Biology subjects

McNaughton, B. L.

Publications and source records attributed to McNaughton, B. L..

At least 19 recordsLinked to original sources

bioRxiv2025

Hippocampal indexing alters the stability landscape of synaptic weight space allowing life-long learning

Sleep replay - the reactivation of memory traces during slow-wave sleep - is widely held to stabilize memories and reduce interference, yet exactly how replay reorganizes synaptic-weight space to preserve existing memories while incorporating new ones remains unclear. Here, we use a biophysically realistic network model to probe the synaptic-weight dynamics underlying this process. We find that replay drives synaptic weights toward stable configurations - synaptic attractors - that jointly support both old and new memories. Hippocampus-driven interactions between sharp-wave ripples and cortical slow waves guide this reorganization, allowing recently acquired memories to be incorporated without degrading prior ones. These results reveal a mechanistic and geometric framework for memory consolidation: sleep does not passively protect memories, but actively sculpts synaptic-weight space into attractor configurations from which forgetting requires escaping a stability basin. SIGNIFICANCE STATEMENTStoring, processing, and retrieving information underpins intelligent behavior. Sleep extracts invariant features from prior experience, promoting the emergence of explicit knowledge and insight. Yet despite abundant empirical findings, our understanding of how sleep reshapes memory representations at the level of synaptic organization remains limited. Here we present a novel framework that describes how memories are encoded in synaptic-weight space and how sleep dynamics reorganize synaptic landscape. These results advance our understanding of how the brain solves core problems of lifelong learning.

neuroscience↗

bioRxiv2025

Dentate spikes comprise a continuum of relative input strength from the lateral and medial entorhinal cortex.

Hippocampal dentate spikes (DS) are synchronous population events generated in the dentate gyrus thought to support memory processing. DS are classified into type 1 (DS1) and type 2 (DS2) based on current sinks in the outer or middle molecular layer, where the axons of the lateral or medial entorhinal cortex terminate, respectively. This widely used classification method constrains DS into a bimodal distribution without properly testing whether such constraint is appropriate. Here we utilized silicon probe recordings with high spatial resolution spanning all layers of the dentate gyrus and discovered that the contribution of LEC/MEC inputs to DS follows a continuous distribution. We introduce a third type (DS3) that captures a previously unreported component of the distribution: simultaneous current sinks in the outer/middle molecular layer, suggestive of synchronized activation from the LEC/MEC which could facilitate binding. We verify DS3 in several data sets from independent laboratories and characterize their brain state dependence and neural recruitment.

neuroscience↗

bioRxiv2025

Enriched experience increases reciprocal synaptic connectivity and coding sparsity in higher-order cortex

The integration of new information during sleep reshapes cortical representations that support categorical knowledge. Auto-associative attractor network theories predict that reciprocal excitatory connections help form stable categorical attractors, but direct evidence is missing. We tested this using ten weeks of enriched experience (ENR) in mice as a model for knowledge accumulation and recorded single-unit activity across hippocampus and neocortex. ENR induced significant remodeling in high- but not low-level neocortex, with a shift from unidirectional to bidirectional 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.

neuroscience↗

bioRxiv2025

Cognitive enrichment improves spatial memory and alters hippocampal synaptic connectivity in a mouse model for early-life stress

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.

animal behavior and cognition↗

bioRxiv2025

Environmental enrichment accelerates cortical memory consolidation

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.

animal behavior and cognition↗

bioRxiv2025

Interleaved Replay of Novel and Familiar Memory Traces During Slow-Wave Sleep Prevents Catastrophic Forgetting

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 animals life are organized within the cortical-hippocampal system to support continual learning and suggests novel principles for a broad range of continual learning AI.

neuroscience↗

bioRxiv2022

Cortical Reactivation of Non-Spatial and Spatial Memory Representations Coordinate with Hippocampus to Form a Memory Dialogue

Episodic memory depends on the association of diverse attribute representations that are distributed across the neocortex, and evidence suggests that these attributes are linked, at least initially, by the hippocampus, which orchestrates retrieval and the offline replay of experience during memory consolidation. The dynamics that characterize this hippocampal-cortical dialogue, however, are only partly understood. Although it was originally proposed that replay is initiated in CA3, with the spontaneous emission of sharp-wave ripple (SWR) bursts, increasing evidence suggests that cortex may seed the process with partial information, leading to pattern completion in CA3 and subsequent global reactivation of the episode. A recent study has shown that the secondary motor cortex (M2), among other areas, carries two distinct types of representations: place cell-like activity, which relies on an intact hippocampus for its development, and responses tied to visuo-tactile cues -- the attributes of the experience, which do not require the hippocampus. Using two-photon Ca2+ imaging, while simultaneously acquiring LFP from the ipsilateral CA1, we assessed the interactions among cortical retrieval of visuo-tactile attributes of previous experiences in a virtual environment, hippocampal SWR, and the cortical reinstatement of the spatial aspects of the same experiences. During rest after the experience, two types of reactivation events occurred, which separately conveyed information about spatial trajectories and visuo-tactile attributes. Reactivation of attribute information preceded that of trajectories in relation to hippocampal SWRs. Furthermore, paired reactivations of cue and trajectory information supported similar features of previous experiences. These results are consistent with the hypothesis that cortical retrieval of non-spatial attributes of recent experience seeds hippocampal reactivation of associated spatial sequences, which is followed by retrieval of episodic memory traces.

neuroscience↗

bioRxiv2022

Conjunctive and complementary CA1 hippocampal cell populations relate sensory events to immobility and locomotion

This study investigated the dynamics of recruitment of cells in the CA1 region of the hippocampus in response to sensory stimuli presented during immobility, movement, and their transitions. Two-photon calcium imaging of somal activity in CA1 neuron populations was done in head fixed mice. Sensory stimuli, either a light flash or an air stream, were delivered to the mice when at rest, when moving spontaneously, and while they were induced to run a fixed distance on the conveyor belt. Overall, 99% of 2083 identified cells (from 5 mice) were active across one or more of 20 sensorimotor events. A larger proportion of cells were active during locomotion. Nevertheless, for any given sensorimotor event, only about 17% of cells were active. When considering pairs of sensorimotor event types, the active cell population consisted of conjunctive (C [isin] A and B) cells, active across both events, and complementary (C [isin] A not B or C [isin] B not A) cells that were active only during individual events. Whereas conjunctive cells characterised stable representations of repeated sensorimotor events, complementary cells characterised recruitment of new cells for encoding novel sensorimotor events. The moment-to-moment recruitment of conjunctive and complementary cells across changing sensorimotor events signifies the involvement of the hippocampus in functional networks integrating sensory information with ongoing movement. This role of the hippocampus is well suited for movement guidance that secondarily might include spatial behavior, episodic learning and memory, context representation, and scene construction.

neuroscience↗

bioRxiv2022

Inhibition is a prevalent mode of activity in the neocortex around awake hippocampal ripples

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.

neuroscience↗

bioRxiv2022

Regional variation in cholinergic terminal activity determines the non-uniform occurrence of cortical slow-wave activity during REM sleep

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 EEG signals, while REM sleep is characterized desynchronized cortical rhythms. While, until recently, it has been widely believed that cortical activity during REM sleep is globally desynchronized, recent electrophysiological studies showed slow waves (SW) in some cortical areas during REM sleep. Electrophysiological techniques, however, have been unable to resolve the regional structure of these activities, due to relatively sparse sampling. We mapped functional gradients in cortical activity during REM sleep using mesoscale imaging in mice, and observed 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 was also explored by calcium imaging of cholinergic terminal activity within the mouse cortex. Terminal activity was weaker in regions exhibiting SW activity more frequently during REM sleep. We also analyzed Allen Mouse Brain Connectivity dataset and found that these regions have weaker cholinergic projections from the basal forebrain.

neuroscience↗

bioRxiv2020

Spatiotemporal structure of sensory-evoked and spontaneous activity revealed by mesoscale imaging in anesthetized and awake mice

Brain activity propagates across the cortex in diverse spatiotemporal patterns, both as a response to sensory stimulation and during spontaneous activity. Despite been extensively studied, the relationship between the characteristics of such patterns during spontaneous and evoked activity is not completely understood. To investigate this relationship, we compared visual, auditory, and tactile evoked activity patterns elicited with different stimulus strengths and spontaneous activity motifs in lightly anesthetized and awake mice using mesoscale wide-field voltage-sensitive dye and glutamate imaging respectively. The characteristics of cortical activity that we compared include amplitude, speed, direction, and complexity of propagation trajectories in spontaneous and evoked activity patterns. We found that the complexity of the propagation trajectories of spontaneous activity, quantified as their fractal dimension, is higher than the one from sensory evoked responses. Moreover, the speed and direction of propagation, are modulated by the amplitude during both, spontaneous and evoked activity. Finally, we found that spontaneous activity had similar amplitude and speed when compared to evoked activity elicited with low stimulus strengths. However, this similarity gradually decreased when the strength of stimuli eliciting evoked responses increased. Altogether, these findings are consistent with the fact that even primary sensory areas receive widespread inputs from other cortical regions, and that, during rest, the cortex tends to reactivate traces of complex, multi-sensory experiences that may have occurred in a range of different behavioural contexts.

neuroscience↗

bioRxiv2020

Coupling between slow-waves and sharp-wave ripples organizes distributed neural activity during sleep in humans

Hippocampal-dependent memory consolidation during sleep is hypothesized to depend on the synchronization of distributed neuronal ensembles, organized by the hippocampal sharp-wave ripples (SWRs, 80-150 Hz) and subcortical/cortical slow-waves (0.5-4 Hz). However, the precise role of SWR-slow-wave interactions in synchronizing subcortical/cortical neuronal activity is unclear. Here, we leverage intracranial electrophysiological recordings from the human hippocampus, amygdala, temporal and frontal cortices, to examine activity modulation and cross-regional coordination during SWRs. Hippocampal SWRs are associated with widespread modulation of high frequency activity (HFA; 70-200 Hz) a measure of local neuronal activation. This peri-SWR HFA modulation is predicted by the coupling between hippocampal SWRs and local subcortical/cortical slow-waves. Finally, local cortical slow-wave phase offsets during SWRs predicted functional connectivity between the frontal and temporal cortex. These findings suggest a selection mechanism wherein hippocampal SWR and cortical slow-wave synchronization governs the transient engagement of distributed neuronal populations supporting hippocampal-dependent memory consolidation.

neuroscience↗

bioRxiv2020

Integration of New Information in Memory: New Insights from a Complementary Learning Systems Perspective

According to complementary learning systems theory, integrating new memories into the neocortex of the brain without interfering with what is already known depends on a gradual learning process, interleaving new items with previously learned items. However, empirical studies show that information consistent with prior knowledge can be integrated very quickly. We use artificial neural networks with properties like those we attribute to the neocortex to develop a theoretical understanding of the role of consistency with prior knowledge in putatively neocortex-like learning systems, providing new insights into when integration will be fast or slow and how integration might be made more efficient when the items to be learned are hierarchically structured. The work relies on deep linear networks that capture the qualitative aspects of the learning dynamics of the more complex non-linear networks used in previous work. The time course of learning in these networks can be linked to the hierarchical structure in the training data, captured mathematically as a set of dimensions that correspond to the branches in the hierarchy. In this context, a new item to be learned can be characterized as having aspects that project onto previously known dimensions, and others that require adding a new branch/dimension. The projection onto the known dimensions can be learned rapidly without interleaving, but learning the new dimension requires gradual interleaved learning. When a new item only overlaps with items within one branch of a hierarchy, interleaving can focus on the previously-known items within this branch, resulting in faster integration with less inter-leaving overall. The discussion considers how the brain might exploit these facts to make learning more efficient and highlights predictions about what aspects of new information might be hard or easy to learn.

neuroscience↗

bioRxiv2019

Spatiotemporal patterns of neocortical activity around hippocampal sharp-wave ripples

A prevalent model is that sharp-wave ripples (SWR) arise spontaneously in CA3 and propagate recent memory traces outward to the neocortex to facilitate memory consolidation there. Using voltage and extracellular glutamate transient recording over widespread regions of mice dorsal neocortex in relation to CA1 multiunit activity (MUA) and SWR, we find that the largest SWR-related modulation occurs in retrosplenial cortex; however, contrary to the unidirectional hypothesis, neocortical activation exhibited a continuum of activation timings relative to SWRs, varying from leading to lagging. Thus, contrary to the model in which SWRs arise spontaneously in the hippocampus, neocortical activation often precedes SWRs and may thus constitute a trigger event in which neocortical information seeds associative reactivation of hippocampal indices. This timing continuum is consistent with a dynamics in which older, more consolidated memories may in fact initiate the hippocampal-neocortical dialog, whereas reactivation of newer memories may be initiated predominantly in the hippocampus.

neuroscience↗

bioRxiv2018

Low acetylcholine during early sleep is important for motor memory consolidation

The synaptic homeostasis theory of sleep proposes that low neurotransmitter activity in sleep is optimal for memory consolidation. We tested this theory by asking whether increasing acetylcholine levels during early sleep would disrupt motor memory consolidation. We trained separate groups of adult mice on the rotarod walking and skilled reaching for food tasks, and after training, administered physostigmine, an acetylcholinesterase inhibitor, to increase cholinergic tone in subsequent sleep. Post-sleep testing suggested that physostigmine impaired motor skill acquisition. Home-cage video monitoring and electrophysiology revealed that physostigmine disrupted sleep structure, delayed non-rapid-eye-movement sleep onset, and reduced slow-wave power in the hippocampus and cortex. The impaired motor performance with physostigmine, however, was not solely due to its effects on sleep structure, as one hour of sleep deprivation after training did not impair rotarod performance. A reduction in cholinergic tone by inactivation of cholinergic neurons during early sleep also affected rotarod performance. Administration of agonists and antagonists of muscarinic and nicotinic acetylcholine receptors revealed that activation of muscarinic receptors during early sleep impaired rotarod performance. The experiments suggest that the increased slow wave activity and inactivation of muscarinic receptors during early sleep due to reduced acetylcholine contribute to motor memory consolidation.

neuroscience↗

bioRxiv2018

Impaired Spatial Reorientation in the 3xTg-AD Mouse Model of Alzheimer’s Disease

In early Alzheimers disease (AD) spatial navigation is impaired; however, the precise cause of this impairment is unclear. Recent evidence suggests that getting lost in new surroundings is one of the first impairments to emerge in AD. It is possible that getting lost in new surroundings represents a failure to use distal cues to get oriented in space. Therefore, we set out to look for impaired use of distal cues for spatial orientation in a mouse model of amyloidosis (3xTg-AD). To do this, we trained mice to shuttle to the end of a track and back to an enclosed start box to receive a water reward. Then, mice were trained to stop in an unmarked reward zone to receive a brain stimulation reward. The time required to remain in the zone for a reward was increased across training, and the track was positioned in a random start location for each trial. We found that 6-month female, but not male, 3xTg-AD mice were impaired. Male and female mice had only intracellular pathology and male mice had less pathology, particularly in the dorsal hippocampus. Thus, AD may cause spatial disorientation as a result of impaired use of landmarks.

neuroscience↗

bioRxiv2017

Encoding of Tactile Context in the Mouse Visual Cortex

Multisensory integration is key for perception and animal survival yet how information from separate senses is integrated has been debated for decades. In the cortex, information from each sense is first processed in primary sensory areas and then combined in association areas. An alternative hypothesis to this hierarchical model is that primary sensory cortices partake in multisensory encoding. We probed tactile and visual responses in primary somatosensory and visual cortices in awake behaving animals using two-photon calcium imaging from layer 2/3 excitatory neurons. In support of an hierarchical model we found segregation of visual and tactile responses. Tactile stimuli evoked responses in S1 neurons. In striking contrast, V1 neurons failed to respond to tactile stimuli. This was true for passive whisker stimulation and for stimulation during active whisking. Furthermore, responses of V1 neurons to congruent visuo-tactile cues during active exploration, a condition where vision precedes touch, were completely abolished in darkness. The rostro-lateral area of the visual cortex responded to both visual and tactile aspects of the stimuli and may form a substrate for encoding multisensory signals during active exploration. Our results indicate that primary sensory areas mainly encode their primary sense and that the impact of other modalities may be restricted to modulatory effects.

neuroscience↗

bioRxiv2017

A high-performance, inexpensive setup for simultaneous multi-site recording of electrophysiological signals and wide-field optical imaging of the mouse cortex

Simultaneous recording of optical and electrophysiological signals from multiple cortical areas may provide crucial information to expand our understanding of cortical function. However, the insertion of multiple electrodes into the brain may compromise optical imaging by both restricting the field of view, and interfering with the approaches used to stabilize the specimen. Existing methods that combine electrophysiological recording and optical imaging in vivo implement either multiple surface electrodes or a single electrode for deeper recordings. To address such limitation, we built a microelectrode array (hyperdrive) compatible with wide-field imaging that allows insertion of up to 12 probes into a large brain area (8 mm diameter). The developed hyperdrive is comprised of a circle of individual microdrives where probes are positioned at an angle leaving a large brain area unobstructed for wide-field imaging. Multiple tetrodes and voltage-sensitive dye imaging (VSDI) were used for simultaneous registration of spontaneous and evoked cortical activity. The electrophysiological signals were used to extract local field potential (LFP) traces, multiunit and single-unit spiking activity. To demonstrate our approach, we compared LFP and VSD signals over multiple regions of the cortex and analyzed the relationship between single-unit and global cortical population activities. The study of the interactions between cortical activity at local and global scales, such as the one presented in this work, can help to expand our knowledge of brain function.

neuroscience↗