Hippocampus

In mouse hippocampal area CA1, excitatory pyramidal neurons referred to as "place cells" fire at specific locations in spatial environments during navigation. Many of the excitatory inputs to place cells are themselves spatially tuned, and prior work has shown that synaptic plasticity at those inputs strongly contributes to a selective increase in excitatory synaptic conductance when an animal is inside a cells "place field." It is less clear whether inhibitory inputs to place cells vary with spatial position. Recent studies have investigated whether place cells receive spatially tuned inhibitory conductances by recording place cell activity in vivo and using computational models to help interpret experimental perturbations. One prior study used inhibitory optogenetics to suppress inhibitory neuron firing rates and observed a uniform depolarization of place cells across spatial locations, supporting a model with spatially uniform synaptic inhibition. In apparent conflict, other studies used excitatory optogenetics to depolarize place cells and observed a selective increase in excitability within place fields, supporting a model with a spatially localized decrease in inhibition. However, the latter studies overlooked the contribution of voltage-gated NMDA-type glutamate receptors (NMDARs) to synaptic integration, which are expected to contribute to the balance of excitatory and inhibitory synaptic currents. Here we show that when NMDARs are included at excitatory synapses in simple CA1 place cell models, all experimentally-observed properties of place cells can be recapitulated regardless of whether inhibition increases, decreases, or remains constant inside a place field. Significance StatementThe hippocampus is a brain region required for the formation of new spatial and episodic memories (what happened where and when). Investigating the cellular and circuit mechanisms of memory recall could identify targets for therapies to combat memory decline associated with aging or neurodegeneration. Here we compare the results of computational models of the hippocampus to experimental recordings from mice to better understand the contribution of inhibitory neurons to the expression of spatial memories. We find that a special type of glutamate receptor, the NMDA receptor, helps to maintain the spatial selectivity of excitatory neurons in the hippocampus by counter-balancing fluctuations in the magnitude of inhibitory synaptic currents.

The dentate gyrus (DG) is thought to play a key role in the formation of dissociable memory representations for similar contexts. Neurons in the DG receive highly processed spatial and nonspatial sensory information from the medial and lateral entorhinal cortices, respectively. Changes in spatially tuned firing patterns of DG place cells occur after spatial changes to an environment, but the degree to which DG place cells respond to ethologically relevant nonspatial stimuli is largely unknown. Spatial and nonspatial information is thought to be transmitted to the DG during discrete local field potential events called dentate spikes. Here, we tested the extent to which different spatial and nonspatial stimuli modulate place cell firing patterns and dentate spike dynamics. We performed extracellular recordings of DG place cells and local field potentials in rats of both sexes exploring a familiar spatial environment, in which social stimuli and nonsocial odors of varying ethological relevance were presented, and a novel spatial environment. As expected, DG place cells exhibited different firing patterns between familiar and novel environments. Significant changes in firing were not observed, however, with any of the nonspatial stimuli. Surprisingly, the occurrence of dentate spikes associated with lateral entorhinal cortex input increased during exploration of ethologically relevant stimuli, and this increase was greater for social stimuli. Altogether, these results suggest that the DG preferentially responds to social stimuli at the network level, providing novel insights into how spatial and nonspatial information is processed in the DG. Significance StatementThe dentate gyrus (DG) encodes spatial and nonspatial sensory information. Here, we investigated how place cells in the DG respond to changes in spatial and nonspatial cues in familiar and novel environments in rats. We found that DG place cell firing patterns significantly changed in a novel spatial environment but did not significantly change when nonspatial stimuli were presented in a familiar environment. Conversely, discrete dentate spike events reflecting presumed nonspatial inputs from the lateral entorhinal cortex increased during investigation of ethologically relevant nonspatial stimuli. These findings suggest novel mechanisms of nonspatial information processing in the DG.

Cajal-Retzius neurons (CRs) are a transient cell type that populates the postnatal hippocampus. To test how the persistence of CRs shapes the maturation of hippocampal function, we used a CRs-specific transgenic mouse line combined with targeted viral delivery to selectively ablate CRs in the postnatal hippocampus. Single cell sequencing revealed that gene networks in superficial CA1 pyramidal cells were more strongly perturbed compared to deep CA1 pyramidal cells. To test if these two subpopulations were also distinctly affected in their function, we performed in vivo recordings from spatially modulated cells in CA1. Our analysis showed an impaired spatial representation specifically in superficial CA1 pyramidal cells. Additionally, we observed an increased CA3 to CA1 excitatory drive, as indicated by increased gamma oscillations, and alterations of intrinsic firing properties in superficial CA1 pyramidal neurons confirmed by in vitro electrophysiological recordings. Together, these results indicate a crucial role for CRs in the maturation of hippocampal subcircuits.

Memory impairment is a common and sometimes overlooked feature of major depressive disorder, and cognitive deficits may precede the onset of depressive symptoms in some cases. However, the cognitive benefits of first-line treatments such as SSRIs are mixed. Tianeptine is an atypical antidepressant and cognitive enhancer that neither interacts with monoamine receptors nor inhibits the reuptake of their neurotransmitters. Its antidepressant efficacy in animal models requires activation of the mu-opioid receptor (mu-OR) and phosphorylation of the AMPA receptor. However, the receptors that mediate its memory enhancing actions have never been investigated. We therefore tested the ability of tianeptine to improve spatial memory in a cross-maze task in wild-type (WT) mice compared to its effects in mice with global knockout of either the mu-OR or delta-OR. In parallel, we assessed the effects of tianeptine on hippocampal oscillatory activity and spontaneous locomotion in the same genotypes. Adult male and female WT, mu -/-, and delta -/- mice on a C57BL/6J background were implanted with hippocampal electrodes for the recording of local field potential (LFP) oscillations. Consistent with our previous observations in anaesthetised rats, injection of tianeptine (10 mg/kg and 30 mg/kg SC) caused a dose-dependent increase in beta-frequency power in WT mice that was maximal at circa 25 Hz. The same effect was observed in delta -/- mice, but the increase in beta was completely absent in mu -/- animals. As others have reported previously, tianeptine also caused a mu-OR-dependent increase in spontaneous locomotor activity, but with a time-course that was distinct from the increase in beta power. Separate groups of WT, mu -/-, and delta -/- mice were tested for their ability to learn a food-rewarded spatial memory task in a cross-maze. Over a 20-day training period, sub-groups of each genotype received either tianeptine (10 mg/kg SC) or vehicle injection 30 min before testing. Tianeptine increased the percentage of correct trials and the number of allocentric (place) responses in WT mice, but did not enhance memory in either mu -/- or delta -/- mice, even though both genotypes were able to learn the task. These results indicate that the ability of tianeptine to drive hippocampal beta oscillations is dependent on the mu-OR, whereas its memory-enhancing actions require the presence of both mu- and delta-ORs. The latter result is consistent with the actions of tianeptine on postsynaptic AMPA receptors, and we are currently exploring the signalling pathways involved in this process.

Interval timing (IT) is the ability to time events in the range from seconds to a few minutes, allowing animals to organize behavior in time at short durations. IT relies on two cognitive functions: 1) Measuring the passage of time; 2) Storing and retrieving temporal memories in a context appropriate manner. The hippocampus (HC) and medial prefrontal cortex (mPFC) have been shown critical to the accuracy and precision of time-contingent instrumental responses in IT. The anatomy supporting mPFC-HC interactions, required for memory encoding and retrieval, include projections from HC to mPFC, and indirect bidirectional connections through the ventral midline thalamus (VMT), most notably reuniens. Here, we explored VMTs role in retrieving fixed-interval (FI) temporal memories. Rats were trained on a 5s FI signaled by an auditory cue and demonstrated temporal memory by poking predominantly at the time of the expected reward. Timing responses on individual trials were classified into on-time, early, and random response. Across sessions, random response trials decreased following training. Next, we switched training to longer intervals (20s or 80s; daily sessions for weeks). To probe the role of the VMT in temporal memory retrieval, we infused the GABAA-agonist muscimol, or saline, before training sessions. Results show that VMT muscimol infusions decreased timing precision. Also, at both intervals, the number of on-time response trials decreased, and the number of random response trials significantly increased. The number of early response trials had no significant change at 20s, and significantly decreased at 80s. Overall, our results suggest that the VMT is critical for precise retrieval of temporal memories. We also describe per-trial response patterns with characteristics consistent across all trained intervals, suggesting multiple behavioral strategies at play during interval timing.

ContextGrid cells in the medial entorhinal cortex (MEC) of head-fixed mice exhibit ultraslow (<0.01 Hz) oscillations (USO) during walking in a 1D running wheel in darkness. It was proposed that these oscillations may have a connection with navigational behavior. ProblemThere is no clear link between the functional role of these oscillations and path integration, a fundamental navigation strategy used by animals to calculate their current position and orientation by continuously summing self-motion cues. HypothesisGiven the synaptic projections from MEC to the hippocampus, we hypothesized that ultraslow oscillations have a role in linking spatiotemporal memories acquired during navigation. MethodologyA realistic computational model of entorhinal-grid with ultraslow oscillations and hippocampal-place cells is proposed using synaptic plasticity between cell types, sustaining path integration of a rodent-like simulated animal. ResultsUltraslow oscillations induced persistent changes in the grid cell dynamics, represented as a positional drift of grid fields. Such drift resulted in position estimation errors but generated new grid-place cell associations when combined with synaptic plasticity. >DiscussionsUltraslow entorhinal oscillations were found to shape spatial memory through grid cell drifting, which could serve as a mechanism for flexibly accessing different spatial memories during navigation. HIGHLIGHTSO_LIPath integration dynamics hide ultraslow oscillations despite coexistence. C_LIO_LIUltraslow oscillations significantly degrade position estimation in path integration. C_LIO_LIGrid and place fields drift after the effect of ultraslow oscillations. C_LIO_LINew spatial memories were created as a result of the ultraslow oscillation drift. C_LIO_LIUltraslow oscillations enable dynamic access of different spatial memories C_LI

Dopamine signaling through dopamine 1 receptors (D1R) and dopamine 2 receptors (D2R) regulates hippocampal synaptic plasticity underlying learning and memory, yet their subcellular localization within the hippocampus is unknown. Here we performed electron microscopic immunocytochemistry to elucidate the distribution of D1R and D2R in subregions of the mouse hippocampus. In CA1 and CA3 stratum radiatum (SR), D1R- and D2R-immunoreactivity was found primarily on pyramidal cell dendritic spines and unmyelinated axons, and to a lesser extent in axon terminals and glia. In both regions, D1R-labeled terminals formed predominantly asymmetric (excitatory-type) synapses on dendritic spines, whereas D2R-labeled terminals formed mainly symmetric (inhibitory-type) synapses on pyramidal cell dendritic shafts. In the dentate gyrus (DG) hilus, D1R-labeling was almost exclusively found in unmyelinated axons and glia. D2R immunoreactivity in the hilus similarly was present in unmyelinated axons and glia but was also detected in dendritic spines originating from mossy cells and in terminals forming symmetric synapses. These findings indicate that dopamine receptors are positioned to influence excitatory and inhibitory signaling in the murine hippocampus. As D1R and D2R exert opposing effects on neuronal signaling, their localization on pyramidal neuron compartments provides a structural substrate for bidirectional modulation of synaptic plasticity and pyramidal cell activity. In addition, the presence of D2Rs on inhibitory terminals contacting pyramidal neurons and hilar interneurons suggests a role in regulating inhibitory circuitry within the hippocampus.

BackgroundFlexibility and robustness of neuronal function are closely linked to degeneracy, the ability of distinct structural or parametric configurations to produce similar functional outcomes. At the cellular level, this often manifests as ion-channel degeneracy, in which multiple combinations of intrinsic conductances yield comparable electrophysiological phenotypes. MethodologyWe used a population-based, data-driven modelling framework to generate large ensembles of biophysically detailed CA1 pyramidal neuron models constrained by somatic electrophysiological features extracted from patch-clamp recordings in acute slices from early-birth rats. 10 reconstructed morphologies were incorporated, and model populations were analyzed using parameter correlation analysis, principal component analysis, and generalization tests to assess robustness, degeneracy, and morphology dependence of intrinsic properties. ConclusionsAcross the model population, similar somatic firing behaviours emerged from widely different combinations of intrinsic parameters, demonstrating robust two-level ion channel degeneracy both within and across morphologies. Each morphology occupied a distinct region of parameter space, indicating morphology-specific compensatory effects, while weak pairwise parameter correlations suggested distributed compensation rather than tight parameter dependencies. Even with a fixed morphology, multiple parameter subspaces supported comparable electrophysiological phenotypes. Generalization across morphologies was structure-dependent and non-reciprocal, with successful parameter similarity occurring preferentially between structurally similar neurons. Interestingly, to accurately simulate spike-frequency adaptation, it was important to retain some kinetic properties of the ion channel models as free parameters during optimization. Together, these findings show that dendrite morphology shapes the valid parameter space, and similar electrophysiology of CA1 pyramidal neurons arises from the interplay between structural variability and ion-channel diversity. This work highlights the importance of population-based modelling for capturing biological variability and provides insights into how neuronal robustness might be maintained despite substantial heterogeneity, and offers a scalable pipeline for generating biophysically realistic CA1 neuron populations for use in network simulations. Author summaryNeurons must reliably process information even though their internal components, such as ion channels and cellular shape, can vary widely from cell to cell. How stable behaviour emerges from such variability is a fundamental question in neuroscience. In this study, we explored this problem using detailed computer models of early-birth rat hippocampal CA1 pyramidal neurons, a cell type that plays a central role in learning and memory. Instead of building a single "average" neuron model, we created large populations of models that all reproduced key experimental recordings but differed in their internal parameters. We found that neurons with different shapes and different combinations of ion channels could nevertheless generate similar electrical activity. This phenomenon, known as ion channel degeneracy, allows neurons to remain functional despite biological variability or perturbations. Our results show that neuronal shape strongly influences which parameter combinations are viable, but that multiple solutions exist even for the same morphology. The population of models we provide offers a resource for future studies of early-birth CA1 pyramidal cell function and dysfunction.

BackgroundHippocampal place cells (PCs) undergo representational drift, i.e., a gradual change in their place fields despite unaltered behavior. While Ca2+ imaging enables long-term tracking of PC populations, distinct PC detection methods have been shown to yield different subpopulations of PCs, with only a few systematic comparisons between methods, especially in open arenas. New MethodWe provide an analysis protocol for one-photon PC data obtained during free foraging in two-dimensional arenas that allows us to compare two widely used PC detection methods, significance of spatial information (SI), and split-half correlation (SHC), and their effect on representational drift. The analysis is demonstrated on previously published Ca2+ data from dorsal CA1 of freely foraging mice, with cells tracked for 10 consecutive days. ResultsBoth criteria, SI and SHC, yielded proportions of approx. 17% PCs with only 40% overlap. SI-identified PCs demonstrated higher stability, higher rate map correlations, and a slower rate of representational drift than SHC-PCs. Comparison with existing methodsPrevious studies comparing SI and SHC PC detection methods in Ca2+ data did not focus on either open field behavior or representational drift. ConclusionOur results indicate that the choice of PC detection method significantly affects the estimate of representational drift in Ca2+ imaging studies.

Spatial memory is crucial for navigation and adapting to changing environmental conditions. Known neurophysiological mechanisms of spatial memory center on the importance of hippocampal activity and its spatial tuning. Yet, the behavioral strategies that support adaptive spatial encoding remain poorly understood. We have shown that dorsal hippocampal activity during rearing is necessary for spatial working memory, highlighting a role of information seeking behaviors for spatial memory encoding. Similarly, spatial tuning by dorsal hippocampal neurons is substantially updated during another information seeking behavior: attentive head scanning. However, the functional relationship between these behaviors is unknown. Here, to assess the relevance of environmental context for the expression of these behaviors, we quantified rearing and head scanning in a radial-arm-maze spatial working memory task while manipulating the height of the maze walls. Our goal was to test whether the stereotyped patterns of rearing that rats generate with tall walls are replaced with attentive head scanning when the walls are short enough to reach the top without rearing. We found that rats reared significantly less often when the walls were shortened and, instead, exhibited frequent attentive head scanning. The head scanning was done when and where the rats had previously exhibited stereotyped rearing. These results support the hypothesis that rearing and head scanning are functionally related behaviors. Future work should test two key inferences: 1) Head scanning is a critical epoch of spatial memory encoding, and 2) Spatial tuning by hippocampal neurons is updated during rearing. Significance statementSpatial memory is a core cognitive function, essential for healthy independent living. Though the hippocampus is critical for spatial memory, it remains unclear when and how. Separate prior studies link rearing and lateral head scanning to key periods of hippocampal processing, suggesting both behaviors support sensory information gathering for updating cognitive maps. However, their relationship is unresolved. Here, we test whether these behaviors are functionally interchangeable, with environmental structure determining expression. In a radial-arm maze, rats reared frequently with 21 cm walls but showed reduced rearing when walls were shortened to 4.6 cm, instead increasing head scanning at similar locations. These findings suggest rearing and head scanning share underlying motivations and provide a basis for comparing hippocampal activity during exploration.

The hippocampus is organized along dorsal-ventral and left-right axes, but whether and how these axes interact within defined neuronal populations across behavioral states remains unresolved. Here, we combined within-animal slice electrophysiology with dual-site fiber photometry to compare dorsal and ventral CA1 activity across contralateral hemispheric configurations in mice expressing CaMKII-jGCaMP8s and SynI-jRCaMP1b at distinct longitudinal sites. Ventral CA1 pyramidal neurons exhibited greater intrinsic excitability and stronger AMPAR-mediated synaptic responses than dorsal CA1 neurons. In vivo, CaMKII-defined pyramidal recordings during home cage rest revealed a left-biased event-rate asymmetry within dorsal but not ventral CA1, with no comparable asymmetry in pan-neuronal SynI recordings. Apparent dorsal-ventral differences in spontaneous event rate were therefore configuration-dependent and resolved into a hemispheric, cell-type-specific effect restricted to the CaMKII-defined population. Lead-lag analysis showed that dorsal-ventral temporal coordination was likewise reorganized across configurations and was restricted to pyramidal-cell-biased recordings. During open-field center entries, dorsal CA1 was preferentially recruited before entry across both configurations, whereas non-coordinated entries revealed a relative post-entry suppression of contralateral ventral CA1. Together, these findings suggest that dorsal-ventral CA1 organization cannot be inferred from hemisphere-pooled designs and identify a pyramidal-cell-specific left dorsal CA1 asymmetry as a structural feature that shapes both spontaneous activity and behaviorally driven recruitment along the longitudinal hippocampal axis. Significance StatementThe hippocampus is widely understood to differ along its long axis, with dorsal regions supporting spatial processing and ventral regions supporting emotional behavior. Whether this organization interacts with the left-right axis between hemispheres has remained essentially untested, because most studies pool hemispheres or record unilaterally. Using bilateral fiber photometry in mice, we show that spontaneous activity in dorsal CA1 is left-biased and that this asymmetry is specific to excitatory pyramidal neurons. The asymmetry explains apparent dorsal-ventral differences that appear configuration-dependent under conventional analysis, and it reshapes how dorsal and ventral CA1 are recruited during open-field exploration. These findings reframe hemispheric configuration from a methodological detail into an organizational variable that should be considered when interpreting hippocampal long-axis function.

The hippocampus participates in crucial functions such as memory consolidation, spatial processing and emotional regulation that require diverse input from multiple cortical areas that is funneled through the upper layers of the entorhinal cortex (EC), mostly from layer II to the dentate gyrus (DG). Traditional models described 200,000 EC layer II neurons projecting to 1 million granule cells (GCs) in the rat, rendering low divergence (1:5), with each EC neuron establishing about 18,000 synapses with GCs and each GC receiving about 4,000 synapses from EC neurons. In this manuscript, we update this model of connectivity incorporating new features described in the last three decades that include updated populations of EC layer II neurons obtained with design-based stereology, a revised definition of EC layer II based on molecular criteria and selecting reelin expressing neurons as the only layer II neurons projecting to the hippocampus. The updated model shows [~]80,000 neurons from EC layer II projecting to the DG, [~]45,000 from the medial entorhinal cortex (MEC) and [~]35,000 from the lateral entorhinal cortex (LEC) with high divergence of 1:20 and 1:30. We also show that EC layer II neurons may establish [~]90,000-115,000 synapses on GCs, while GCs receive about 8,000 synapses from EC layer II neurons. We estimate a [~]25% redundancy in the connectivity, so each EC neuron may contact [~]68,000-86,000 GCs and each GC would be contacted by [~]3000 neurons from MEC and 3,000 from LEC. In addition, we quantitatively assess a potential projection of mossy cells to the medial molecular layer described in mice, which could have a potential impact on GC inhibition. Overall, we produced a detailed, complete, and updated quantitative model of EC projections to the DG that reveals a much more divergent and richer projection than previously described, with implications for functional models (e.g.: pattern separation) and more widely for building realistic hippocampal models or establishing comparisons across species.

Episodic memory depends on neural representations encoded in the hippocampus. Experimental and computational evidence suggests that the hippocampus encodes pattern-separated representations that support later recall of episodic event elements. While extant data in humans predominantly focus on assaying the relationship between the similarity of spatial neural patterns at encoding and later memory performance, similarity of neural patterns in the temporal domain may also reveal encoding computations predictive of future memory. To examine how the similarity among temporal patterns of hippocampal activity during encoding relates to later episodic retrieval (associative cued recall and recognition memory), hippocampal activity was recorded from human participants (n=7) with implanted intracranial electrodes while they encoded arbitrary (A-B) paired-associates. Subsequent memory analyses first revealed that hippocampal high-frequency broadband power (HFB; 70-180Hz) was linked to a graded increase in memory strength; HFB power was greater during the encoding of pairs later correctly recalled relative to events later recognized and was lowest for events later forgotten. Second, and critically, subsequent memory analyses further revealed that more distinctive temporal patterns in the hippocampus during encoding -- indexed by the similarity of the HFB timeseries elicited by a given event to that elicited by other events -- were associated with superior subsequent memory performance. Finally, exploratory analyses revealed stimulus category effects on hippocampal HFB power during encoding and retrieval cuing. These results indicate that the temporal distinctiveness of hippocampal traces during encoding is important for subsequent retrieval of episodic event elements, consistent with theories that posit that pattern separation facilitates future remembering.

The hippocampal CA1 subregion supports learning, memory formation, and spatial navigation. Although its three-layered architecture has been described in ex-vivo investigations, the in-vivo microstructural profile of CA1 and its relation to individual variations in memory performance remain poorly characterized. In this study, we used ultra-high field structural MRI at 7 Tesla to investigate the depth-dependent myelination patterns (measured by quantitative T1) of CA1 in younger adults, their relation to the local arterial architecture, and their association with individual differences in cognitive functions, specifically memory performance. Results show that left and right CA1 present depth-dependent patterns of myelination, with the outer and inner compartments showing higher myelination than the middle compartment. No significant relationship between layer-specific myelination of CA1 and distance to the nearest artery was observed. Right CA1 was found to be more myelinated than left CA1. Pairwise correlations and regression models showed that higher left CA1 myelination is linked to higher accuracy in object localization. Together, our data demonstrates the feasibility of describing the three layered myelin architecture of CA1 in vivo, and provides information on how alterations in the architecture of CA1 may relate to alterations in cognitive performance in younger adults.

Traumatic stress can cause long-lasting changes in cognition and affect, sometimes leading to diagnoses such as post-traumatic stress disorder (PTSD). The stress-enhanced fear learning (SEFL) model recapitulates understudied components of PTSD, such as stress-induced sensitization of fear learning. The SEFL procedure entails exposing mice to footshock stress followed later by fear conditioning in a different context. When tested later for recall of fear conditioning, previously stressed mice exhibit enhanced freezing compared to non-stressed controls. Studies have shown that dorsal and ventral dentate gyrus (DG) generates neural ensemble representations of contextual fear, such that fear recall involves reactivation of a sparse set of "engram cells" that were active during fear memory acquisition. How stress affects these hippocampal ensemble representations is unknown. We used SEFL and activity-dependent neuronal tagging with FosTRAP2 mice to investigate effects of stress on fear memory ensembles in rostral and caudal hippocampal DG. FosTRAP2/Ai6 mice received footshock stress or equivalent context exposure without shock in Context A on day 1. Five days later, mice received 1-shock conditioning in Context B and immediately received an injection of 4-OHT (55mg/kg) to tag fear acquisition neurons with the zsGreen reporter. One day later, mice were tested for fear recall in Context B and were perfused 90 minutes after testing. Confirming prior studies, prior stress potentiated 1-shock conditioning in Context B, with stressed mice displaying higher freezing in the Context B test session than non-stressed mice. At the level of neural activity, results showed stress had no effect on the number of zsGreen+ fear ensemble cells or the number of cfos+ recall-activated cells in rostral or caudal DG. However, stress increased reactivation (percentage of zsGreen+ cells expressing cfos) in the caudal but not rostral DG. The results suggest stress potentiates later fear learning by enhancing fear representations in caudal hippocampus, a region of the hippocampus specialized for integrating emotional and motivational valence into memory.

Current evidence suggests that older adults perform worse at tasks involving spatial memory and navigation, yet the underlying reasons remain unclear. Here, we tested the hypothesis that age-related declines in spatial memory stem from difficulties in recognizing spatial environments from rotated perspectives. Young and older adults underwent fMRI as they encoded virtual scenes which were later viewed either from the same or rotated perspective. Older adults were worse at identifying changes in these scenes, although the age effect was equally robust across perspective conditions. Neural specificity of scene representations was examined with the phenomenon of fMRI repetition adaptation. We predicted that young adults would show significant fMRI adaptation to the same but not rotated perspective, indicative of intact viewpoint specificity, while older adults show would adaptation effects to both. While analyses of raw fMRI BOLD produced results consistent with these predictions, follow-up analyses revealed a general attenuation of activity in older adults across both perspective conditions. Additionally, although older adults showed both lower fMRI BOLD and worse spatial memory, lower trial-wise BOLD was associated with better performance independent of age. This suggests that the variance associated with fMRI adaptation is reflective of two independent sources of variance: age and cognition. Our results suggest that age differences in spatial memory may manifest due to cognitive and neural factors that are shared across same and rotated perspectives, and thus they cannot be explained by a selective deficit in allocentric (viewpoint-independent) processing. Significance StatementIncreasing age is often associated with reduced spatial memory and navigation. Prior research suggests that age differences in spatial memory could be exacerbated by changes in perspective, possibly due to increased difficulties in the ability to construct allocentric (viewpoint-independent) representations from previously encoded egocentric perspectives. Here, we demonstrate that older adults are equally disadvantaged when recognizing layouts across same and rotated perspectives. FMRI analyses indicate that older age is associated with reduced fMRI BOLD in higher-level visual cortex across both perspective conditions, as opposed to altered specificity of perspective coding. Consequently, the present study challenges the notion that aging is associated with a selective decline in allocentric spatial memory and instead supports a more general age-related difficulty with scene processing.

Brain networks that support episodic memory development in the first years of life remain poorly understood. Protracted growth of regions such as the hippocampus have been suggested as a causal role in episodic memory development, but development of these memory brain networks and their role in episodic memory development is not yet fully elucidated. In this study, subcortical memory network regions (hippocampus, thalamus, amygdala) were segmented from MRI images in 835 visits spanning 0-4 years of age across 322 participants in the Baby Connectome Project. Hippocampal segmentations were further subdivided into head, body, and tail subregions manually for 426 visits, which were used to train models that automatically segmented hippocampal subregions for the remaining visits. 58 participants returned for an early school-age follow-up, including two episodic memory tasks. Volumetric growth trajectories differed across regions and across subregions within the hippocampus, with the head of the hippocampus showing steep growth that plateaued months later than the body or tail of the hippocampus. In the right hemispheres hippocampal head, age- and sex- adjusted volumes positively predicted future early school-age episodic memory performance. After accounting for total brain volume, the right thalamus also predicted memory performance. Total sleep duration at the follow-up visit accounted for performance variance above and beyond brain volume correlations. Altogether, results suggest that trajectories of growth and relationships between volume and episodic memory performance are region and subregion specific, and provide evidence for the important role of sleep in associations between brain networks and early episodic memory development. SignificanceThe hippocampus is a critical structure in episodic memory, yet precise longitudinal developmental trajectories of this structure have yet to be elucidated. This study provides detailed, subregion specific hippocampal trajectories, and demonstrates that variation in these trajectories is associated with variation in later episodic memory performance. This insight fills a current gap in the literature delineating how brain development and episodic memory behaviors are related in the first five years of life. Considering this is the same age range during which adults begin to have long-term memories available from childhood, this gap represents an important opportunity to understand how changes in the brain support the development of basic episodic memory skills.

By keeping its activity low even when strongly stimulated, the dentate gyrus (DG) serves as the main entry point to the hippocampal circuit and helps separate different patterns of incoming information. However, the mechanisms supporting this low-level activity remain unclear. Here, we used in vitro patch-clamp recordings, two-photon calcium imaging, and optogenetics in hippocampal slices from adult mice to understand how local GABAergic interneurons control lateral entorhinal cortex (LEC) input-mediated drive in the DG. Under control conditions, LEC inputs rarely elicited granule cell (GC) firing because GABAA receptor-mediated inhibition strongly restrained GC excitability. Whole-cell patch clamp recordings of DG interneurons revealed that LEC activation prevalently recruited fast-spiking parvalbumin-expressing and molecular layer interneurons, while most dendrite-targeting interneuron types responded only weakly to LEC input and fired action potentials only after feedback excitation from GCs was enhanced by pharmacological block of GABAA-receptors. Optogenetic inhibition of defined interneuron populations showed that silencing dendrite-targeting interneurons caused a larger increase in GC population spiking than silencing perisomatic-targeting interneurons, suggesting that both molecular layer and feedback-recruited interneurons have a prevalent role in controlling DG recruitment after an increase in LEC drive. In summary, our data indicate that GABAergic inhibition engages distinct DG interneuron types in feedforward and feedback circuits to tightly gate entorhinal inputs. By maintaining sparse GC firing, this dynamic inhibitory gating supports the role of the dentate gyrus in the hippocampal pattern-separation process.

Memory performance typically declines with age, but the underlying neurobiological mechanisms remain unclear. Superagers, people over 80 years of age with episodic memory performance comparable to individuals 30 years younger, appear to resist this decline. Novelty and expectation violations are known to engage the hippocampus-midbrain system to enhance memory formation. Here, we examined whether superagers superior memory performance is supported by preserved hippocampal-midbrain function during novelty and expectation processing. We manipulated item and contextual novelty (i.e., expectation violations) during encoding to test whether superagers show greater mnemonic benefits than their age-matched peers, whether these benefits reflect enhanced hippocampal and midbrain functioning as measured by fMRI, and whether they are associated with preserved dopaminergic integrity measured with neuromelanin-sensitive MRI. Our results show that, although superagers demonstrated overall superior memory performance, both groups exhibited superior recognition of contextually unexpected items. Nevertheless, differences emerged in the processing of expectation during encoding. Superagers exhibited stronger hippocampal responses to expectation violations and habituation to expected events, irrespective of item novelty. Conversely, typical older adults exhibited reduced midbrain response when expected novelty was absent. Neuromelanin accumulation did not account for group differences in midbrain activity or memory performance. Taken together, these findings suggest superagers benefit from adaptive responses to expectation and its violation, which is therefore a candidate mechanism distinguishing exceptional from typical cognitive ageing. SIGNIFICANCE STATEMENTAlthough memory typically declines with age, superagers are individuals aged over 80 who maintain memory performance comparable to people 30 years younger. We examined whether preserved hippocampal-midbrain function during novelty and expectation processing could underlie their superior memory. Superagers exhibited adaptive hippocampal responses to expectation and its violation, with higher activation for unexpected events and habituation to expected events. In contrast, typical older adults showed hippocampal and midbrain responses oriented towards anticipated novel content, despite not showing differences in neuromelanin accumulation. These findings underscore the critical role of hippocampal function in supporting memory preservation in late life and advance our understanding of the neural mechanisms underlying healthy cognitive ageing.

CaMKII promoter is widely used to label and manipulate hippocampal pyramidal neurons via transgenic mouse lines or viral approaches. While it targets most excitatory neurons, a small subset remains unlabeled and often overlooked. We present an AAV-based strategy combined with CaMKII-driven Cre expression to access and study this remaining population. Furthermore, we provide a detailed protocol for in-house AAV production, targeted stereotaxic delivery, and functional validation of targeted neurons through slice electrophysiology and behavior. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=194 HEIGHT=200 SRC="FIGDIR/small/723440v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@3a31ccorg.highwire.dtl.DTLVardef@9b7e90org.highwire.dtl.DTLVardef@92297borg.highwire.dtl.DTLVardef@1e159eb_HPS_FORMAT_FIGEXP M_FIG C_FIG