The integration of new information during sleep reshapes cortical representations that support categorical knowledge. Autoassociative attractor network theories predict that reciprocal excitatory connections help form stable categorical attractors, but direct evidence is missing. We tested this using 10 weeks of enriched experience [environmental enrichment (ENR)] in mice as a model for knowledge accumulation and recorded single-unit activity across the hippocampus and neocortex. ENR induced significant remodeling in high-level but not low-level neocortex, with a major shift from unidirectional to bidirectional functional excitatory-excitatory connections, suggestive of increased "cell assemblies." This was accompanied by increased inhibitory-to-excitatory connections and sparser, more orthogonal population activity during awake rest and slow-wave sleep, particularly in deep layers. Thus, ENR reorganizes cortical circuits into a symmetric, inhibition-balanced network that improves coding efficiency, supporting long-standing attractor network predictions.

Early life stress (ELS) and enrichment often have opposing effects on long-term cognitive abilities. Deprivation, such as institutionalized care during early childhood neurodevelopmental periods, results in lifelong working memory and recall deficits. In contrast, enrichment facilitates new learning and slows cognitive decline due to aging and neurodegenerative diseases. Similarly, in rodent models, enrichment facilitates learning whereas ELS induces prominent spatial memory deficits. Environmental enrichment (EE) and ELS can cause opposing changes in hippocampal structure (e.g. shifts in synaptic density) that largely depend on experimental conditions. However, it remains untested whether EE can rescue the behavioral disruptions caused by ELS and how this would impact the hippocampus at advanced ages. To address this, we conducted a longitudinal study on ELS mice, extensively training them on a cognitive enrichment track (ET) or an exercise alone control track (CT). After this, the mice underwent repeated memory testing followed by brain extraction for anatomical analysis of their hippocampus. We found that ET reversed spatial memory deficits at 6, 13 and 20 months and reduced the number of dentate gyrus (DG) to CA3 synapses. Surprisingly, this reduction occurred at excitatory MF synapses surrounding CA3 somas in the stratum pyramidale-a layer not typically associated with MF terminals. Collectively, these findings suggest that cognitive enrichment during early adulthood may reverse ELS-induced spatial memory deficits by adjusting synaptic connectivity between the DG and CA3.

Humans and animals can learn continuously, acquiring new knowledge while integrating it into a lifelong memory pool. In contrast, artificial neural networks (ANNs) suffer from catastrophic forgetting, where new training disrupts existing memories. This issue can be alleviated in ANNs by interleaving training on new tasks with past data; however, whether the brain uses a similar strategy is unknown. In this work, we show that slow-wave sleep interleaves replay of familiar and novel (i.e. hippocampal-dependent) memory traces within individual slow waves, allowing new memories to integrate into the existing cortical pool without interference. This study presents a novel theory for how memory traces acquired across an animal's life are organized within the cortical-hippocampal system to support continual learning and suggests novel principles for a broad range of continual learning AI.

Continual learning (CL) refers to an agent's capability to learn from a continuous stream of data and transfer knowledge without forgetting old information. One crucial aspect of CL is forward transfer, i.e., improved and faster learning on a new task by leveraging information from prior knowledge. While this ability comes naturally to biological brains, it poses a significant challenge for artificial intelligence (AI). Here, we suggest that environmental enrichment (EE) can be used as a biological model for studying forward transfer, inspiring human-like AI development. EE refers to animal studies that enhance cognitive, social, motor, and sensory stimulation and is a model for what, in humans, is referred to as 'cognitive reserve'. Enriched animals show significant improvement in learning speed and performance on new tasks, typically exhibiting forward transfer. We explore anatomical, molecular, and neuronal changes post-EE and discuss how artificial neural networks (ANNs) can be used to predict neural computation changes after enriched experiences. Finally, we provide a synergistic way of combining neuroscience and AI research that paves the path toward developing AI capable of rapid and efficient new task learning.

Environmental enrichment is an established strategy to enhance learning and to build resilience against neurodegeneration. In humans, this is known as 'cognitive reserve'. Though the beneficial effects of exposure to a complex environment in animal models have been well-documented by behavioural, immunohistological and morphological observations, its impact on the functional properties of neuronal populations remains poorly understood. This study aimed to compare the functional encoding and offline memory retrieval dynamics of cortical neurons in enriched and control mice performing a virtual spatial foraging task. Thy1-GCaMP6s mice aged 21 days were enriched for 9 weeks by running a complex obstacle course, during which they were gradually exposed to many different types of obstacles requiring climbing, jumping, and/or balancing elements. Control animals were exercise-matched by running a similar track containing only repeating ramps. At the age of 3 months, two-photon calcium imaging was conducted on populations of neurons from the secondary motor cortex in both groups before, during, and after repeated locomotion through a virtual environment with salient visual-tactile cues. We observed an increase in memory reactivation in the enriched group during the first day of exposure. With training, enriched animals exhibited a stronger anticipatory reduction in running speed near the reward location. Moreover, cortical neuron activity representing locations on the track became substantially more stable and precise over days in enriched but not control animals. Altogether, these results indicate that prior environmental enrichment accelerates the consolidation of stable and task-relevant memory representations in the cortex for a novel task, and enables faster and more robust acquisition of new sequence representations.

Spatial learning is impaired in humans with preclinical Alzheimer’s disease (AD). We reported similar impairments in 3xTg-AD mice learning a spatial reorientation task. Memory reactivation during sleep is critical for learning-related plasticity, and memory consolidation is correlated with hippocampal sharp wave ripple (SWR) density, cortical delta waves (DWs), cortical spindles, and the temporal coupling of these events—postulated as physiological substrates for memory consolidation. Further, hippocampal-cortical discoordination is prevalent in individuals with AD. Thus, we hypothesized that impaired memory consolidation mechanisms in hippocampal-cortical networks could account for spatial memory deficits. We assessed sleep architecture, SWR-DW dynamics, and memory reactivation in a mouse model of tauopathy and amyloidosis implanted with a recording array targeting isocortex and hippocampus. Mice underwent daily recording sessions of rest-task-rest while learning the spatial reorientation task. We assessed memory reactivation by matching activity patterns from the approach to the unmarked reward zone to patterns during slow-wave sleep (SWS). AD mice had more SWS, but reduced SWR density. The increased SWS compensated for reduced SWR density so there was no reduction in SWR number. In control mice, spindles were phase-coupled with DWs, and hippocampal SWR-cortical DW coupling was strengthened in post-task sleep and was correlated with performance on the spatial reorientation task the following day. However, in AD mice, SWR-DW and spindle-DW coupling were impaired. Thus, reduced SWR-DW coupling may cause impaired learning in AD, and spindle-DW coupling during short rest-task-rest sessions may serve as a biomarker for early AD-related changes in these brain dynamics.

During navigation, the neocortex actively integrates learned spatial context with current sensory experience to guide behaviors. However, the relative encoding of spatial and sensorimotor information among cortical cells, and whether hippocampal feedback continues to modify these properties after learning, remains poorly understood. Thus, two-photon microscopy of male and female Thy1-GCaMP6s mice was used to longitudinally image neurons spanning superficial retrosplenial cortex and layers II-Va of primary and secondary motor cortices before and after bilateral dorsal hippocampal lesions. During behavior on a familiar cued treadmill, the locations of two obstacles were interchanged to decouple place-tuning from cue-tuning among position-correlated cells with fields at those locations. Subpopulations of place and cue cells each formed interareal gradients such that higher-level cortical regions exhibited higher fractions of place cells, whereas lower-level regions exhibited higher fractions of cue cells. Position-correlated cells in the motor cortex also formed translaminar gradients; more superficial cells were more likely to exhibit fields and were more sparsely and precisely tuned than deeper cells. After dorsal hippocampal lesions, a neural representation of the learned environment persisted, but retrosplenial cortex exhibited significantly increased cue-tuning, and, in motor cortices, both position-correlated cell recruitment and population activity at the unstable obstacle locations became more homogeneously elevated across laminae. Altogether, these results support that the hippocampus continues to modulate cortical responses in familiar environments, and the relative impact of descending feedback obeys hierarchical interareal and interlaminar gradients opposite to the flow of ascending sensory inputs.

Psychedelic drugs have profound effects on perception, cognition and mood. How psychedelics affect neural signaling to produce these effects remains poorly understood. We investigated the effect of the classic psychedelic psilocybin on neural activity patterns and spatial encoding in the retrosplenial cortex of head-fixed mice navigating on a treadmill. The place specificity of neurons to distinct locations along the belt was reduced by psilocybin. Moreover, the stability of place-related activity across trials decreased. Psilocybin also reduced the functional correlation among simultaneously recorded neurons. The 5-HT2AR (serotonin 2A receptor) antagonist ketanserin blocked these effects. These data are consistent with proposals that psychedelics increase the entropy of neural signaling and provide a potential neural mechanism contributing to disorientation frequently reported by humans after taking psychedelics.

Lesions and pharmacological inactivation of the hippocampus have long been important tools for assessing the critical role of the hippocampus in learning and memory. Such studies often require a substantial investment of time and resources and, so, a tool for estimating lesion extent and screening animals prior to histological verification would be of considerable utility. Mice with bilateral hippocampal lesions have previously been observed to be deficient at nest building. Therefore, non-maternal nest construction was assessed as a predictor of the extent of hippocampal lesions. Mice with complete bilateral dorsal hippocampal lesions (comprising >50 % of the total volume of both hippocampi) exhibited severe deficits in nest building, failing to shred and/or gather nesting materials. In contrast, incomplete dorsal hippocampal lesions were not sufficient to cause impairments. Overall, among both male and female mice, nest construction score was highly positively correlated with the total volume of intact dorsal hippocampus. Importantly, reduced nesting behaviours could not be explained by gross motor deficits, which were evaluated by running performance on a non-motorized treadmill. Altogether, spontaneous nest building behaviour was confirmed to be a simple, cost-effective, and reliable predictor of bilateral dorsal hippocampal lesion extent in an otherwise healthy mouse strain.

Sleep consists of two basic stages: non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. NREM sleep is characterized by slow high-amplitude cortical electroencephalogram (EEG) signals, while REM sleep is characterized by desynchronized cortical rhythms. Despite this, recent electrophysiological studies have suggested the presence of slow waves (SWs) in local cortical areas during REM sleep. Electro-physiological techniques, however, have been unable to resolve the regional structure of these activities because of relatively sparse sampling. Here, we map functional gradients in cortical activity during REM sleep using mesoscale imaging in mice and show local SW patterns occurring mainly in somatomotor and auditory cortical regions with minimum presence within the default mode network. The role of the cholinergic system in local desynchronization during REM sleep is also explored by calcium imaging of cholinergic activity within the cortex and analyzing structural data. We demonstrate weaker cholinergic projections and terminal activ-ity in regions exhibiting frequent SWs during REM sleep.

Coordinated peri-ripple activity in the hippocampal-neocortical network is essential for mnemonic information processing in the brain. Hippocampal ripples likely serve different functions in sleep and awake states. Thus, the corresponding neocortical activity patterns may differ in important ways. We addressed this possibility by conducting voltage and glutamate wide-field imaging of the neocortex with concurrent hippocampal electrophysiology in awake mice. Contrary to our previously published sleep results, deactivation and activation were dominant in post-ripple neocortical voltage and glutamate activity, respectively, especially in the agranular retrosplenial cortex (aRSC). Additionally, the spiking activity of aRSC neurons, estimated by two-photon calcium imaging, revealed the existence of two subpopulations of excitatory neurons with opposite peri-ripple modulation patterns: one increases and the other decreases firing rate. These differences in peri-ripple spatiotemporal patterns of neocortical activity in sleep versus awake states might underlie the reported differences in the function of sleep versus awake ripples.

Background:The ability of psychedelic compounds to profoundly alter mental function has been long known, but the underlying changes in cellular-level information encoding remain poorly understood. Methods:We used two-photon microscopy to record from the retrosplenial cortex in head-fixed mice running on a treadmill before and after injection of the nonclassic psychedelic ibogaine (40 mg/kg intraperitoneally). Results:We found that the cognitive map, formed by the representation of position encoded by ensembles of individual neurons in the retrosplenial cortex, was destabilized by ibogaine when mice had to infer position between tactile landmarks. This corresponded with increased neural activity rates, loss of correlation structure, and increased responses to cues. Ibogaine had surprisingly little effect on the size-frequency distribution of network activity events, suggesting that signal propagation within the retrosplenial cortex was largely unaffected. Conclusions:Taken together, these data support proposals that compounds with psychedelic properties disrupt representations that are important for constraining neocortical activity, thereby increasing the entropy of neural signaling. Furthermore, the loss of expected position encoding between landmarks recapitulated effects of hippocampal impairment, suggesting that disruption of cognitive maps or other hippocampal processing may be a contributing mechanism of discoordinated neocortical activity in psychedelic states.

Principles governing the encoding, storage, and updating of memories in cortical networks are poorly understood. In retrosplenial cortex (RSC), cells respond to the animal's position as it navigates a real or virtual (VR) linear track. Position correlated cells (PCCs) in RSC require an intact hippocampus to form. To examine whether PCCs undergo pattern completion and remapping like hippocampal cells, neuronal activity in RSC or CA1 was recorded using two-photon calcium imaging in mice running on VR tracks. RSC and CA1 PCC activity underwent global and rate remapping depending on the degree of change to familiar environments. The formation of position correlated fields in both regions required stability across laps; however, once formed, PCCs became robust to object destabilization, indicating pattern completion of the previously formed memory. Thus, memory and remapping properties were conserved between RSC and CA1, suggesting that these functional properties are transmitted to cortex to support memory functions.

Systems-level memory consolidation, a key concept in memory research, involves the conversion of memories that depend on the hippocampus for their formation into efficient hippocampus-independent forms, presumably encoded by cortico-cortical connections. Yet, little is understood about the nature of consolidated neural codes at the cellular ensemble level. Mice require an intact hippocampus for "virtual" spatial learning and to develop neocortical representations of the corresponding experiences. We find that, whereas a novel virtual environment is neither learned nor represented in superficial cortex following severe damage to hippocampus, pre-operatively learned memories and their corresponding sparse and widespread neural ensemble representations in cortical layers II-III are preserved, a sine qua non of memory consolidation. These findings provide a new window for future study of the cellular mechanisms of memory consolidation.

Episodic memories comprise diverse attributes of experience distributed across neocortical areas. The hippocampus is integral to rapidly binding these diffuse representations, as they occur, to be later reinstated. However, the nature of the information exchanged during this hippocampal-cortical dialogue remains poorly understood. A recent study has shown that the secondary motor cortex carries two types of representations: place cell-like activity, which were impaired by hippocampal lesions, and responses tied to visuo-tactile cues, which became more pronounced following hippocampal lesions. Using two-photon Ca2+ imaging to record neuronal activities in the secondary motor cortex of male Thy1-GCaMP6s mice, we assessed the cortical retrieval of spatial and non-spatial attributes from previous explorations in a virtual environment. We show that, following navigation, spontaneous resting state reactivations convey varying degrees of spatial (trajectory sequences) and non-spatial (visuo-tactile attributes) information, while reactivations of non-spatial attributes tend to precede reactivations of spatial representations surrounding hippocampal sharp-wave ripples.

AbstractSpatial cognition research requires behavioral paradigms that can distinguish between different navigational elements, such as allocentric (map-like) navigation and egocentric (e.g., body centered) navigation. To fill this need, we developed a flexible experimental platform that can be quickly modified without the need for significant changes to software and hardware. In this paper, we present this inexpensive and flexible behavioral platform paired with software which we are making freely available. Our behavioral platform serves as the foundation for a range of experiments, and although developed for assessing spatial cognition, it also has applications in the nonspatial domain of behavioral testing. There are two components of the software platform, “Maze” and “Stim Trigger.” While intended as a general platform, presently both programs can work in conjunction with Neuralynx and Open Ephys electrophysiology acquisition systems, allowing for precise time stamping of neural events. The Maze program includes functionality for automatic reward delivery based on user defined zones. “Stim Trigger” permits control of brain stimulation via any equipment that can be paired with an Arduino board. We seek to share our software and leverage the potential by expanding functionality in the future to meet the needs of a larger community of researchers.

Spatial cognition research requires behavioral paradigms that can distinguish between different navigational elements, such as allocentric (map-like) navigation and egocentric (e.g., body centered) navigation. To fill this need, we developed a flexible experimental platform that can be quickly modified without the need for significant changes to software and hardware. In this paper, we present this inexpensive and flexible behavioral platform paired with software which we are making freely available. Our behavioral platform serves as the foundation for a range of experiments, and although developed for assessing spatial cognition, it also has applications in the nonspatial domain of behavioral testing. There are two components of the software platform, "Maze" and "Stim Trigger." While intended as a general platform, presently both programs can work in conjunction with Neuralynx and Open Ephys electrophysiology acquisition systems, allowing for precise time stamping of neural events. The Maze program includes functionality for automatic reward delivery based on user defined zones. "Stim Trigger" permits control of brain stimulation via any equipment that can be paired with an Arduino board. We seek to share our software and leverage the potential by expanding functionality in the future to meet the needs of a larger community of researchers.