border) at longer times. When fi ring rate is the periodic output is modulated by cells, another class of MEC cells plotted as a function of time, these both speed and heading direction, it that fi re selectively when the rat is ‘time fi elds’ look just like place fi elds will function as a positioning system located at or near the boundary of an that are plotted as a function of (place/grid cells). environment, may provide information location along a linear track. When to support place cell fi ring, at least rats run in place on a treadmill, some Remapping in small environments. Based on the place cells also are affected by Only a fraction of place cells are anatomical feedback loops described the virtual distance traveled on the active in a given environment, and above, the relationship between grid treadmill. this active subset changes when the cells and boundary cells in MEC, It appears that the same pyramidal animal enters a new environment. and place cells in the hippocampus, cells can encode time, distance, or The activation of separate spatial probably cannot be described in a location, depending on the conditions. maps in different environments or simple feedforward model, but rather Although these three properties are contexts is called ‘remapping’. Even the different types of cells affect each phenomenologically very distinct, in the same environment, the place other in recursive processing loops. current computational theories cell representations can remap in of path integration can provide a response to changes in the shape or Time and distance coding unifying framework. According to color of the environment, changes in Under certain conditions, such as both continuous attractor theories the task of the animal, or behavioral when rats run in place in a running and oscillatory interference theories, manipulations that disorient the wheel during the delay period of the same neural network can in animal. Remapping can take the a memory task, or when they are principle produce all three properties form of a complete reorganization confi ned in a small space during such depending on the precise nature of the of place fi elds, with an independent a delay period, hippocampal cells inputs that update the system. If the set of active cells (called ‘global encode the time elapsed since the network has some type of unvarying, remapping’). Alternatively, under some start of the epoch. If the fi ring of the periodic output, it will function as conditions, the place cells can alter

External sensory input Path integration/movement animal in the larger place fi eld, the phase precession provides one of the Perirhinal Postrhinal Pre/Para- subiculum; ADN more robust examples of a temporal (superficial) (superficial) code in the brain. Numerous models Items Scenes Retrosplenial have been generated about the origin and functional signifi cance of LEC (superficial) MEC (superficial) phase precession, including that it Content Context Items and events Spatiotemporal framework allows sequences of place fi elds to What is out there? Where am I? be recapitulated in a compressed Where is it? Where am I going? DG sequence amenable to LTP Pattern separation mechanisms to encode a memory Hil trace of the sequence. When the rodent is engaged in CA3 nonexploratory behaviors, such as Autoassociation, CA2 CA1 distal CA1 proximal eating or grooming, and when it is Attractor dynamics in the slow-wave stage of sleep, the proximal distal hippocampal EEG enters the ‘large irregular activity’ (LIA) mode. During DG/CA3 side loop combines this mode, intermittent bursts of LEC and MEC input streams Output loop back to deep EC to create conjunctive representations (Direct and indirect, via subiculum) synchronized neural activity cause of item + place (content + context) large defl ections in the EEG called Current Biology sharp wave/ripples. The place cell activity during the sharp wave/ripples in Figure 3. Anatomical model of information fl ow and functions of the hippocampal system slow wave sleep or quiet wakefulness in support of memory. recapitulate, on a very compressed In this highly simplifi ed schematic, the LEC pathway (blue) receives input from the perirhinal cor- time scale, the sequences of activity tex (as well as other inputs, such as olfactory cortex). It is thought to convey information about individual items and events in the external world, including information about their spatial loca- that the rat recently experienced during tion. The MEC pathway (red) receives input from postrhinal cortex (parahippocampal cortex in behavior — that is, the place cells fi re primates) about scenes as well as information about self-movement, head direction, and path in the same sequence as their place integration from presubiculum, parasubiculum, and retrosplenial cortex. Head direction input ar- fi elds were experienced. This ‘replay’ rives via the anterior dorsal nucleus (ADN) of the thalamus. The DG and CA3 combine overlapping is hypothesized to be involved in the input from both pathways to store in memory conjunctive representations of the content of an systems consolidation process, as experience within its spatiotemporal context. Putative attractor networks in CA3 support mne- monic computations associated with distributed memory systems, such as pattern separation a mechanism whereby the events and pattern completion. The output of the DG/CA3 processing loop is sent to CA1, both directly recently experienced by the animal and indirectly via CA2, where it is compared with direct input from EC. The output of this com- are replayed to the neocortex in order parison is fed back to the deep layers of EC, which distribute the information to other neocortical to update the permanent, neocortical areas as well as back to the superfi cial EC layers, where it can infl uence the next stage of memory memory stores. processing. Nonlocal representations during their fi ring rates substantially (in the representations of the MEC and of the behavior extreme case shutting off entirely), but hippocampus. When the rat is performing a the fi ring fi elds of active cells remain behavioral task, the hippocampus in the same locations (called ‘rate Theta and large irregular activity generates brief (50–100 millisecond) remapping’). Partial remapping can In rodents, the hippocampal EEG is sequences that represent locations occur when some place fi elds remap dominated by a striking oscillation away from the current location of the and others do not. of approximately 8 Hz when the rat (‘nonlocal representations’). These The remapping phenomenon may animal is locomoting, performing sequences can occur during sharp refl ect the ability of the hippocampus other investigatory behaviors, or is wave/ripples that are generated during to support context-dependent memory. in the REM stage of sleep. Principal behavior, for example at a reward site, The creation of new maps for different neurons and interneurons are strongly and can take the form of sequences of environments, or different behavioral modulated by this theta rhythm, fi ring locations that replay the animal’s most situations in the same environment, in bursts that are phase-locked to recent trajectory, as well as the same may allow the hippocampus to store the theta rhythm. Place cells show trajectory played in reverse order. the specifi c memories and behavioral a strong phenomenon called theta Nonlocal representations can contingencies specifi c to each situation. phase precession: as the rat runs also be prospective in nature: when Because grid cells of the MEC do through a place fi eld, each theta- the animal is at the choice point of not share this remapping property, modulated burst of fi ring of the cell a maze, it sometimes performs a the creation of context-specifi c occurs at increasingly earlier phases behavior called vicarious trial and representations in the hippocampus may of the theta rhythm. Because the error, moving its head back and forth be the most important transformation phase of theta provides information as it appears to evaluate the different that occurs between the spatial about the precise location of the behavioral choices and potential

outcomes. Bursts of theta-related system, the fi eld is converging on Eichenbaum, H., and Cohen, N.J. (2014). Can we reconcile the declarative memory and spatial hippocampal activity can represent a consensus that the hippocampus navigation views on hippocampal function? sweeps of spatial sequences that supports episodic memory by Neuron 83, 764–770. correspond to the animal’s choices combining a spatial/temporal signal Hassabis, D., Kumaran, D., Vann, S.D., and Maguire, E.A. (2007). Patients with on the maze. In other cases, when (from the MEC) with a signal related hippocampal amnesia cannot imagine new the animal is about to make a to individual items experienced by experiences. Proc. Natl. Acad. Sci. USA. 104, 1726–1731. trajectory to a known goal location, the animal (from the LEC) to form Hasselmo, M.E. (2012). 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