A population code for spatial representation in the zebrafish telencephalon.

Spatial learning in teleost fish requires an intact telencephalon1, a brain region that contains putative analogues to components of the mammalian limbic system (for example, hippocampus)2-4. However, cells fundamental to spatial cognition in mammals-for example, place cells (PCs)5,6-have yet to be established in any fish species. In this study, using tracking microscopy to record brain-wide calcium activity in freely swimming larval zebrafish7, we compute the spatial information content8 of each neuron across the brain. Strikingly, in every recorded animal, cells with the highest spatial specificity were enriched in the zebrafish telencephalon. These PCs form a population code of space from which we can decode the animal's spatial location across time. By continuous recording of population-level activity, we found that the activity manifold of PCs refines and untangles over time. Through systematic manipulation of allothetic and idiothetic cues, we demonstrate that zebrafish PCs integrate multiple sources of information and can flexibly remap to form distinct spatial maps. Using analysis of neighbourhood distance between PCs across environments, we found evidence for a weakly preconfigured network in the telencephalon. The discovery of zebrafish PCs represents a step forward in our understanding of spatial cognition across species and the functional role of the early vertebrate telencephalon.

Stereotypical Hippocampal Clustering Predicts Navigational Success in Virtualized Real-World Environments.

Structural differences along the hippocampal long axis are believed to underlie meaningful functional differences. Yet, recent data-driven parcellations of the hippocampus subdivide the hippocampus into a 10-cluster map with anterior-medial, anterior-lateral, and posteroanterior-lateral, middle, and posterior components. We tested whether task and experience could modulate this clustering using a spatial learning experiment where male and female participants were trained to virtually navigate a novel neighborhood in a Google Street View-like environment. Participants were scanned while navigating routes early in training and after a 2 week training period. Using the 10-cluster map as the ideal template, we found that participants who eventually learn the neighborhood well have hippocampal cluster maps consistent with the ideal-even on their second day of learning-and their cluster mappings do not deviate over the 2 week training period. However, participants who eventually learn the neighborhood poorly begin with hippocampal cluster maps inconsistent with the ideal template, though their cluster mappings may become more stereotypical after the 2 week training. Interestingly this improvement seems to be route specific: after some early improvement, when a new route is navigated, participants' hippocampal maps revert back to less stereotypical organization. We conclude that hippocampal clustering is not dependent solely on anatomical structure and instead is driven by a combination of anatomy, task, and, importantly, experience. Nonetheless, while hippocampal clustering can change with experience, efficient navigation depends on functional hippocampal activity clustering in a stereotypical manner, highlighting optimal divisions of processing along the hippocampal anterior-posterior and medial-lateral axes.

Object-vector coding in the medial entorhinal cortex.

The hippocampus and the medial entorhinal cortex are part of a brain system that maps self-location during navigation in the proximal environment1,2. In this system, correlations between neural firing and an animal's position or orientation are so evident that cell types have been given simple descriptive names, such as place cells3, grid cells4, border cells5,6 and head-direction cells7. While the number of identified functional cell types is growing at a steady rate, insights remain limited by an almost-exclusive reliance on recordings from rodents foraging in empty enclosures that are different from the richly populated, geometrically irregular environments of the natural world. In environments that contain discrete objects, animals are known to store information about distance and direction to those objects and to use this vector information to guide navigation8-10. Theoretical studies have proposed that such vector operations are supported by neurons that use distance and direction from discrete objects11,12 or boundaries13,14 to determine the animal's location, but-although some cells with vector-coding properties may be present in the hippocampus15 and subiculum16,17-it remains to be determined whether and how vectorial operations are implemented in the wider neural representation of space. Here we show that a large fraction of medial entorhinal cortex neurons fire specifically when mice are at given distances and directions from spatially confined objects. These 'object-vector cells' are tuned equally to a spectrum of discrete objects, irrespective of their location in the test arena, as well as to a broad range of dimensions and shapes, from point-like objects to extended surfaces. Our findings point to vector coding as a predominant form of position coding in the medial entorhinal cortex.

Midkine is upregulated in the hippocampus following both spatial and olfactory reward association learning and enhances memory.

Hippocampal neuronal plasticity is a fundamental process underpinning learning and memory formation and requiring elaborate molecular mechanisms that result in the dynamic remodelling of synaptic connectivity. The neurotrophic properties of midkine (Mdk) have been implicated in the development and repair of the nervous system, while Mdk knockout resulted in deficits in the formation of certain types of memory. The role of Mdk in the process of memory-associated neuronal plasticity, however, remains poorly understood. We investigated the learning-induced regulation of Mdk in spatial navigation and association learning using the water maze and the odour reward association learning paradigms, characterising a temporal profile of Mdk protein expression post-learning. Both learning events revealed similar patterns of upregulation of expression of the protein in the rat hippocampal dentate gyrus, which were rapid and transient. Moreover, administration of recombinant Mdk during the endogenous Mdk upregulation following learning enhanced memory in the water maze task revealing a pro-cognitive action of Mdk. We further show that, within the adult hippocampus, Mdk mRNA is predominantly expressed in granular and pyramidal neurons and that hippocampal neuronal Mdk expression is regulated by the canonical plasticity-associated neurotransmitter glutamate. Finally, we confirm that the positive action of Mdk on neurite outgrowth previously noted in cortical and cerebellar neurons extends to hippocampal neurons. Together, our findings suggest a role for Mdk in glutamate-mediated hippocampal neuronal plasticity important for long-term memory consolidation.

Cerebral hypoperfusion exacerbates traumatic brain injury in male but not female mice.

Mild-moderate traumatic brain injuries (TBIs) are prevalent, and while many individuals recover, there is evidence that a significant number experience long-term health impacts, including increased vulnerability to neurodegenerative diseases. These effects are influenced by other risk factors, such as cardiovascular disease. Our study tested the hypothesis that a pre-injury reduction in cerebral blood flow (CBF), mimicking cardiovascular disease, worsens TBI recovery. We induced bilateral carotid artery stenosis (BCAS) and a mild-moderate closed-head TBI in male and female mice, either alone or in combination, and analyzed CBF, spatial learning, memory, axonal damage, and gene expression. Findings showed that BCAS and TBI independently caused a ~10% decrease in CBF. Mice subjected to both BCAS and TBI experienced more significant CBF reductions, notably affecting spatial learning and memory, particularly in males. Additionally, male mice showed increased axonal damage with both BCAS and TBI compared to either condition alone. Females exhibited spatial memory deficits due to BCAS, but these were not worsened by subsequent TBI. Gene expression analysis in male mice highlighted that TBI and BCAS individually altered neuronal and glial profiles. However, the combination of BCAS and TBI resulted in markedly different transcriptional patterns. Our results suggest that mild cerebrovascular impairments, serving as a stand-in for preexisting cardiovascular conditions, can significantly worsen TBI outcomes in males. This highlights the potential for mild comorbidities to modify TBI outcomes and increase the risk of secondary diseases.

BV2-derived extracellular vesicles modulate microglia inflammatory profile, neuronal plasticity, and behavioural performances in late adult mice.

BACKGROUND: During aging, both the brain and the immune system undergo a progressive impairment of physiological functions. Microglia, the immunocompetent cells of the central nervous system, shift towards a chronic mild inflammatory state that impacts brain homeostasis. Extracellular vesicles (EVs) released by microglia transport packages of molecular information that mirror the inflammatory status of donor cells and modulate the inflammatory phenotype of recipient microglia and other cell types. RESULTS: We demonstrated that intranasal administration of EVs derived from microglial-like BV2 cells to late adult mice (16-20 months of age) shifts microglia toward a "juvenile" morphology affecting their inflammatory profile. Mice treated with BV2-derived EVs have a reduction of anxiety-like behavior and an increased spatial learning, with sex-dependent differences. Further, BV2-derived EVs increased neuronal plasticity both in male and female mice. These findings suggest the involvement of microglial cells in vesicles-mediated anti-aging effect. CONCLUSIONS: Our data indicate that BV2-derived EVs could represent a resource to slow down age-dependent inflammation in the mouse brain.

The effects of estrogens on spatial learning and memory in female rodents - A systematic review and meta-analysis.

Estrogens have inconsistent effects on learning and memory in both the clinical and preclinical literature. Preclinical literature has the advantage of investigating an array of potentially important factors contributing to the varied effects of estrogens on learning and memory, with stringently controlled studies. This study set out to identify specific factors in the animal literature that influence the effects of estrogens on cognition, for possible translation back to clinical practice. The literature was screened and studies meeting strict inclusion criteria were included in the analysis. Eligible studies included female ovariectomized rodents with an adequate vehicle for the estrogen treatment, with an outcome of spatial learning and memory in the Morris water maze. Training days of the Morris water maze were used to assess acquisition of spatial learning, and the probe trial was used to evaluate spatial memory recall. Continuous outcomes were pooled using a random effects inverse variance method and reported as standardized mean differences with 95 % confidence intervals. Subgroup analyses were developed a priori to assess important factors. The overall analysis favoured treatment for the later stages of training and for the probe trial. Factors including the type of estrogen, route, schedule of administration, age of animals, timing relative to ovariectomy, and duration of treatment were all found to be important. The subgroup analyses showed that chronic treatment with 17ß-estradiol, either cyclically or continuously, to young animals improved spatial recall. These results, observed in animals, can inform and guide further clinical research on hormone replacement therapy for cognitive benefits.

Noncanonical projections to the hippocampal CA3 regulate spatial learning and memory by modulating the feedforward hippocampal trisynaptic pathway.

The hippocampal formation (HF) is well documented as having a feedforward, unidirectional circuit organization termed the trisynaptic pathway. This circuit organization exists along the septotemporal axis of the HF, but the circuit connectivity across septal to temporal regions is less well described. The emergence of viral genetic mapping techniques enhances our ability to determine the detailed complexity of HF circuitry. In earlier work, we mapped a subiculum (SUB) back projection to CA1 prompted by the discovery of theta wave back propagation from the SUB to CA1 and CA3. We reason that this circuitry may represent multiple extended noncanonical pathways involving the subicular complex and hippocampal subregions CA1 and CA3. In the present study, multiple retrograde viral tracing approaches produced robust mapping results, which supports this prediction. We find significant noncanonical synaptic inputs to dorsal hippocampal CA3 from ventral CA1 (vCA1), perirhinal cortex (Prh), and the subicular complex. Thus, CA1 inputs to CA3 run opposite the trisynaptic pathway and in a temporal to septal direction. Our retrograde viral tracing results are confirmed by anterograde-directed viral mapping of projections from input mapped regions to hippocampal dorsal CA3 (dCA3). We find that genetic inactivation of the projection of vCA1 to dCA3 impairs object-related spatial learning and memory but does not modulate anxiety-related behaviors. Our data provide a circuit foundation to explore novel functional roles contributed by these noncanonical hippocampal circuit connections to hippocampal circuit dynamics and learning and memory behaviors.

Impact of Sleep Deprivation on the Brain's Inflammatory Response Triggered by Lipopolysaccharide and Its Consequences on Spatial Learning and Memory and Long-Term Potentiation in Male Rats.

INTRODUCTION: Both sleep deprivation (SD) and inflammation can negatively affect cognitive function. This study aimed to investigate how SD impacts the brain's inflammatory response to lipopolysaccharide (LPS) and its subsequent effects on cognitive functions. METHODS: To this end, male rats were tested through a Morris water maze (MWM) to assess their spatial learning and memory. Also, in vivo field potential recordings (to evaluate synaptic plasticity) were done in the Saline, SD, LPS1 (1 mg/kg/7 days), and LPS1+SD groups. Cytokine levels were measured using an enzyme-linked immunosorbent assay (ELISA). RESULTS: Based on the results, the LPS1+SD group showed increased total distance and escape latency compared to the other groups in the MWM test. Besides, the LPS1+SD group exhibited a significant decrease in long-term potentiation (LTP) induction and maintenance in the CA1 area of the brain. Finally, the inflammatory cytokine interleukin-1ß (IL-1ß) levels were significantly higher in the LPS1+SD group than in the Saline group. CONCLUSION: These findings suggest that the combined effects of SD and brain inflammatory response can have more harmful effects on cognitive function, LTP, and inflammatory factors than either SD or LPS1 alone.

m6A facilitates hippocampus-dependent learning and memory through YTHDF1.

N6-methyladenosine (m6A), the most prevalent internal RNA modification on mammalian messenger RNAs, regulates the fates and functions of modified transcripts through m6A-specific binding proteins1-5. In the nervous system, m6A is abundant and modulates various neural functions6-11. Whereas m6A marks groups of mRNAs for coordinated degradation in various physiological processes12-15, the relevance of m6A for mRNA translation in vivo remains largely unknown. Here we show that, through its binding protein YTHDF1, m6A promotes protein translation of target transcripts in response to neuronal stimuli in the adult mouse hippocampus, thereby facilitating learning and memory. Mice with genetic deletion of Ythdf1 show learning and memory defects as well as impaired hippocampal synaptic transmission and long-term potentiation. Re-expression of YTHDF1 in the hippocampus of adult Ythdf1-knockout mice rescues the behavioural and synaptic defects, whereas hippocampus-specific acute knockdown of Ythdf1 or Mettl3, which encodes the catalytic component of the m6A methyltransferase complex, recapitulates the hippocampal deficiency. Transcriptome-wide mapping of YTHDF1-binding sites and m6A sites on hippocampal mRNAs identified key neuronal genes. Nascent protein labelling and tether reporter assays in hippocampal neurons showed that YTHDF1 enhances protein synthesis in a neuronal-stimulus-dependent manner. In summary, YTHDF1 facilitates translation of m6A-methylated neuronal mRNAs in response to neuronal stimulation, and this process contributes to learning and memory.

Prioritized experience replays on a hippocampal predictive map for learning.

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

Follistatin mediates learning and synaptic plasticity via regulation of Asic4 expression in the hippocampus.

The biological mechanisms underpinning learning are unclear. Mounting evidence has suggested that adult hippocampal neurogenesis is involved although a causal relationship has not been well defined. Here, using high-resolution genetic mapping of adult neurogenesis, combined with sequencing information, we identify follistatin (Fst) and demonstrate its involvement in learning and adult neurogenesis. We confirmed that brain-specific Fst knockout (KO) mice exhibited decreased hippocampal neurogenesis and demonstrated that FST is critical for learning. Fst KO mice exhibit deficits in spatial learning, working memory, and long-term potentiation (LTP). In contrast, hippocampal overexpression of Fst in KO mice reversed these impairments. By utilizing RNA sequencing and chromatin immunoprecipitation, we identified Asic4 as a target gene regulated by FST and show that Asic4 plays a critical role in learning deficits caused by Fst deletion. Long-term overexpression of hippocampal Fst in C57BL/6 wild-type mice alleviates age-related decline in cognition, neurogenesis, and LTP. Collectively, our study reveals the functions for FST in adult neurogenesis and learning behaviors.

Investigating Transfer Learning in Noisy Environments: A Study of Predecessor and Successor Features in Spatial Learning Using a T-Maze.

In this study, we investigate the adaptability of artificial agents within a noisy T-maze that use Markov decision processes (MDPs) and successor feature (SF) and predecessor feature (PF) learning algorithms. Our focus is on quantifying how varying the hyperparameters, specifically the reward learning rate (αr) and the eligibility trace decay rate (λ), can enhance their adaptability. Adaptation is evaluated by analyzing the hyperparameters of cumulative reward, step length, adaptation rate, and adaptation step length and the relationships between them using Spearman's correlation tests and linear regression. Our findings reveal that an αr of 0.9 consistently yields superior adaptation across all metrics at a noise level of 0.05. However, the optimal setting for λ varies by metric and context. In discussing these results, we emphasize the critical role of hyperparameter optimization in refining the performance and transfer learning efficacy of learning algorithms. This research advances our understanding of the functionality of PF and SF algorithms, particularly in navigating the inherent uncertainty of transfer learning tasks. By offering insights into the optimal hyperparameter configurations, this study contributes to the development of more adaptive and robust learning algorithms, paving the way for future explorations in artificial intelligence and neuroscience.

Towards neuroadaptive navigation assistance to reduce spatial de-skilling.

Maps have been invaluable navigation aids for millennia and thus have been critical for human survival. The increasing popularity of and high dependence on digital, location-aware assistive navigation technology, however, has been shown to divert our attention from the environment and to negatively influence innate spatial abilities. To mitigate this, neuroadaptive mobile geographic information displays (namGIDs) are proposed that respond in real-time to navigators' cognitive task demands and wayfinder's situated visuo-spatial attention needs. In doing so, namGIDs may not only help navigators maintain navigation efficiency but more importantly, also continuously scaffold spatial learning. To do this, the proposed navigation assistance must strike the appropriate balance between welcomed mobility efficiency gains while limiting human spatial deskilling. Leveraging neuroadaptive cartography, we can ensure to remain effective navigators, empowered to explore the world with confidence.

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

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

Inhibition of hippocampal palmitoyl acyltransferase activity impairs spatial learning and memory consolidation.

Protein palmitoylation regulates trafficking, mobilization, localization, interaction, and distribution of proteins through the palmitoyl acyltransferases (PATs) enzymes. Protein palmitoylation controls rapid and dynamic changes of the synaptic architecture that modifies the efficiency and strength of synaptic connections, a fundamental mechanism to generate stable and long-lasting memory traces. Although protein palmitoylation in functional synaptic plasticity has been widely described, its role in learning and memory processes is poorly understood. In this work, we found that PATs inhibition into the hippocampus before and after the training of Morris water maze (MWM) and object location memory (OLM) impaired spatial learning. However, we demonstrated that PATs inhibition during the retrieval does not affect the expression of spatial memory in both MWM and OLM. Accordingly, long-term potentiation induction is impaired by inhibiting PATs into the hippocampus before high-frequency electrical stimulation but not after. These findings suggest that PATs activity is necessary to modify neural plasticity, a mechanism required for memory acquisition and consolidation. Like phosphorylation, active palmitoylation is required to regulate the function of already existing proteins that change synaptic strength in the hippocampus to acquire and later consolidate spatial memories.

Eye movements shape visual learning.

Most people easily learn to recognize new faces and places, and with more extensive practice they can become experts at visual tasks as complex as radiological diagnosis and action video games. Such perceptual plasticity has been thoroughly studied in the context of training paradigms that require constant fixation. In contrast, when observers learn under more natural conditions, they make frequent saccadic eye movements. Here we show that such eye movements can play an important role in visual learning. Observers performed a task in which they executed a saccade while discriminating the motion of a cued visual stimulus. Additional stimuli, presented simultaneously with the cued one, permitted an assessment of the perceptual integration of information across visual space. Consistent with previous results on perisaccadic remapping [M. Szinte, D. Jonikaitis, M. Rolfs, P. Cavanagh, H. Deubel, J. Neurophysiol. 116, 1592-1602 (2016)], most observers preferentially integrated information from locations representing the presaccadic and postsaccadic retinal positions of the cue. With extensive training on the saccade task, these observers gradually acquired the ability to perform similar motion integration without making eye movements. Importantly, the newly acquired pattern of spatial integration was determined by the metrics of the saccades made during training. These results suggest that oculomotor influences on visual processing, long thought to subserve the function of perceptual stability, also play a role in visual plasticity.

Reward does not facilitate visual perceptual learning until sleep occurs.

A growing body of evidence indicates that visual perceptual learning (VPL) is enhanced by reward provided during training. Another line of studies has shown that sleep following training also plays a role in facilitating VPL, an effect known as the offline performance gain of VPL. However, whether the effects of reward and sleep interact on VPL remains unclear. Here, we show that reward interacts with sleep to facilitate offline performance gains of VPL. First, we demonstrated a significantly larger offline performance gain over a 12-h interval including sleep in a reward group than that in a no-reward group. However, the offline performance gains over the 12-h interval without sleep were not significantly different with or without reward during training, indicating a crucial interaction between reward and sleep in VPL. Next, we tested whether neural activations during posttraining sleep were modulated after reward was provided during training. Reward provided during training enhanced rapid eye movement (REM) sleep time, increased oscillatory activities for reward processing in the prefrontal region during REM sleep, and inhibited neural activation in the untrained region in early visual areas in non-rapid eye movement (NREM) and REM sleep. The offline performance gains were significantly correlated with oscillatory activities of visual processing during NREM sleep and reward processing during REM sleep in the reward group but not in the no-reward group. These results suggest that reward provided during training becomes effective during sleep, with excited reward processing sending inhibitory signals to suppress noise in visual processing, resulting in larger offline performance gains over sleep.

The Role of Smad2 in Adult Neuroplasticity as Seen through Hippocampal-Dependent Spatial Learning/Memory and Neurogenesis.

Adult neural plasticity is an important and intriguing phenomenon in the brain, and adult hippocampal neurogenesis is directly involved in modulating neural plasticity by mechanisms that are only partially understood. We have performed gain-of-function and loss-of-function experiments to study Smad2, a transcription factor selected from genes that are demethylated after exercise through the analysis of an array of physical activity-induced factors, and their corresponding gene expression, and an efficient inducer of plasticity. In these studies, changes in cell number and morphology were analyzed in the hippocampal dentate gyrus (cell proliferation and survival, including regional distribution, and structural maturation/differentiation, including arborization, dendritic spines, and neurotransmitter-specific vesicles) of sedentary male mice, after evaluation in a battery of behavioral tests. As a result, we reveal a role for Smad2 in the balance of proliferation versus maturation of differentiating immature cells (Smad2 silencing increases both the proliferation and survival of cycling cells in the dentate granule cell layer), and in the plasticity of both newborn and mature neurons in mice (by decreasing dendritic arborization and dendritic spine number). Moreover, Smad2 silencing specifically compromises spatial learning in mice (through impairments of spatial tasks acquisition both in long-term learning and working memory). These data suggest that Smad2 participates in adult neural plasticity by influencing the proliferation and maturation of dentate gyrus neurons.SIGNIFICANCE STATEMENT Smad2 is one of the main components of the transforming growth factor-ß (TGF-ß) pathway. The commitment of cell fate in the nervous system is tightly coordinated by SMAD2 signaling, as are further differentiation steps (e.g., dendrite and axon growth, myelination, and synapse formation). However, there are no studies that have directly evaluated the role of Smad2 gene in hippocampus of adult animals. Modulation of these parameters in the adult hippocampus can affect hippocampal-dependent behaviors, which may shed light on the mechanisms that regulate adult neurogenesis and behavior. We demonstrate here a role for Smad2 in the maturation of differentiating immature cells and in the plasticity of mature neurons. Moreover, Smad2 silencing specifically compromises the spatial learning abilities of adult male mice.

Increased Hippocampal Excitability and Altered Learning Dynamics Mediate Cognitive Mapping Deficits in Human Aging.

Learning the spatial layout of a novel environment is associated with dynamic activity changes in the hippocampus and in medial parietal areas. With advancing age, the ability to learn spatial environments deteriorates substantially but the underlying neural mechanisms are not well understood. Here, we report findings from a behavioral and a fMRI experiment where healthy human older and younger adults of either sex performed a spatial learning task in a photorealistic virtual environment (VE). We modeled individual learning states using a Bayesian state-space model and found that activity in retrosplenial cortex (RSC)/parieto-occipital sulcus (POS) and anterior hippocampus did not change systematically as a function learning in older compared with younger adults across repeated episodes in the environment. Moreover, effective connectivity analyses revealed that the age-related learning deficits were linked to an increase in hippocampal excitability. Together, these results provide novel insights into how human aging affects computations in the brain's navigation system, highlighting the critical role of the hippocampus.SIGNIFICANCE STATEMENT Key structures of the brain's navigation circuit are particularly vulnerable to the deleterious consequences of aging, and declines in spatial navigation are among the earliest indicators for a progression from healthy aging to neurodegenerative diseases. Our study is among the first to provide a mechanistic account about how physiological changes in the aging brain affect the formation of spatial knowledge. We show that neural activity in the aging hippocampus and medial parietal areas is decoupled from individual learning states across repeated episodes in a novel spatial environment. Importantly, we find that increased excitability of the anterior hippocampus might constitute a potential neural mechanism for cognitive mapping deficits in old age.