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Locomotion-related signals in the brain To calculate where we are in space, continuous knowledge of one’ s speed is necessary. How does the brain know how fast the body is traveling during locomotion? Using in vivo calcium imaging, electrophysiology, optogenetics, cell tracing, and histology, Farrell et al . identified neurons in the rodent supramammillary nucleus of the hypothalamus that encode future locomotor speed and potently drive locomotion when stimulated. Because these locomotor neurons have extensive axons in brain areas that support spatial navigation, this cell type distributes this information selectively to areas that require knowledge of speed. This nucleus is functionally positioned between input from a higher-order cognitive center and the downstream midbrain where locomotor nuclei reside. —PRS

Spatial memories that can last a lifetime are thought to be encoded during ‘online’ periods of exploration and subsequently consolidated into stable cognitive maps through their ‘offline’ reactivation. However, the mechanisms and computational principles by which offline reactivation stabilize long-lasting spatial representations remain poorly understood. Here, we employed simultaneous fast calcium imaging and electrophysiology to track hippocampal place cells over 2 weeks of online spatial reward learning behavior and offline resting. We describe that recruitment to persistent network-level offline reactivation of spatial experiences in mice predicts the future representational stability of place cells days in advance of their online reinstatement. Moreover, while representations of reward-adjacent locations are generally more stable across days, offline-reactivation-related stability is, conversely, most prominent for reward-distal locations. Thus, while occurring on the tens of milliseconds timescale, offline reactivation is uniquely associated with the stability of multiday representations that counterbalance the overall reward-adjacency bias, thereby predicting the stabilization of cognitive maps that comprehensively reflect entire underlying spatial contexts. These findings suggest that post-learning offline-related memory consolidation plays a complimentary and computationally distinct role in learning compared to online encoding. Grosmark et al. use simultaneous calcium imaging and electrophysiology to track the formation and long-term evolution of hippocampal memory traces in mice and uncover a role for post-learning reactivation in the formation of spatially uniform cognitive maps.

Hippocampal place cells underlie spatial navigation and memory. Remarkably, CA1 pyramidal neurons can form new place fields within a single trial by undergoing rapid plasticity. However, local feedback circuits likely restrict the rapid recruitment of individual neurons into ensemble representations. This interaction between circuit dynamics and rapid feature coding remains unexplored. Here, we developed "all-optical" approaches combining novel optogenetic induction of rapidly forming place fields with 2-photon activity imaging during spatial navigation in mice. We find that induction efficacy depends strongly on the density of co-activated neurons. Place fields can be reliably induced in single cells, but induction fails during co-activation of larger subpopulations due to local circuit constraints imposed by recurrent inhibition. Temporary relief of local inhibition permits the simultaneous induction of place fields in larger ensembles. We demonstrate the behavioral implications of these dynamics, showing that our ensemble place field induction protocol can enhance subsequent spatial association learning.

Hippocampal place cells form a physiological substrate for spatial navigation and memory in the brain. Remarkably, CA1 pyramidal neurons can acquire stable place fields in a few trials through a novel behavioral timescale" synaptic plasticity rule (BTSP). While this process can enable rapid learning, local feedback circuits likely tightly restrict the recruitment of individual cells into ensemble representations; this interaction between local circuit dynamics and BTSP remains unexplored. Here we developed \all-optical" approaches that combine novel optogenetic induction of place fields via BTSP in CA1 pyramidal cells with 2-photon calcium activity imaging during spatial navigation. We find that induction efficacy depends strongly on the density of co-activated neurons. Place fields can be reliably induced in single cells, but induction fails during co-activation of larger CA1 populations. Our results implicate local circuit constraints on the induction of place fields, whereby recurrent inhibition regulates the prevalence of BTSP across the ensemble. Consistent with this interpretation, we found that temporary relief of local inhibition permitted the simultaneous induction of place fields in larger CA1 ensembles. We demonstrate the behavioral consequences of these dynamics, as applying our ensemble optogenetic induction protocol at an arbitrary location enhanced animals' subsequent performance in a spatial reward learning task involving that location.

Neurological and psychiatric disorders are associated with pathological neural dynamics. The fundamental connectivity patterns of cell-cell communication networks that enable pathological dynamics to emerge remain unknown. We studied epileptic circuits using a newly developed integrated computational pipeline applied to cellular resolution functional imaging data. Control and preseizure neural dynamics in larval zebrafish and in chronically epileptic mice were captured using large-scale cellular-resolution calcium imaging. Biologically constrained effective connectivity modeling extracted the underlying cell-cell communication network. Novel analysis of the higher-order network structure revealed the existence of ‘superhub’ cells that are unusually richly connected to the rest of the network through feedforward motifs. Instability in epileptic networks was causally linked to superhubs whose involvement in feedforward motifs critically enhanced downstream excitation. Disconnecting individual superhubs was significantly more effective in stabilizing epileptic networks compared to disconnecting hub cells defined traditionally by connection count. Collectively, these results predict a new, maximally selective and minimally invasive cellular target for seizure control.HighlightsHigher-order connectivity patterns of large-scale neuronal communication networks were studied in zebrafish and miceControl and epileptic networks were modeled from in vivo cellular resolution calcium imaging dataRare ‘superhub’ cells unusually richly connected to the rest of the network through higher-order feedforward motifs were identifiedDisconnecting single superhub neurons more effectively stabilized epileptic networks than targeting conventional hub cells defined by high connection count.These data predict a maximally selective novel single cell target for minimally invasive seizure control

Summary Interneurons expressing cholecystokinin (CCK) and parvalbumin (PV) constitute two key GABAergic controllers of hippocampal pyramidal cell output. Although the temporally precise and millisecond-scale inhibitory regulation of neuronal ensembles delivered by PV interneurons is well established, the in vivo recruitment patterns of CCK-expressing basket cell (BC) populations has remained unknown. We show in the CA1 of the mouse hippocampus that the activity of CCK BCs inversely scales with both PV and pyramidal cell activity at the behaviorally relevant timescales of seconds. Intervention experiments indicated that the inverse coupling of CCK and PV GABAergic systems arises through a mechanism involving powerful inhibitory control of CCK BCs by PV cells. The tightly coupled complementarity of two key microcircuit regulatory modules demonstrates a novel form of brain-state-specific segregation of inhibition during spontaneous behavior.

Spatial memories that can last a lifetime are thought to be encoded during 'online' periods of exploration and subsequently consolidated into stable cognitive maps through their 'offline' reactivation. However, the mechanisms and computational principles by which offline reactivation stabilize long-lasting spatial representations remain poorly understood. Here, we employed simultaneous fast calcium imaging and electrophysiology to track hippocampal place cells over 2 weeks of online spatial reward learning behavior and offline resting. We describe that recruitment to persistent network-level offline reactivation of spatial experiences in mice predicts the future representational stability of place cells days in advance of their online reinstatement. Moreover, while representations of reward-adjacent locations are generally more stable across days, offline-reactivation-related stability is, conversely, most prominent for reward-distal locations. Thus, while occurring on the tens of milliseconds timescale, offline reactivation is uniquely associated with the stability of multiday representations that counterbalance the overall reward-adjacency bias, thereby predicting the stabilization of cognitive maps that comprehensively reflect entire underlying spatial contexts. These findings suggest that post-learning offline-related memory consolidation plays a complimentary and computationally distinct role in learning compared to online encoding.

Spatial memories which can last a lifetime are thought to be encoded during ‘online’ periods of exploration and subsequently consolidated into stable cognitive maps through their ‘offline’ reactivation1–5. However, the mechanisms and computational principles by which offline reactivation stabilize long-lasting spatial representations remain poorly understood. Here we employed simultaneous fast calcium imaging and electrophysiology to track hippocampal place cells over weeks of online spatial reward learning behavior and offline resting. We describe that recruitment to persistent network-level offline reactivation of spatial experiences predicts cells’ future multi-day representational stability. Moreover, while representations of reward-adjacent locations are generally more stable across days, reactivation-related stabilization is, conversely, most prominent for reward-distal locations. Thus, while occurring on millisecond time-scales, offline reactivation counter-balances the observed multi-day representational reward-adjacency bias, promoting the stabilization of cognitive maps which comprehensively reflect entire underlying spatial contexts. These findings suggest that post-learning offline-related memory consolidation plays complimentary and computationally distinct role in learning as compared to online encoding.

Temporal lobe epilepsy (TLE) is characterized by recurrent seizures driven by synchronous neuronal activity. The reorganization of the dentate gyrus (DG) in TLE may create pathological conduction pathways for synchronous discharges in the temporal lobe, though critical microcircuit-level detail is missing from this pathophysiological intuition. In particular, the relative contribution of adult-born (abGC) and mature (mGC) granule cells to epileptiform network events remains unknown. We assess dynamics of abGCs and mGCs during interictal epileptiform discharges (IEDs) in mice with TLE as well as sharp-wave ripples (SPW-Rs) in healthy mice, and find that abGCs and mGCs are desynchronized and differentially recruited by IEDs compared to SPW-Rs. We introduce a neural topic model to explain these observations, and find that epileptic DG networks organize into disjoint, cell-type specific pathological ensembles in which abGCs play an outsized role. Our results characterize identified GC subpopulation dynamics in TLE, and reveal a specific contribution of abGCs to IEDs., The dentate gyrus is involved in synchronous discharges and seizures, but its microcircuit functional organization in TLE is unclear. Here, the authors show that interictal discharges recruit specific granule cell ensembles dominated by adult-born immature neurons.

Temporal lobe epilepsy (TLE) is characterized by recurrent seizures driven by synchronous neuronal activity. The dentate gyrus (DG) region of the hippocampal formation is highly reorganized in chronic TLE; in particular, pathological remodeling of the “dentate gate” is thought to open up pathological conduction pathways for synchronous discharges and seizures in the mesial temporal lobe. However, this pathophysiological framework lacks a mechanistic explanation of how macroscale synchronous dynamics emerge from alterations of the DG at the microcircuit level. In particular, the relative contribution of developmentally defined subpopulations of adult-born (abGCs) and mature (mGCs) granule cells to epileptiform network events remains unknown. To address this question, we optically recorded activity dynamics of identified populations of abGCs and mGCs during interictal epileptiform discharges (IEDs) in mice with chronic TLE. We find that disjoint subsets of IEDs differentially recruit abGC and mGC populations. We used these observations to develop a neural topic modeling framework, under which we find that the epileptic DG network organizes into disjoint, cell-type specific pathological ensembles, a subset of which are recruited by each IED. We found that statistics of this ensemble structure are highly conserved across animals, with abGCs disproportionately driving network activity in the epileptic DG during IEDs. Our results provide the first in vivo characterization of activity dynamics of identified GC subpopulations in the epileptic DG, the first microcircuit-level correlates of IEDs in vivo, and reveal a specific contribution of abGCs to interictal epileptic events.HighlightsWe relate electrographic signatures of epilepsy to microcircuit dynamics at single-cell resolutionThe chronically epileptic dentate gyrus granule cell network is organized in lineage-specific pathological ensemblesA novel generative model framework for ensemble recruitment relates local field potential signatures to microcircuit activation during interictal epileptiform dischargesAdult-born granule cell-dominated ensembles are disproportionately represented among the inferred ensemblesThe most active ensemble during an interictal epileptiform discharge can be decoded directly from the local field potential spectrumThis Latent Ensemble Recruitment model of cell recruitment by interictal events is the first application of Bayesian topic modeling to in vivo two-photon calcium imaging data

The hippocampus plays a critical role in memory consolidation, mediated by coordinated network activity during sharp-wave ripple (SWR) events. Despite the link between SWRs and hippocampal plasticity, little is known about how network state affects information processing in dendrites, the primary sites of synaptic input integration and plasticity. Here, we monitored somatic and basal dendritic activity in CA1 pyramidal cells in behaving mice using longitudinal two-photon calcium imaging integrated with simultaneous local field potential recordings. We found immobility was associated with an increase in dendritic activity concentrated during SWRs. Coincident dendritic and somatic activity during SWRs predicted increased coupling during subsequent exploration of a novel environment. In contrast, somatic-dendritic coupling and SWR recruitment varied with cells' tuning distance to reward location during a goal-learning task. Our results connect SWRs with the stabilization of information processing within CA1 neurons and suggest that these mechanisms may be dynamically biased by behavioral demands.

Neurological and psychiatric disorders are associated with pathological neural dynamics. The fundamental connectivity patterns of cell-cell communication networks that enable pathological dynamics to emerge remain unknown. Here, we studied epileptic circuits using a newly developed computational pipeline that leveraged single-cell calcium imaging of larval zebrafish and chronically epileptic mice, biologically constrained effective connectivity modeling, and higher-order motif-focused network analysis. We uncovered a novel functional cell type that preferentially emerged in the preseizure state, the superhub, that was unusually richly connected to the rest of the network through feedforward motifs, critically enhancing downstream excitation. Perturbation simulations indicated that disconnecting superhubs was significantly more effective in stabilizing epileptic circuits than disconnecting hub cells that were defined traditionally by connection count. In the dentate gyrus of chronically epileptic mice, superhubs were predominately modeled adult-born granule cells. Collectively, these results predict a new maximally selective and minimally invasive cellular target for seizure control.

Hippocampal place cells represent the cellular substrate of episodic memory. Place cell ensembles reorganize to support learning but must also maintain stable representations to facilitate memory recall. Despite extensive research, the learning-related role of place cell dynamics in health and disease remains elusive. Using chronic two-photon Ca2+ imaging in hippocampal area CA1 of wild-type and Df(16)A+/− mice, an animal model of 22q11.2 deletion syndrome, one of the most common genetic risk factors for cognitive dysfunction and schizophrenia, we found that goal-oriented learning in wild-type mice was supported by stable spatial maps and robust remapping of place fields toward the goal location. Df(16)A+/− mice showed a significant learning deficit accompanied by reduced spatial map stability and the absence of goal-directed place cell reorganization. These results expand our understanding of the hippocampal ensemble dynamics supporting cognitive flexibility and demonstrate their importance in a model of 22q11.2-associated cognitive dysfunction.

Training in the active place avoidance task changes hippocampus synaptic function, the dynamics of hippocampus local field potentials, place cell discharge, and active place avoidance memory is maintained by persistent PKMζ activity. The extent to which these changes reflect memory processes and/or stress responses is unknown. We designed a study to assess stress within the active place avoidance task by measuring serum corticosterone (CORT) at different stages of training. CORT levels did not differ between trained mice that learned to avoid the location of the mild foot shock, and untrained no-shock controls exposed to the same environment for the same amount of time. Yoked mice, that received unavoidable shocks in the same time sequence as the trained mice, had significantly higher CORT levels than mice in the trained and no-shock groups after the first trial. This increase in CORT disappeared by the fourth trial the following day, and levels of CORT for all groups matched that of home cage controls. The data demonstrate that place avoidance training is no more stressful than experiencing a familiar environment. We conclude that changes in neural function as a result of active place avoidance training are likely to reflect learning and memory processes rather than stress. © 2016 Wiley Periodicals, Inc.

Calcium imaging using two-photon scanning microscopy has become an essential tool in neuroscience. However, in its typical implementation, the tradeoffs between fields of view, acquisition speeds, and depth restrictions in scattering brain tissue pose severe limitations. Here, using an integrated systems-wide optimization approach combined with multiple technical innovations, we introduce a new design paradigm for optical microscopy based on maximizing biological information while maintaining the fidelity of obtained neuron signals. Our modular design utilizes hybrid multi-photon acquisition and allows volumetric recording of neuroactivity at single-cell resolution within up to 1 × 1 × 1.22 mm volumes at up to 17 Hz in awake behaving mice. We establish the capabilities and potential of the different configurations of our imaging system at depth and across brain regions by applying it to in vivo recording of up to 12,000 neurons in mouse auditory cortex, posterior parietal cortex, and hippocampus.

SummarySilence of FMR1 causes loss of fragile X mental retardation protein (FMRP) and dysregulated translation at synapses, resulting in the intellectual disability and autistic symptoms of Fragile X Syndrome (FXS). Synaptic dysfunction hypotheses for how intellectual disabilities like cognitive inflexibility arise in FXS, predict impaired neural coding in the absence of FMRP. We tested the prediction by comparing hippocampus place cells in wild-type and FXS-model mice. Experience-driven CA1 synaptic function and synaptic plasticity changes are excessive in Fmr1-null mice, but CA1 place fields are normal. However, Fmr1-null discharge relationships to local field potential oscillations are abnormally weak, stereotyped, and homogeneous; also discharge coordination within Fmr1-null place cell networks is weaker and less reliable than wild-type. Rather than disruption of single-cell neural codes, these findings point to invariant tuning of single-cell responses and inadequate discharge coordination within neural ensembles as a pathophysiological basis of cognitive inflexibility in FXS.

The standard model of systems consolidation holds that the hippocampus (HPC) is involved only in the initial storage and retrieval of a memory. With time hippocampal–neocortical interactions slowly strengthen the neocortical memory, ultimately enabling retrieval of the memory without the HPC. Key support for this idea comes from experiments measuring memory recall in the socially-transmitted food preference (STFP) task in rats. HPC damage within a day or two of STFP learning can abolish recall, but similar damage five or more days after learning has no effect. We hypothesize that disruption of cellular consolidation outside the HPC could contribute to the amnesia with recent memories, perhaps playing a more important role than the loss of HPC. This view predicts that intraHPC infusion of Tetrodotoxin (TTX), which can block conduction of action potentials from the lesion sites, will block the retrograde amnesia in the STFP task. Here we confirm the previously reported retrograde amnesia with neurotoxic HPC damage within the first day after learning, but show that co-administration of TTX with the neurotoxin blocks the retrograde amnesia despite very extensive HPC damage. These results indicate that HPC damage disrupts cellular consolidation of the recent memory elsewhere; STFP memory may not ever depend on the HPC.

Calcium imaging using two-photon scanning microscopy has become an essential tool in neuroscience. However, in its typical implementation, the tradeoffs between fields of view, acquisition speeds, and depth restrictions in scattering brain tissue pose severe limitations. Here, using an integrated systems-wide optimization approach combined with multiple technical innovations, we introduce a new design paradigm for optical microscopy based on maximizing biological information while maintaining the fidelity of obtained neuron signals. Our modular design utilizes hybrid multi-photon acquisition and allows volumetric recording of neuroactivity at single-cell resolution within up to 1 × 1 × 1.22 mm volumes at up to 17 Hz in awake behaving mice. We establish the capabilities and potential of the different configurations of our imaging system at depth and across brain regions by applying it to in vivo recording of up to 12,000 neurons in mouse auditory cortex, posterior parietal cortex, and hippocampus.

There are still basic uncertainties concerning the role of the hippocampus (HPC) in maintaining long-term context memories. All experiments examining the effects of extensive HPC damage on context memory for a single learning episode find that damage soon after learning results in robust retrograde amnesia. Some experiments find that if the learning-to-damage interval is extended, remote context memories are spared. In contrast, other experiments fail to find spared remote context memory. One possible explanation for inconsistency might be the potency of the context memory conditioning procedure, as the experiments showing spared remote memory used a greater number of context-shock pairings, likely creating a stronger context fear memory. We designed an experiment to directly test the question: does increasing the number of context-shock pairings result in sparing of remote context memory after HPC damage? Six independent groups of rats received either 3 or 12 context-shock pairings during a single conditioning session and then either received extensive HPC damage or Control surgery at 1-week, 2-months, or 4-months after conditioning. 10 days after surgery rats were tested for memory of the shock context. Consistent with all relevant studies, HPC damage at the shortest training-surgery interval produced robust retrograde amnesia for both 3- and 12-shock groups whereas the Control rats expressed significantly high levels of memory. At the longer training-surgery interval, HPC damage produced similarly robust retrograde amnesia in the rats in both the 3- and 12-shock groups. These results clearly demonstrate that increasing the number of context-shock pairings within a single learning session does not change the dependence of the memory on the HPC. Current evidence from our group on retrograde amnesia has now shown that partial damage, dorsal vs. ventral damage, discrete cue + context conditioning, time after training, and number of context-shock pairings do not affect HPC dependence of context fear memories. When taken together, the evidence strongly supports a permanent role of the HPC in context memory.

There are still uncertainties about the role of the hippocampus (HPC) in memory consolidation. One theory, systems consolidation, states that the HPC is required for the initial storage of certain memories that subsequently become established in non-HPC networks through a lengthy process, involving an interaction with the HPC. A similar process may underlie the ability of multiple, distributed learning episodes of contextual fear conditioning to create a HPC-independent context fear memory, in a memory task that does not undergo systems consolidation with the mere passage of time [5]. The current study examined whether post-learning HPC activity is necessary to establish these HPC-independent context memories through distributed learning episodes. Rats received either three or six context conditioning sessions over the course of three days. The HPC-dependence of context memories was assessed using multisite, temporary inactivation of the HPC using ropivacaine during retention testing. We established that six conditioning sessions, but not three, created a memory that could be retrieved while the HPC was inactive. To directly test our hypothesis, HPC was inactivated after half of the six context-shock pairings in an independent group of rats. The rats were then tested for retention of context fear in the absence of HPC activity. Post-learning inactivation of the HPC did not affect the establishment of a HPC-independent context memory. These results favor the idea that at least one memory system outside the HPC can acquire context memories independently.

Training in the active place avoidance task changes hippocampus synaptic function, the dynamics of hippocampus local field potentials, place cell discharge, and active place avoidance memory is maintained by persistent PKMζ activity. The extent to which these changes reflect memory processes and/or stress responses is unknown. We designed a study to assess stress within the active place avoidance task by measuring serum corticosterone (CORT) at different stages of training. CORT levels did not differ between trained mice that learned to avoid the location of the mild foot shock, and untrained no-shock controls exposed to the same environment for the same amount of time. Yoked mice, that received unavoidable shocks in the same time sequence as the trained mice, had significantly higher CORT levels than mice in the trained and no-shock groups after the first trial. This increase in CORT disappeared by the fourth trial the following day, and levels of CORT for all groups matched that of home cage controls. The data demonstrate that place avoidance training is no more stressful than experiencing a familiar environment. We conclude that changes in neural function as a result of active place avoidance training are likely to reflect learning and memory processes rather than stress. © 2016 Wiley Periodicals, Inc.

We assessed the involvement of the hippocampus in recall of learned fear of a discrete visual stimulus using a fear-potentiated startle (FPS) procedure. Recall was measured by an increase in acoustic startle in the presence of a light that was paired with footshock. In Experiment 1, rats either received sham, dorsal, ventral, or complete (dorsal and ventral) NMDA-induced damage of the hippocampus following FPS acquisition. During the post-surgery retention test, only the rats with complete hippocampal damage showed a significant FPS deficit. In Experiment 2, we examined whether recent and remote memory for FPS would be differentially affected by complete hippocampal damage. Rats received sham or complete hippocampal damage 1- or 4-wk after FPS acquisition. During the retention test, sham rats exhibited significant FPS, whereas rats with hippocampal damage showed a large FPS deficit that was equivalent for recent and remote memories. In Experiment 3, we found that rats with complete hippocampal damage induced before conditioning showed levels of FPS that did not significantly differ from sham rats. Combined, these findings suggest that extensive damage to the hippocampus causes retrograde amnesia for a memory involving a light-shock association that is not temporally graded. The same damage does not cause anterograde amnesia in the same memory task. Partial damage of the hippocampus, whether of the dorsal or ventral region, was insufficient to cause retrograde amnesia. Thus, the hippocampus normally has a critical and long-lasting role enabling recall of fear conditioning to a discrete visual stimulus. In the absence of the hippocampus other memory systems support new learning.

We present evidence that certain learning parameters can make a memory, even a very recent one, become independent of the hippocampus. We confirm earlier findings that damage to the hippocampus causes severe retrograde amnesia for context memories, but we show that repeated learning sessions create a context memory that is not vulnerable to the damage. The findings demonstrate that memories normally dependent on the hippocampus are incrementally strengthened in other memory networks with additional learning. The latter provides a new account for patterns of hippocampal retrograde amnesia and how memories may become independent of the hippocampus.

We present an overview of two of our on-going projects relating processes in the hippocampus to memory. We are trying to understand why retrograde amnesia occurs after damage to the hippocampus. Our experiments establish the generality of several new retrograde amnesia phenomena that are at odds with the consensus view of the role of the hippocampus in memory. We show in many memory tasks that complete damage to the hippocampus produces retrograde amnesia that is equivalent for recent and remote memories. Retrograde amnesia affects a much wider range of memory tasks than anterograde amnesia. Normal hippocampal processes can interfere with retention of a long-term memory stored outside the hippocampus. We conclude that the hippocampus competes with nonhippocampal systems during memory encoding and retrieval. Finally, we outline a project to understand and manipulate adult hippocampal neurogenesis in order to repair damaged hippocampal circuitry to recover lost cognitive functions.

Behavior is used to assess memory and cognitive deficits in animals like Fmr1-null mice that model Fragile X Syndrome, but behavior is a proxy for unknown neural events that define cognitive variables like recollection. We identified an electrophysiological signature of recollection in mouse dorsal Cornu Ammonis 1 (CA1) hippocampus. During a shocked-place avoidance task, slow gamma (SG) (30–50 Hz) dominates mid-frequency gamma (MG) (70–90 Hz) oscillations 2–3 s before successful avoidance, but not failures. Wild-type (WT) but not Fmr1-null mice rapidly adapt to relocating the shock; concurrently, SG/MG maxima (SGdom) decrease in WT but not in cognitively inflexible Fmr1-null mice. During SGdom, putative pyramidal cell ensembles represent distant locations; during place avoidance, these are avoided places. During shock relocation, WT ensembles represent distant locations near the currently correct shock zone, but Fmr1-null ensembles represent the formerly correct zone. These findings indicate that recollection occurs when CA1 SG dominates MG and that accurate recollection of inappropriate memories explains Fmr1-null cognitive inflexibility., Author summary Behavior is often used as proxy to study memory and cognitive deficits in animals like Fmr1-KO mice that model Fragile X Syndrome, the most prevalent single-gene cause of intellectual disability and autism. However, it is unclear what neural events define cognitive variables like recollection of memory and cognitive inflexibility. We identified a signature of recollection in the local field potentials of mouse dorsal CA1 hippocampus. When mice on a rotating platform avoided an invisible, fixed shock zone, slow gamma (30–50 Hz) oscillations dominated mid-frequency gamma (70–90 Hz) oscillations (SGdom) 2–3 s before mice successfully avoided the shock zone. Wild-type but not Fmr1-KO mice adapt to relocating the shock zone; concurrently, SGdom decreases in wild-type but not in cognitively inflexible Fmr1-KO mice. During SGdom, principal cell ensembles represent distant locations; during place avoidance, these are avoided places in the shock zone vicinity. During shock relocation, wild-type ensembles encode distant locations near the currently correct shock zone, but Fmr1-KO ensembles manifest representational inflexibility, encoding the formerly correct zone. These findings suggest evidence for competition amongst CA1 inputs for CA1 information-processing modes and indicate that recollection occurs when CA1 slow gamma dominates mid-frequency gamma and that accurate recollection of inappropriate memories explains Fmr1-KO cognitive inflexibility.

The time when an event occurs can become part of autobiographical memories. In brain structures that support such memories, a neural code should exist that represents when or how long ago events occurred. Here we describe a neuronal coding mechanism in hippocampus that can be used to represent the recency of an experience over intervals of hours to days. When the same event is repeated after such time periods, the activity patterns of hippocampal CA1 cell populations progressively differ with increasing temporal distances. Coding for space and context is nonetheless preserved. Compared with CA1, the firing patterns of hippocampal CA3 cell populations are highly reproducible, irrespective of the time interval, and thus provide a stable memory code over time. Therefore, the neuronal activity patterns in CA1 but not CA3 include a code that can be used to distinguish between time intervals on an extended scale, consistent with behavioral studies showing that the CA1 area is selectively required for temporal coding over such periods.

Context memories normally depend on the hippocampus (HPC) but, in the absence of the HPC, other memory systems are capable of acquiring and supporting these memories. This suggests that the HPC can interfere with other systems during memory acquisition. Here we ask whether the HPC can also interfere with the retrieval of a context memory that was independently acquired by a non-HPC system. Specifically, we assess whether the HPC can impair the retrieval of a contextual fear-conditioning memory that was acquired while the HPC was temporarily inactive. Rats were infused with the γ-aminobutyric acid (GABA)(A) receptor agonist muscimol in the dorsal and ventral HPC either before acquisition, retrieval, or prior to both acquisition and retrieval, consistent with the effects of permanent HPC lesions on contextual fear conditioning, if the HPC was inactive at the time of acquisition and retention memory was intact. Thus, non-HPC systems acquired and supported this memory in absence of the HPC. However, if the HPC was inactive during acquisition but active thereafter, rats displayed severe deficits during the retention test. Moreover, when the same rats received a second retention test but with the HPC inactive at this time, the memory was recovered, suggesting that removal of a form of interference allowed the memory to be expressed. Combined, these findings imply that the HPC competes and/or interferes with retrieval of a long-term memory that was established in non-HPC systems.

Damage to the hippocampus (HPC) using the excitotoxin N-methyl-D-aspartate (NMDA) can cause retrograde amnesia for contextual fear memory. This amnesia is typically attributed to loss of cells in the HPC. However, NMDA is also known to cause intense neuronal discharge (seizure activity) during the hours that follow its injection. These seizures may have detrimental effects on retrieval of memories. Here we evaluate the possibility that retrograde amnesia is due to NMDA-induced seizure activity or cell damage per se. To assess the effects of NMDA induced activity on contextual memory, we developed a lesion technique that utilizes the neurotoxic effects of NMDA while at the same time suppressing possible associated seizure activity. NMDA and tetrodotoxin (TTX), a sodium channel blocker, are simultaneously infused into the rat HPC, resulting in extensive bilateral damage to the HPC. TTX, co-infused with NMDA, suppresses propagation of seizure activity. Rats received pairings of a novel context with foot shock, after which they received NMDA-induced, TTX+NMDA-induced, or no damage to the HPC at a recent (24 hours) or remote (5 weeks) time point. After recovery, the rats were placed into the shock context and freezing was scored as an index of fear memory. Rats with an intact HPC exhibited robust memory for the aversive context at both time points, whereas rats that received NMDA or NMDA+TTX lesions showed a significant reduction in learned fear of equal magnitude at both the recent and remote time points. Therefore, it is unlikely that observed retrograde amnesia in contextual fear conditioning are due to disruption of non-HPC networks by propagated seizure activity. Moreover, the memory deficit observed at both time points offers additional evidence supporting the proposition that the HPC has a continuing role in maintaining contextual memories.

The properties of retrograde amnesia after damage to the hippocampus have been explicated with some success using a rat model of human medial temporal lobe amnesia. We review the results of this experimental work with rats focusing on several areas of consensus in this growing literature. We evaluate the theoretically significant hypothesis that hippocampal retrograde amnesia normally exhibits a temporal gradient, affecting recent, but sparing remote memories. Surprisingly, the evidence does not provide much support for the idea that there is a lengthy process of systems consolidation following a learning episode. Instead, recent and remote memories tend to be equally affected. The extent of damage to the hippocampus is a significant factor in this work since it is likely that spared hippocampal tissue can support at least partial memory retrieval. With extensive hippocampal damage gradients are flat or, in the case of memory tasks with flavour/odour retrieval cues, the retrograde amnesia covers a period of about 1 – 3 days. There is consistent evidence that at the time of learning the hippocampus interferes with or overshadows memory acquisition by other systems. This contributes to the breadth and severity of retrograde amnesia relative to anterograde amnesia in the rat. The fact that multiple, distributed learning episodes can overcome this overshadowing is consistent with a parallel dual-store theory or a Distributed Reinstatement Theory in which each learning episode triggers a short period of memory replay that provides a brief hippocampal-dependent systems consolidation.

Previous work indicates an essential role of the basolateral amygdala in stimulus-reward learning and the dorsal hippocampus in spatial learning and memory. The goal of the present, experiments was to examine the involvement of the amygdala and hippocampus in performance of tasks requiring stimulus-reward and spatial/relational learning and memory processes in the retrograde direction. Accordingly, this series of experiments tested the effects of temporary, inactivations directed at the basolateral nucleus of the amygdala or dorsal hippocampus on the, expression of a conditioned place preference (CPP) task or a spatial navigation water task. The results, of Experiments 1a and b showed that inactivations of the amygdala impaired the expression of a, previously acquired CPP but did not impair the expression of a learned spatial response required for, accurate performance of a spatial navigation task. The results of Experiments 2a and b showed that, inactivations of the dorsal hippocampus impaired expression of a learned response required for the, accurate performance of a spatial navigation task but did not impair the learned response required for, the expression of a CPP. Taken together, the results showed a functional dissociation between the, effects of amygdala or hippocampal dysfunction on the expression of these different classes of tasks.

Performance in several memory tasks is known to be unaffected by hippocampal damage sustained before learning, but is severely disrupted if the same damage occurs after learning. Memories for preferred locations, or home bases, in exploratory tasks can be formed by rats with hippocampal damage, but it is unknown if the memory for a home base survives hippocampal damage. To examine this question, for 30 min each day for five consecutive days, rats explored a circular open field containing one local cue. By Day 5 the rats preferentially went directly to that location, spent the majority of their time at that location, made rapid direct trips to that location when returning from an excursion and so demonstrated that the location was a home base. Memory for the cued location was examined after a 24 h or 14-day interval with the cue removed. In Experiments 1 and 2, con- trol rats and rats with prior N-methyl-D-aspartic acid hippocampal lesions demonstrated memory of the home base location by making direct trips to that location. In Experiment 3, rats that had first explored the open field and cue and then received hippocampal lesions showed no memory for the cued location. The absence of anterograde impair- ment vs. the presence of retrograde impairment for memory of a spatial home base confirms a role for the hippocampus in the retention of spa- tial memory acquired during exploration. V C 2009 Wiley-Liss, Inc.

An animal confronts numerous challenges when constructing an optimal navigational route. Spatial representations used for path optimization are likely constrained by critical environmental factors that dictate which neural systems control navigation. Multiple coding schemes depend upon their ecological relevance for a particular species, particularly when dealing with the third, or vertical, dimension of space.

SummaryThe hippocampal CA2 subregion has a different anatomical connectivity pattern within the entorhino-hippocampal circuit than either the CA1 or CA3 subregion. Yet major differences in the neuronal activity patterns of CA2 compared with the other CA subregions have not been reported. We show that standard spatial and temporal firing patterns of individual hippocampal principal neurons in behaving rats, such as place fields, theta modulation, and phase precession, are also present in CA2, but that the CA2 subregion differs substantially from the other CA subregions in its population coding. CA2 ensembles do not show a persistent code for space or for differences in context. Rather, CA2 activity patterns become progressively dissimilar over time periods of hours to days. The weak coding for a particular context is consistent with recent behavioral evidence that CA2 circuits preferentially support social, emotional, and temporal rather than spatial aspects of memory.