Hippocampus

Hippocampal place cells encode spatial information within a theta-organized temporal framework paced by the medial septum (MS). Lesions or inactivation of the MS impair spatial learning and disrupt hippocampal theta rhythmicity, long-term potentiation, and plasticity-related gene expression, while often sparing spatially selective firing of CA1 neurons (but not CA3 neurons). Although many rodent studies argue against classical systems consolidation by showing persistent hippocampal dependence of spatial memories, other work has suggested that training structure, spaced vs. massed trials, can influence this dependence. To investigate this possibility, we used DREADD-based, reversible, inhibition of MS GABAergic neurons, some of which are known to project to hippocampus. DREADD activation reduced hippocampal theta power and spatial information encoded by hippocampal neurons while largely preserving overall neuronal firing. We then examined the effect of inhibition of medial septal GABAergic neurons on learning the correct goal arm in an 8-arm maze when the correct arm was randomly changed each day. On each day, the mice were given two forced-choice trials indicating the correct arm and then 5 free-choice trials (without correction) and were always started from an opaque cylinder in the maze center, in a random orientation, to eliminate possible use of a simple response strategy. When the correct goal arm varied randomly daily, MS cell inhibition severely and repeatedly impaired acquisition. In contrast, when the correct goal arm was subsequently fixed across days, performance was initially impaired but became resistant to DREADD activation over time. Once performance reached asymptote, the goal arm was switched to a new (random) position. In this case, learning was no longer impaired by DREADD activation. This generalization suggests that repeated fixed-goal training in the same environment induces a broader reorganization of the neural systems supporting spatial behaviour. One possibility is that mice develop a septal-independent task-solving strategy that supports both retrieval of established goal locations and acquisition of new ones within a stable environment. This transition could reflect the gradual adoption of a non-spatial strategy such as visual pattern recognition, or the use of a directional cue. Moving the most salient distal cue in the environment (a single room light) produced a substantial change in the visual configurations seen from the arm entry points, and disrupted performance; however, it did not produce a consistent directional shift relative to the cue, suggesting that the light contributed to an integrated visuo-spatial representation rather than serving as the reference frame origin. We conclude that the mice switched from a hippocampus/MS-dependent spatial strategy to a non-hippocampus-dependent visual pattern matching solution.

One of the central tensions in memory research is whether consistency or differentiation across events is beneficial for remembering. While theoretical models posit that the hippocampal subfield CA1 subserves both types of computations, it remains unclear how it can simultaneously express both in service of recognition memory. Here, we contrasted the two prominent functions of CA1: reinstatement (consistency) and novelty processing (differentiation) to address this gap. To this end, we analysed the Natural Scenes Dataset featuring eight participants who completed a continuous recognition memory task spanning 41 separate days with 213,000 trials in total. We calculated reinstatement and novelty indices for each image and then examined the degree to which these reflected successful memory encoding. We found that CA1 showed evidence for encoding-related reinstatement as well as for novelty processing even after controlling for each other. Reinstatement was specific to retrieving the initial representation during the first retrieval attempt and did not extend to other forms of reinstatement. Exploratory analyses additionally identified reinstatement in CA3, which exhibited different response profiles compared to CA1. Our work thus highlights that computations of consistency as well as differentiation can be orthogonal signals contributing independently to memory success and can simultaneously co-exist within the same region of the hippocampus.

The laminar anatomy of the hippocampal microcircuit is conserved across mammals, and its physiology has been characterized extensively in rodents, yet how this circuitry is organized physiologically in the primate brain remains poorly understood. Here we used high-density Neuropixels probes to record simultaneously across the subfields of CA1, CA3 and the dentate gyrus in two awake macaques. Sharp-wave ripples and dentate spikes produced current source density signatures that provided physiological landmarks for CA1 and the dentate gyrus, enabling alignment of recordings to hippocampal cytoarchitecture. Theta-band (3-7 Hz) oscillatory activity occurred in discrete bouts whose prevalence peaked in the stratum lacunosum-moleculare. In CA1, gamma-band amplitude was modulated by theta-band phase, with fast and slow gamma preferentially coupled to distinct phases of the theta cycle. Putative principal cells and two interneuron classes differed systematically in firing rate, burstiness, and rhythmic modulation, with principal cells showing theta-rhythmic firing and wide-waveform interneurons showing alpha- and beta-rhythmic firing. Cross-correlogram analyses revealed sparse, distance-dependent functional coupling with a consistent directional hierarchy in which principal cells led interneurons. Together, these results identify the laminar microcircuit organization of the primate hippocampus in vivo and provide a new physiological framework for interpreting primate hippocampal recordings.

We recently reported that rats performed better at a task distance of 2 m than at 0 m in a T-maze delayed alternation paradigm using a movable home cage in the longer-delay condition (Takita & Ichitani, 2026). We simultaneously recorded local field potentials from the bilateral prefrontal cortex, intermediate hippocampus, and ventral hippocampus. Across task epochs, coherence and two cross-frequency measures (phase-locking value and modulation index [MI]) revealed differences between correct and error trials in prefrontal interactions with hippocampal subregions. Among these measures, only MI was affected by task distance during the pre-task delay epoch. MI was highest in 2-m error trials and lowest in correct trials. In 0-m error trials, MI transiently increased during arm entry to levels comparable to those in 2-m error trials before declining toward the levels observed in correct trials during the later post-task delay. These MI dynamics appeared to be consistent with distance-dependent differences in behavioral performance. In addition, normalized Correct-Error Indices calculated for each electrophysiological measure revealed differential contributions of prefrontal coupling with the intermediate and ventral hippocampus across task distances. These findings suggest the existence of distinct near and far working memory states underlying distance-dependent behavioral differences, with distinct yet complementary contributions of the intermediate and ventral hippocampus to prefrontal interactions.

Hippocampal replay is proposed to support memory and planning by preferentially reactivating behaviorally significant locations. Although learning can alter which locations are reactivated and how frequently, whether it also alters the dynamics by which replay propagates through the cognitive map remains unknown. To address this, we recorded large-scale CA1 activity while rats collected identical rewards at multiple spatial locations, only one of which was consistently rewarded and served as the Goal. Replay events occurred nearly twice as often during reward consumption at the Goal compared to Non-Goal sites and were accompanied by reduced inhibition. Goal-associated replays were also slower, shorter, and more locally confined. Replays originating elsewhere in the arena slowed and preferentially terminated when nearing the Goal, indicating that the Goal locally resists replay propagation regardless of where the replay was initiated. Increasing evidence suggests that hippocampal sequences arise from adaptation-like mechanisms that propagate neural activity away from recently active states. We hypothesized that the slowing and spatial confinement of Goal-associated replay arises from reduced effective adaptation near the Goal. A recurrent network model showed that reducing adaptation strength reproduces these effects and correctly predicted increased population firing rates and weaker avoidance of recently traveled or reactivated paths. Finally, we found evidence for reduced interneuron-mediated feedback inhibition near the Goal, providing a potential circuit mechanism for locally modulating adaptation. Our findings show that learning locally reshapes the dynamics governing internally generated activity, causing replay to linger near behaviorally significant locations and providing a new mechanism for their preferential reactivation.

Spatial navigation requires animals to integrate current environmental information with previously acquired spatial memories. The locus coeruleus provides neuromodulatory input to the hippocampus, but whether this pathway facilitates spatial learning in general or preferentially supports the updating of established representations remains unclear. Here, we selectively activated LC projections to the dorsal hippocampus while mice performed object-location recognition and an appetitive radial-maze task involving initial spatial learning followed by reversal. LC-hippocampal activation enhanced object-location memory and improved reversal learning, reducing total and working-memory errors, but did not affect initial spatial reference acquisition or retention. To characterize navigation beyond classical performance measures, we developed a graph-based analysis comparing each observed trajectory with paths generated from random, regular, small-world and heuristic goal-directed network models. Radial-maze trajectories contained a structured mixture of goal-directed-like and regular or serial-like patterns that evolved across learning. In addition, agreement with the goal-directed model was associated with fewer errors and greater proximity to the rewarded arm. Together, these findings indicate that LC inputs to the hippocampus preferentially facilitate spatial memory updating rather than uniformly enhancing spatial learning, and introduce a complementary framework for quantifying the organization of radial-maze trajectories.

The GABAA positive allosteric modulator diazepam is taken systemically by millions of people daily. GABAA signaling is essential for hippocampal circuit function, but the effects of systemic diazepam on hippocampal information processing during behavior has not been studied. To answer this question, large neural ensembles were recorded from rats running a linear track under systemic diazepam administration. A cross-correlation of spiking activity revealed significantly increased inhibition from interneurons, aligned with the timescale of GABAA, suggesting a direct effect on local circuits. Local field potentials (LFP) showed an increase in theta and lo-gamma (30-50 Hz) power but a decrease in hi-gamma (80-120 Hz) power. We also found decreased amplitude and rate of sharp wave ripple (SWR) events and a reduction of firing rate and proportion of cells recruited to the SWRs. An autocorrelation of single-cell spike trains revealed a decrease and shift from shorter to longer timescales, aligning differently with theta frequencies. Phase coupling measurements showed decreased cellular coupling to theta and increased coupling to lo-gamma and hi-gamma. Finally, entropy of decoding along the track was increased, suggesting less precise spatial representations under diazepam. These changes suggest mechanisms that would likely disrupt hippocampal memory storage and consolidation processes under systemic diazepam.

Older adults typically exhibit reduced episodic memory precision, while maintaining relatively preserved retrieval success. However, little is known about whether these age-related differences are influenced by internal biological factors (e.g., chronotype) or external testing conditions (e.g., experiment format, time of day). To address this question, younger and older adults completed an object-location memory task online, either in the morning or evening, and either with or without video-based supervision. Memory performance was assessed using mean absolute error and Bayesian hierarchical mixture modelling, which dissociated memory precision ({kappa}) from the probability of memory-based responding ({theta}). Immediate memory performance was high across age groups, irrespective of time of day. Greater encoding error predicted greater retrieval error, and participants tested in the video condition exhibited lower recall error and higher recognition performance than those tested without supervision. Consistent with prior studies, older adults exhibited reduced memory precision relative to younger adults, whereas retrieval success remained largely intact. However, Bayesian Hierarchical Modelling provided no evidence that time of day, experiment format, or their interactions with age influenced either memory precision or retrieval probability. Older adults reported stronger morning preferences than younger adults, and participants generally selected testing times that aligned with their chronotype. Nevertheless, alignment between chronotype and testing time did not modulate memory performance. The results indicate that age-related differences in episodic memory precision are robust across variations in testing context, including time of day, experiment format, and individual differences in chronotype. More broadly, the results support the feasibility of remote and unsupervised testing for memory precision research and suggest that chronotype and testing time are unlikely to be major sources of variability in immediate object-location memory performance.

Modest positive associations between episodic memory performance and whole hippocampal and hippocampal subfield volumes have been reported in numerous prior studies. A smaller number of studies have reported associations between hippocampal volume and performance on tests of non-mnemonic cognition. The present study examined whether these associations were evident in a lifespan sample of cognitively healthy adults. Of particular interest was whether any identified associations were sensitive to age, and whether associations between subfield volumes and mnemonic and non-mnemonic performance were subfield dependent. We acquired high-resolution T1- and T2-weighted structural images from 163 adults (18-87 years of age). Participants also undertook a comprehensive neuropsychological test battery and an in-scanner test of source memory. Principal components analysis was employed to reduce the neuropsychological test scores to 5 cognitive components. Two components reflected memory performance while the other three reflected different aspects of non-mnemonic cognition. Hippocampal subfields (Cornu Ammonis (CA)1, CA2-3, dentate gyrus (DG) and subiculum) were segmented and measured with the Automated Segmentation of Hippocampus Subfields (ASHS) package. Source memory performance was selectively associated across participants with CA2-3 volume. By contrast, both mnemonic and non-mnemonic component scores derived from the test battery were associated exclusively with the volume of the DG. All associations were age-invariant. The findings indicate that different cognitive domains can be dissociated by virtue of their associations with different hippocampal subfields. Of importance, these associations appear to be life-long and hence are unlikely to reflect individual differences in age-related decline in structural integrity.

Working memory has been considered a delay-dependent retention system, but variability in delay duration across species and tasks suggests that task-intrinsic factors may also contribute. Here, we investigated the effects of delay duration (75 s vs. 150 s) and task distance (0 m vs. 2 m) on working memory using a T-maze delayed alternation task with a movable home-cage apparatus in rats. At the 150-s delay, accuracy was 9% lower at 0 m than at 2 m (75% vs. 84%), with a similar numerical tendency observed at the 75-s delay (4% lower). A two-way repeated measures ANOVA revealed significant main effects of both task distance and delay duration, with no significant interaction (p = 0.217). Post hoc pairwise comparisons indicated that accuracy in the 0-m condition was significantly lower at 150 s than at 75 s (adjusted p = 0.038). At the 150-s delay, accuracy was also significantly lower in the 0-m condition than in the 2-m condition (adjusted p = 0.019). These results suggest that working memory retention is influenced not only by temporal constraints but also by task-intrinsic factors such as task distance, with the observed effects appearing independent and consistent with a two-factor framework.

Hippocampal sharp-wave ripple (SWR) events occur during post-experience rest and sleep and play a significant role in memory consolidation. Recent ex vivo studies have found orexin-driven neuromodulatory effects on SWR parameters and proposed that they can influence memory consolidation. Additionally, behavioral studies demonstrate contradictory results regarding orexinergic effects on memory acquisition depending on task structure and intervention time. This inconsistency, along with the diffuse spread of orexin receptors (OXR) in the CA1 and CA3 hippocampus, challenges theoretical interpretation of orexinergic effects on memory. To reconcile this problem, we propose a rate-based model linking orexinergic tone-dependent SWR statistics to memory performance. The model combines an encoding module whose gain scales with the global orexinergic tone with a consolidation module driven by OX2R-specific replay dynamics. The model is based on a plasticity rule that considers SWR events as the unit of induction. Therefore, weight change requires sufficient replay content and depolarizing drive. We observed that, depending on the task structure, encoding-dominant learning benefits discrimination as the orexin drive increases. Consolidation-dominant learning shows a non-monotonic relationship with an internal optimum level of orexinergic tone. This interaction highlights that stronger truncation at higher receptor engagement shortens memory replay and reduces the efficacy of the consolidation process. The model predicts that the optimal regime depends on task complexity reflected in sequence length. Together, these results demonstrate how task demands determine whether increased orexinergic drive enhances or impairs effective consolidation and SWR-dependent replay in the hippocampus.

Schema memory refers to generalized knowledge extracted from multiple related episodes. According to systems consolidation theory, such representations emerge during sleep through the transformation of hippocampus-dependent episodic memories into neocortical schema representations. Whether this process requires mature episodic memory expression during early development remains unclear. Here, we examined schema formation in infant rats with an immature hippocampus. At postnatal day (PD) 25, pups (n=24) were tested in an adapted object-place paradigm enabling abstraction of a spatial regularity across eight consecutive episodes. Following encoding, pups either slept or remained awake for two hours, and schema memory was tested 22 hours later. Control groups were exposed to pseudorandomized object configurations. Schema memory was expressed only after exposure to spatial regularities and only when sleep followed encoding. To directly assess episodic memory under comparable conditions, an additional group of pups (n=12) was tested in a standard single-episode object-place recognition (OPR) task with post-encoding sleep. At a 4-hours test, these pups did not show episodic object-place memory. These findings indicate that sleep supports schema memory formation during early life under conditions in which the expression of robust single-episode memory is not yet evident, suggesting that schema abstraction in infancy does not depend on fully developed hippocampal episodic representations.

Automated segmentation has made hippocampal subfield volumes a routine measurement, and studies now report which subfield relates to an outcome rather than whether the hippocampus does. Those reports do not agree with one another, and the standard explanation is insufficient statistical power. We argue that a second limit operates independently of sample size. Using 638 participants from a population-derived adult lifespan cohort, we first show that no individual subfield contributes to a general cognitive factor beyond a single global size component: no coefficient interval excludes zero, the local block carries half a percent of outcome variance, and no model improves out-of-sample prediction over the global factor alone. Because an observed null cannot distinguish an absent effect from an effect the design cannot locate, we then planted effects of known location and size in the measured design and in a whitened copy of it that preserves sample size, dimensionality and effect size while removing only the correlation between subfields. The arms were paired down to the noise vector. Collinearity did not place recovery out of reach; it multiplied the required sample size by a factor of roughly two to three, and the penalty widened as cohorts grew. At the effect sizes this literature reports, neither design reached an adequate recovery rate at any sample size, and coarsening the parcellation rescued neither. The choice of estimator moved recovery further than collinearity did. We provide a calibration surface on which a planned design can be located before data collection.

Hippocampal area CA3 is widely believed to serve a core memory function: retrieving distributed patterns of neural activity that were previously stored in the recurrent connections between neurons. However, it remains unknown how the physiological properties of individual neurons contribute to this function. Here, we present a mathematical analysis of a canonical recurrent neural network model of CA3. Our analysis provides three main, experimentally testable predictions for recurrent circuits performing stable memory recall. Two of these predictions, that pyramidal cells should be characterized by elevated intrinsic excitability and by inhibition-dominated recurrent connections, are consistent with previous experimental findings. We thus focused on testing the third prediction: that neuronal activation functions have an exponent slightly above $1$. For this, we performed \textit{in vivo} intracellular recordings of 49 pyramidal neurons from the CA3 area of behaving mice. Fitting a range of parametric models to these voltage traces and performing statistical model comparison revealed an average neural activation exponent slightly above $1$, confirming our theoretical predictions, with substantial heterogeneity across cells, which remains to be accounted for by the theory. An analysis of 133 further cells from two other previous studies provided neural activation exponent estimates highly consistent with those we found in our data. Our results suggest that the properties of hippocampal CA3 area are tuned to support reliable memory recall even at the level of single neurons.

Food carrying is an adaptive component of foraging that integrates resource evaluation with home-directed navigation, providing a naturalistic model for investigating how the brain organizes goal-directed behaviour. Despite extensive work on hippocampal coding during navigation and homing, how CA1 representations are reorganized when animals spontaneously transport acquired food home remains largely unexplored. We recorded dorsal CA1 population activity using one-photon calcium imaging with a V4 Miniscope while mice performed a self-paced foraging task in which food could be consumed at the acquisition site followed by a homeward return or carried to the home for consumption. Mice preferentially carried larger pellets, indicating that transport behaviour was sensitive to resource value. CA1 spatial coding differed systematically across behavioural outcomes. During carry-homeward runs, spatial representations were sparser, conveyed more spatial information, and showed greater trial-to-trial stability than during eat-inward runs, indicating a more precise and reliable place code during home-directed transport. Place fields also shifted forward during carrying, consistent with a retrospective bias toward recently traversed locations. By linking a self-generated food-handling decision to coordinated changes in the precision, stability, and temporal organization of CA1 activity, these findings extend hippocampal spatial-coding frameworks from trained navigation to ecologically grounded foraging behaviour.

The formation of long-term memory during sleep depends on the reactivation and redistribution of recently acquired mnemonic information during non-rapid eye movement (NREM) sleep. Animal studies suggest that hippocampal memory replay during slow-wave sleep is coordinated through the interaction of sharp-wave ripples, thalamocortical sleep spindles, and neocortical slow oscillations (SOs). However, direct evidence for the contribution of hippocampal network dynamics to sleep-dependent memory consolidation in humans remains limited. Here, we investigated sleep-dependent memory consolidation in patients (n=13) with transient global amnesia (TGA), a clinical syndrome associated with focal and transient lesions of the hippocampal CA1 region. Patients completed a verbal paired-associative learning task followed by nocturnal polysomnography and subsequent memory retrieval during the acute phase of TGA (acute condition) and again after clinical recovery (follow-up condition). Overnight memory consolidation was significantly impaired during the acute phase compared with the follow-up session. NREM EEG theta power (4-8 Hz) was reduced during the acute phase of TGA. Importantly, increases in theta power from the acute to the follow-up session predicted corresponding improvements in memory consolidation within individuals. In contrast, established NREM markers of sleep-dependent memory consolidation, including sleep spindle density, SO density, and SO-spindle coupling, did not differ between the acute and follow-up conditions. These findings suggest that transient hippocampal CA1 dysfunction disrupts sleep-related hippocampal network dynamics reflected in reduced NREM theta activity, which in turn is associated with impaired memory consolidation. Sleep-related theta oscillations may therefore represent a functional marker of hippocampal network integrity during sleep-dependent memory consolidation in humans.

The hippocampus is essential for learning and memory and undergoes prolonged development throughout childhood and adolescence. Evidence concerning hippocampal maturation is based primarily on volumetric measures. However, macrostructural growth and myelination processes may represent distinct biological processes. Using Hippunfold, we quantified hippocampal subfield volumes and myelin-sensitive tissue concentrations as proxies for tissue maturation using T1w/T2w ratios in 175 community-recruited participants aged 9 months to 21 years. Hippocampal subfield volumes were best described by quadratic developmental trajectories, whereas T1w/T2w ratios increased linearly with age across all subfields. Males exhibited larger hippocampal volumes, and females demonstrated higher and steeper age-related increases in T1w/T2w ratios. Sex-related hippocampal subfield differences were observed despite largely comparable cognitive and behavioural profiles. Hippocampal subfield volumes and myelin follow distinct developmental pathways, revealing sex-specific patterns of development that are not fully captured by morphology alone.

Single-cell or single-nucleus RNA sequencing are common methods to investigate gene expression. However, to clarify the genes in specific types of cells in a small circuit there are limitations to current approaches. Here we present modifications to standard protocols to overcome the limitations and do so in a manner that will be accessible to novices. Then the modified methods are applied to a question about a small area of the brain, the dentate gyrus (DG) of the mouse, where information about cell types was of interest. The question arose from data acquired in a mouse model of Alzheimers disease where early hyperactivity of the principal cells, granule cells (GCs), was identified that was difficult to explain by existing data. Therefore, we investigated altered gene expression in GCs, and other DG cell types that influence GCs, to identify putative mechanisms. Validations of the modified methods are addressed, comparisons are made to other methods, and comparisons of mouse and human data are presented.

Accurate alignment of hippocampal anatomy across individuals remains challenging due to complex and highly variable folding patterns that are not well captured by conventional volumetric approaches. HippUnfold introduced a surface-based representation of the hippocampus, but key components--including coordinate estimation and inter-subject correspondence--were defined in the volumetric domain, making them susceptible to topological errors and interpolation artifacts. Here, we introduce a surface-intrinsic formulation of hippocampal unfolding in which geometry, intrinsic coordinates, and correspondence are defined directly on subject-specific surface manifolds. Intrinsic anterior-posterior and proximal-distal coordinates are computed by solving Laplace equations on the surface, and correspondence is established through surface-based resampling in unfolded space, replacing inverse volumetric warping. Relative to the original HippUnfold approach, this formulation improves test-retest consistency, subject identifiability, and mesh quality, while better preserving subject-specific gyral and sulcal morphology. Surface representations show reduced distortion between folded and unfolded spaces and eliminate misplaced or outlier vertices associated with volumetric warping. These improvements translate to enhanced sensitivity in a clinical application, improving lateralization of temporal lobe epilepsy. These results demonstrate that a surface-intrinsic formulation provides a principled and robust foundation for hippocampal unfolding, enabling topology-preserving alignment and more accurate characterization of inter-individual variability in health and disease.

Flexible decision making depends on internal representations that capture the latent structure of a task, allowing prior knowledge to be applied in novel circumstances. Spatial navigation provides a useful model for studying flexible choice behavior, because spatial location is itself a latent variable that must be inferred rather than directly perceived. Here, we trained rats on a navigation task that required them to reach the same goal via two distinct paths from different starting locations, and then return to one of the two starting locations before beginning the next trial. Some rats were trained to rely on distal visual landmarks, allowing task states to be identified from current sensory information, whereas others were trained to rely on path integration, requiring task states to be inferred from self-motion information accumulated over the preceding trajectory. Rats trained to rely on path integration acquired the task similarly to rats trained to rely on distal visual landmarks. However, reliance on path integration enhanced rats' ability to generalize their learning to novel situations, including finding the goal from an untrained starting location and adapting to a relocated goal that reversed learned choice sequences. These findings suggest that reliance on path integration promotes the acquisition and use of mental representations that capture the latent spatial structure of navigational tasks, thereby favoring flexible navigational decisions over rigid retrieval of reinforced responses. More broadly, our findings demonstrate how information available during training can shape representations learned from experience and thereby constrain the flexibility of decision making during inference.