Mechanisms of memory-supporting neuronal dynamics in hippocampal area CA3.

Hippocampal CA3 is central to memory formation and retrieval. Although various network mechanisms have been proposed, direct evidence is lacking. Using intracellular Vm recordings and optogenetic manipulations in behaving mice, we found that CA3 place-field activity is produced by a symmetric form of behavioral timescale synaptic plasticity (BTSP) at recurrent synapses among CA3 pyramidal neurons but not at synapses from the dentate gyrus (DG). Additional manipulations revealed that excitatory input from the entorhinal cortex (EC) but not the DG was required to update place cell activity based on the animal's movement. These data were captured by a computational model that used BTSP and an external updating input to produce attractor dynamics under online learning conditions. Theoretical analyses further highlight the superior memory storage capacity of such networks, especially when dealing with correlated input patterns. This evidence elucidates the cellular and circuit mechanisms of learning and memory formation in the hippocampus.

Hippocampal neurons construct a map of an abstract value space.

The hippocampus is thought to encode a "cognitive map," a structural organization of knowledge about relationships in the world. Place cells, spatially selective hippocampal neurons that have been extensively studied in rodents, are one component of this map, describing the relative position of environmental features. However, whether this map extends to abstract, cognitive information remains unknown. Using the relative reward value of cues to define continuous "paths" through an abstract value space, we show that single neurons in primate hippocampus encode this space through value place fields, much like a rodent's place neurons encode paths through physical space. Value place fields remapped when cues changed but also became increasingly correlated across contexts, allowing maps to become generalized. Our findings help explain the critical contribution of the hippocampus to value-based decision-making, providing a mechanism by which knowledge of relationships in the world can be incorporated into reward predictions for guiding decisions.

The Statistical Structure of the Hippocampal Code for Space as a Function of Time, Context, and Value.

Hippocampal activity represents many behaviorally important variables, including context, an animal's location within a given environmental context, time, and reward. Using longitudinal calcium imaging in mice, multiple large virtual environments, and differing reward contingencies, we derived a unified probabilistic model of CA1 representations centered on a single feature-the field propensity. Each cell's propensity governs how many place fields it has per unit space, predicts its reward-related activity, and is preserved across distinct environments and over months. Propensity is broadly distributed-with many low, and some very high, propensity cells-and thus strongly shapes hippocampal representations. This results in a range of spatial codes, from sparse to dense. Propensity varied ∼10-fold between adjacent cells in salt-and-pepper fashion, indicating substantial functional differences within a presumed cell type. Intracellular recordings linked propensity to cell excitability. The stability of each cell's propensity across conditions suggests this fundamental property has anatomical, transcriptional, and/or developmental origins.

Targeted Activation of Hippocampal Place Cells Drives Memory-Guided Spatial Behavior.

The hippocampus is crucial for spatial navigation and episodic memory formation. Hippocampal place cells exhibit spatially selective activity within an environment and have been proposed to form the neural basis of a cognitive map of space that supports these mnemonic functions. However, the direct influence of place cell activity on spatial navigation behavior has not yet been demonstrated. Using an 'all-optical' combination of simultaneous two-photon calcium imaging and two-photon optogenetics, we identified and selectively activated place cells that encoded behaviorally relevant locations in a virtual reality environment. Targeted stimulation of a small number of place cells was sufficient to bias the behavior of animals during a spatial memory task, providing causal evidence that hippocampal place cells actively support spatial navigation and memory.

The temporal and contextual stability of activity levels in hippocampal CA1 cells.

Recent long-term optical imaging studies have demonstrated that the activity levels of hippocampal neurons in a familiar environment change on a daily to weekly basis. However, it is unclear whether there is any time-invariant property in the cells' neural representations. In this study, using miniature fluorescence microscopy, we measured the neural activity of the mouse hippocampus in four different environments every 3 d. Although the activity level of hippocampal neurons fluctuated greatly in each environment across days, we found a significant correlation between the activity levels for different days, and the correlation was higher for averaged activity levels across multiple environments. When the number of environments used for averaging was increased, a higher activity correlation was observed. Furthermore, the number of environments in which a cell showed activity was preserved. Cells that showed place cell activity in many environments had greater spatial information content and more stable spatial representation, and thus carried more abundant and stable information about the current position. In contrast, cells that were active only in a small number of environments provided sparse representation for the environment. These results suggest that each cell has not only an inherent activity level but also play a characteristic role in the coding of space.

Spontaneous Dynamics of Hippocampal Place Fields in a Model of Combinatorial Competition among Stable Inputs.

We present computer simulations illustrating how the plastic integration of spatially stable inputs could contribute to the dynamic character of hippocampal spatial representations. In novel environments of slightly larger size than typical apparatus, the emergence of well-defined place fields in real place cells seems to rely on inputs from normally functioning grid cells. Theoretically, the grid-to-place transformation is possible if a place cell is able to respond selectively to a combination of suitably aligned grids. We previously identified the functional characteristics that allow a synaptic plasticity rule to accomplish this selection by synaptic competition during rat foraging behavior. Here, we show that the synaptic competition can outlast the formation of place fields, contributing to their spatial reorganization over time, when the model is run in larger environments and the topographical/modular organization of grid inputs is taken into account. Co-simulated cells that differ only by their randomly assigned grid inputs display different degrees and kinds of spatial reorganization-ranging from place-field remapping to more subtle in-field changes or lapses in firing. The model predicts a greater number of place fields and propensity for remapping in place cells recorded from more septal regions of the hippocampus and/or in larger environments, motivating future experimental standardization across studies and animal models. In sum, spontaneous remapping could arise from rapid synaptic learning involving inputs that are functionally homogeneous, spatially stable, and minimally stochastic.

Replay Comes of Age.

Hippocampal place cells take part in sequenced patterns of reactivation after behavioral experience, known as replay. Since replay was first reported, nearly 20 years ago, many new results have been found, necessitating revision of the original interpretations. We review some of these results with a focus on the phenomenology of replay.

Distal but not local auditory information supports spatial representations by place cells.

Sound is an important navigational cue for mammals. During spatial navigation, hippocampal place cells encode spatial representations of the environment based on visual information, but to what extent audiospatial information can enable reliable place cell mapping is largely unknown. We assessed this by recording from CA1 place cells in the dark, under circumstances where reliable visual, tactile, or olfactory information was unavailable. Male rats were exposed to auditory cues of different frequencies that were delivered from local or distal spatial locations. We observed that distal, but not local cue presentation, enables and supports stable place fields, regardless of the sound frequency used. Our data suggest that a context dependency exists regarding the relevance of auditory information for place field mapping: whereas locally available auditory cues do not serve as a salient spatial basis for the anchoring of place fields, auditory cue localization supports spatial representations by place cells when available in the form of distal information. Furthermore, our results demonstrate that CA1 neurons can effectively use auditory stimuli to generate place fields, and that hippocampal pyramidal neurons are not solely dependent on visual cues for the generation of place field representations based on allocentric reference frames.

Comparison of head direction cell firing characteristics across thalamo-parahippocampal circuitry.

Head direction (HD) cells, which fire persistently when an animal's head is pointed in a particular direction, are widely thought to underlie an animal's sense of spatial orientation and have been identified in several limbic brain regions. Robust HD cell firing is observed throughout the thalamo-parahippocampal system, although recent studies report that parahippocampal HD cells exhibit distinct firing properties, including conjunctive aspects with other spatial parameters, which suggest they play a specialized role in spatial processing. Few studies, however, have quantified these apparent differences. Here, we performed a comparative assessment of HD cell firing characteristics across the anterior dorsal thalamus (ADN), postsubiculum (PoS), parasubiculum (PaS), medial entorhinal (MEC), and postrhinal (POR) cortices. We report that HD cells with a high degree of directional specificity were observed in all five brain regions, but ADN HD cells display greater sharpness and stability in their preferred directions, and greater anticipation of future headings compared to parahippocampal regions. Additional analysis indicated that POR HD cells were more coarsely modulated by other spatial parameters compared to PoS, PaS, and MEC. Finally, our analyses indicated that the sharpness of HD tuning decreased as a function of laminar position and conjunctive coding within the PoS, PaS, and MEC, with cells in the superficial layers along with conjunctive firing properties showing less robust directional tuning. The results are discussed in relation to theories of functional organization of HD cell tuning in thalamo-parahippocampal circuitry.

Prioritized experience replays on a hippocampal predictive map for learning.

Hippocampal cells are central to spatial and predictive representations, and experience replays by place cells are crucial for learning and memory. Nonetheless, how hippocampal replay patterns dynamically change during the learning process remains to be elucidated. Here, we designed a spatial task in which rats learned a new behavioral trajectory for reward. We found that as rats updated their behavioral strategies for a novel salient location, hippocampal cell ensembles increased theta-sequences and sharp wave ripple-associated synchronous spikes that preferentially replayed salient locations and reward-related contexts in reverse order. The directionality and contents of the replays progressively varied with learning, including an optimized path that had never been exploited by the animals, suggesting prioritized replays of significant experiences on a predictive map. Online feedback blockade of sharp wave ripples during a learning process inhibited stabilizing optimized behavior. These results implicate learning-associated experience replays that act to learn and reinforce specific behavioral strategies.

Animal-to-Animal Variability in Partial Hippocampal Remapping in Repeated Environments.

Hippocampal place cells form a map of the environment of an animal. Changes in the hippocampal map can be brought about in a number of ways, including changes to the environment, task, internal state of the subject, and the passage of time. These changes in the hippocampal map have been called remapping. In this study, we examine remapping during repeated exposure to the same environment. Different animals can have different remapping responses to the same changes. This variability across animals in remapping behavior is not well understood. In this work, we analyzed electrophysiological recordings from the CA3 region of the hippocampus performed by Alme et al. (2014), in which five male rats were exposed to 11 different environments, including a variety of repetitions of those environments. To compare the hippocampal maps between two experiences, we computed average rate map correlation coefficients. We found changes in the hippocampal maps between different sessions in the same environment. These changes consisted of partial remapping, a form of remapping in which some place cells maintain their place fields, whereas other place cells remap their place fields. Each animal exhibited partial remapping differently. We discovered that the heterogeneity in hippocampal representational changes across animals is structured; individual animals had consistently different levels of partial remapping across a range of independent comparisons. Our findings highlight that partial hippocampal remapping between repeated environments depends on animal-specific factors.SIGNIFICANCE STATEMENT Context identification is a difficult problem. Animals are not provided with objective context identity labels, so they must infer which experiences come from which contexts. Different animals may have different strategies for performing this inference. We find that different animals have stereotypically different extents of partial hippocampal remapping, a neural correlate of subjective assessment of context identity.

Hyper-Rigid Phasic Organization of Hippocampal Activity But Normal Spatial Properties of CA1 Place Cells in the Ts65Dn Mouse Model of Down Syndrome.

Down syndrome (DS) in humans is caused by trisomy of chromosome 21 and is marked by prominent difficulties in learning and memory. Decades of research have demonstrated that the hippocampus is a key structure in learning and memory, and recent work with mouse models of DS has suggested differences in hippocampal activity that may be the substrate of these differences. One of the primary functional differences in DS is thought to be an excess of GABAergic innervation from medial septum to the hippocampus. In these experiments, we probe in detail the activity of region CA1 of the hippocampus using in vivo electrophysiology in male Ts65Dn mice compared with their male nontrisomic 2N littermates. We find the spatial properties of place cells in CA1 are normal in Ts65Dn animals. However, we find that the phasic relationship of both CA1 place cells and gamma rhythms to theta rhythm in the hippocampus is profoundly altered in these mice. Since the phasic organization of place cell activity and gamma oscillations on the theta wave are thought to play a critical role in hippocampal function, the changes we observe agree with recent findings that organization of the hippocampal network is potentially of more relevance to its function than the spatial properties of place cells.SIGNIFICANCE STATEMENT Recent evidence has disrupted the view that spatial deficits are associated with place cell abnormalities. In these experiments, we record hippocampal place cells and local field potential from the Ts65Dn mouse model of Down syndrome, and find phenomenologically normal place cells, but profound changes in the association of place cells and gamma rhythms with theta rhythm, suggesting that the overall network state is critically important for hippocampal function. These findings also agree with evidence suggesting that excess inhibitory control is the cause of hippocampal dysfunction in Down syndrome. The findings also confirm new avenues for pharmacological treatment of Down syndrome.

Attractor-like Dynamics in the Subicular Complex.

Distinct computations are performed at multiple brain regions during the encoding of spatial environments. Neural representations in the hippocampal, entorhinal, and head direction (HD) networks during spatial navigation have been clearly documented, while the representational properties of the subicular complex (SC) are relatively underexplored, although it has extensive anatomic connections with various brain regions involved in spatial information processing. We simultaneously recorded single units from different subregions of the SC in male rats while they ran clockwise on a centrally placed textured circular track (four different textures, each covering a quadrant), surrounded by six distal cues. The neural activity was monitored in standard sessions by maintaining the same configuration between the cues, while in cue manipulation sessions, the distal and local cues were either rotated in opposite directions to create a mismatch between them or the distal cues were removed. We report a highly coherent neural representation of the environment and a robust coupling between the HD cells and the spatial cells in the SC, strikingly different from previous reports of coupling between cells from co-recorded sites. Neural representations were (1) originally governed by the distal cues under local-distal cue-conflict conditions, (2) controlled by the local cues in the absence of distal cues, and (3) governed by the cues that are perceived to be stable. We propose that such attractor-like dynamics in the SC might play a critical role in the orientation of spatial representations, thus providing a "reference map" of the environment for further processing by other networks.SIGNIFICANCE STATEMENT The subicular complex (SC) receives major inputs from the entorhinal cortex and the hippocampus, and head direction (HD) information directly from the HD system. Using cue-conflict experiments, we studied the hierarchical representation of the local and distal cues in the SC to understand its role in the cognitive map, and report a highly coherent neural representation with robust coupling between the HD cells and the spatial cells in different subregions of the SC exhibiting attractor-like dynamics unaffected by the cue manipulations, strikingly different from previous reports of coupling between cells from co-recorded sites. This unique feature may allow the SC to function as a single computational unit during the representation of space, which may serve as a reference map of the environment.

Spatial Learning Drives Rapid Goal Representation in Hippocampal Ripples without Place Field Accumulation or Goal-Oriented Theta Sequences.

The hippocampus is critical for rapid acquisition of many forms of memory, although the circuit-level mechanisms through which the hippocampus rapidly consolidates novel information are unknown. Here, the activity of large ensembles of hippocampal neurons in adult male Long-Evans rats was monitored across a period of rapid spatial learning to assess how the network changes during the initial phases of memory formation and retrieval. In contrast to several reports, the hippocampal network did not display enhanced representation of the goal location via accumulation of place fields or elevated firing rates at the goal. Rather, population activity rates increased globally as a function of experience. These alterations in activity were mirrored in the power of the theta oscillation and in the quality of theta sequences, without preferential encoding of paths to the learned goal location. In contrast, during brief "offline" pauses in movement, representation of a novel goal location emerged rapidly in ripples, preceding other changes in network activity. These data demonstrate that the hippocampal network can facilitate active navigation without enhanced goal representation during periods of active movement, and further indicate that goal representation in hippocampal ripples before movement onset supports subsequent navigation, possibly through activation of downstream cortical networks.SIGNIFICANCE STATEMENT Understanding the mechanisms through which the networks of the brain rapidly assimilate information and use previously learned knowledge are fundamental areas of focus in neuroscience. In particular, the hippocampal circuit is a critical region for rapid formation and use of spatial memory. In this study, several circuit-level features of hippocampal function were quantified while rats performed a spatial navigation task requiring rapid memory formation and use. During periods of active navigation, a general increase in overall network activity is observed during memory acquisition, which plateaus during memory retrieval periods, without specific enhanced representation of the goal location. During pauses in navigation, rapid representation of the distant goal well emerges before either behavioral improvement or changes in online activity.

Aged Rats Exhibit Altered Behavior-Induced Oscillatory Activity, Place Cell Firing Rates, and Spatial Information Content in the CA1 Region of the Hippocampus.

Hippocampal gamma and theta oscillations are associated with mnemonic and navigational processes and adapt to changes in the behavioral state of an animal to optimize spatial information processing. It has been shown that locomotor activity modulates gamma and theta frequencies in rats, although how age alters this modulation has not been well studied. Here, we examine gamma and theta local-field potential and place cell activity in the hippocampus CA1 region of young and old male rats as they performed a spatial eye-blink conditioning task across 31 d. Although mean gamma frequency was similar in both groups, gamma frequency increased with running speed at a slower rate in old animals. By contrast, theta frequencies scaled with speed similarly in both groups but were lower across speeds in old animals. Although these frequencies scaled equally well with deceleration and speed, acceleration was less correlated with gamma frequency in both age groups. Additionally, spike phase-locking to gamma, but not theta, was greater in older animals. Finally, aged rats had reduced within-field firing rates but greater spatial information per spike within the field. These data support a strong relationship between locomotor behavior and local-field potential activity and suggest that age significantly affects this relationship. Furthermore, observed changes in CA1 place cell firing rates and information content lend support to the hypothesis that age may result in more general and context-invariant hippocampal representations over more detailed information. These results may explain the observation that older adults tend to recall the gist of an experience rather than the details.SIGNIFICANCE STATEMENT Hippocampal oscillations and place cell activity are sensitive to sensorimotor input generated from active locomotion, yet studies of aged hippocampal function often do not account for this. By considering locomotion and spatial location, we identify novel age-associated differences in the scaling of oscillatory activity with speed, spike-field coherence, spatial information content, and within-field firing rates of CA1 place cells. These results indicate that age has an impact on the relationship between locomotion and hippocampal oscillatory activity, perhaps indicative of alterations to afferent input. These data also support the hypothesis that aged hippocampal place cells, compared with young, may more often represent more general spatial information. If true, these results may help explain why older humans tend to recall less specific and more gist-like information.

Significance of visual scene-based learning in the hippocampal systems across mammalian species.

The hippocampus and its associated cortical regions in the medial temporal lobe play essential roles when animals form a cognitive map and use it to achieve their goals. As the nature of map-making involves sampling different local views of the environment and putting them together in a spatially cohesive way, visual scenes are essential ingredients in the formative process of cognitive maps. Visual scenes also serve as important cues during information retrieval from the cognitive map. Research in humans has shown that there are regions in the brain that selectively process scenes and that the hippocampus is involved in scene-based memory tasks. The neurophysiological correlates of scene-based information processing in the hippocampus have been reported as "spatial view cells" in nonhuman primates. Like primates, it is widely accepted that rodents also use visual scenes in their background for spatial navigation and other kinds of problems. However, in rodents, it is not until recently that researchers examined the neural correlates of the hippocampus from the perspective of visual scene-based information processing. With the advent of virtual reality (VR) systems, it has been demonstrated that place cells in the hippocampus exhibit remarkably similar firing correlates in the VR environment compared with that of the real-world environment. Despite some limitations, the new trend of studying hippocampal functions in a visually controlled environment has the potential to allow investigation of the input-output relationships of network functions and experimental testing of traditional computational predictions more rigorously by providing well-defined visual stimuli. As scenes are essential for navigation and episodic memory in humans, further investigation of the rodents' hippocampal systems in scene-based tasks will provide a critical functional link across different mammalian species.

Distinct effects of reward and navigation history on hippocampal forward and reverse replays.

To better understand the functional roles of hippocampal forward and reverse replays, we trained rats in a spatial sequence memory task and examined how these replays are modulated by reward and navigation history. We found that reward enhances both forward and reverse replays during the awake state, but in different ways. Reward enhances the rate of reverse replays, but it increases the fidelity of forward replays for recently traveled as well as other alternative trajectories heading toward a rewarding location. This suggests roles for forward and reverse replays in reinforcing representations for all potential rewarding trajectories. We also found more faithful reactivation of upcoming than already rewarded trajectories in forward replays. This suggests a role for forward replays in preferentially reinforcing representations for high-value trajectories. We propose that hippocampal forward and reverse replays might contribute to constructing a map of potential navigation trajectories and their associated values (a "value map") via distinct mechanisms.

Modality-Specific Impairment of Hippocampal CA1 Neurons of Alzheimer's Disease Model Mice.

Impairment of episodic memory, a class of memory for spatiotemporal context of an event, is an early symptom of Alzheimer's disease. Both spatial and temporal information are encoded and represented in the hippocampal neurons, but how these representations are impaired under amyloid ß (Aß) pathology remains elusive. We performed chronic imaging of the hippocampus in awake male amyloid precursor protein (App) knock-in mice behaving in a virtual reality environment to simultaneously monitor spatiotemporal representations and the progression of Aß depositions. We found that temporal representation is preserved, whereas spatial representation is significantly impaired in the App knock-in mice. This is because of the overall reduction of active place cells, but not time cells, and compensatory hyperactivation of remaining place cells near Aß aggregates. These results indicate the differential impact of Aß aggregates on two major modalities of episodic memory, suggesting different mechanisms for forming and maintaining these two representations in the hippocampus.

The Ontogeny of Hippocampus-Dependent Memories.

The formation of memories that contain information about the specific time and place of acquisition, which are commonly referred to as "autobiographical" or "episodic" memories, critically relies on the hippocampus and on a series of interconnected structures located in the medial temporal lobe of the mammalian brain. The observation that adults retain very few of these memories from the first years of their life has fueled a long-standing debate on whether infants can make the types of memories that in adults are processed by the hippocampus-dependent memory system, and whether the hippocampus is involved in learning and memory processes early in life. Recent evidence shows that, even at a time when its circuitry is not yet mature, the infant hippocampus is able to produce long-lasting memories. However, the ability to acquire and store such memories relies on molecular pathways and network-based activity dynamics different from the adult system, which mature with age. The mechanisms underlying the formation of hippocampus-dependent memories during infancy, and the role that experience exerts in promoting the maturation of the hippocampus-dependent memory system, remain to be understood. In this review, we discuss recent advances in our understanding of the ontogeny and the biological correlates of hippocampus-dependent memories.

Long-Term Characterization of Hippocampal Remapping during Contextual Fear Acquisition and Extinction.

Hippocampal CA1 place cell spatial maps are known to alter their firing properties in response to contextual fear conditioning, a process called "remapping." In the present study, we use chronic calcium imaging to examine remapping during fear retrieval and extinction of an inhibitory avoidance task in mice of both sexes over an extended period of time and with thousands of neurons. We demonstrate that hippocampal ensembles encode space at a finer scale following fear memory acquisition. This effect is strongest near the shock grid. We also characterize the long-term effects of shock on place cell ensemble stability, demonstrating that shock delivery induces several days of high fear and low between-session place field stability, followed by a new, stable spatial representation that appears after fear extinction. Finally, we identify a novel group of CA1 neurons that robustly encode freeze behavior independently from spatial location. Thus, following fear acquisition, hippocampal CA1 place cells sharpen their spatial tuning and dynamically change spatial encoding stability throughout fear learning and extinction.SIGNIFICANCE STATEMENT The hippocampus contains place cells that encode an animal's location. This spatial code updates, or remaps, in response to environmental change. It is known that contextual fear can induce such remapping; in the present study, we use chronic calcium imaging to examine inhibitory avoidance-induced remapping over an extended period of time and with thousands of neurons and demonstrate that hippocampal ensembles encode space at a finer scale following electric shock, an effect which is enhanced by threat proximity. We also identify a novel group of freeze behavior-activated neurons. These results suggest that, more than merely shuffling their spatial code following threat exposure, place cells enhance their spatial coding with the possible benefit of improved threat localization.