Biology subjects

Magee, J. C.

Publications and source records attributed to Magee, J. C..

12 recordsLinked to original sources

bioRxiv2026

Plateau-gated one-shot plasticity supports continual recognition memory

Biological memory systems store single experiences while continuing to learn, but how one-shot plasticity limits interference with existing memories is unclear. Behavioral timescale synaptic plasticity (BTSP) rapidly modifies synapses active within seconds of a dendritic plateau. We isolate its plateau-triggered component in a model where plastic weights and a stable instructive pathway jointly determine whether a plateau occurs, closing a feedback loop between the synaptic state and the plastic event that modifies it. For unstructured inputs, instantiated by independent uniform signed patterns, the dynamics reduce exactly to pathway alignment, which determines the fidelity of the instructed representation, the synaptic-turnover rate and the mean rewrite interval. For structured inputs, instantiated by correlated bimodal Curie--Weiss patterns, the instructive pathway biases which component of input structure enters the plastic synaptic state. In a BTSP-inspired continual-recognition network, combined instructive and plastic drives determined the selected memory unit for each one-shot write, whereas a Hebbian control used the same plastic weights for credit assignment and memory storage. The BTSP-inspired network remained accurate at longer repeat lags than Hebbian controls, an advantage that grew with network size, with both architectures optimized independently at every repeat lag. A reduced theory predicted held-out accuracy, lag capacity and dynamics of memory-trace strength directly from optimized parameters. It showed why intermediate proximal and distal coupling was optimal: proximal plastic drive guided plateau generation toward selected memory units, slowing synaptic turnover but limiting new encoding, whereas distal instructive drive enhanced familiar responses but could also make novel inputs appear familiar. The memory-trace strength in the rate-and-depth-matched Hebbian control still decayed faster and showed less effective credit assignment than in the BTSP-inspired network. These results connect dendritic plateau physiology to continual memory and support partial separation of allocation from storage as a mechanism for limiting interference during continual learning.

neuroscience↗

bioRxiv2026

Unconstrained Plasticity Disrupts Memory Consolidation in a Mouse Model of Rett Syndrome

Memory impairment is a hallmark cognitive deficit in Rett syndrome (RTT). Yet, long-term memory deficits in RTT animal models remain poorly understood, largely due to the technical challenges inherent in tracking neural activity over extended periods. Here, we used longitudinal two-photon calcium imaging to follow the same population of hippocampal CA1 neurons as female RTT mice and their littermate controls formed cognitive maps of their environment during a spatial learning task. Neural representations in RTT mice were marked by excessive place cell (PC) activity, with individual PCs exhibiting pronounced instability across days. This disrupted single-cell stability propagated to the population level, resulting in unstable ensemble codes that poorly retained previously learned task information. Both excessive PC recruitment and instability could be attributed to a higher incidence of behavioral timescale synaptic plasticity (BTSP) in RTT mice. In wild-type littermates, place-cell consolidation across days is reflected by an increased likelihood of neuron-specific synaptic plasticity at the location of prior PC coding. This cellular mechanism of memory consolidation based on the location of BTSP was disrupted in RTT mice, where excessive and ectopic plasticity reduced PC stability, and degraded long-term stable representations. Backed by theoretical modeling, these results identify a plausible cellular and circuit-level mechanism underlying memory impairments in RTT mice and suggest principles that may be generalized to other neurological disorders involving memory deficits.

neuroscience↗

bioRxiv2025

Dendrite-targeting OLM interneurons regulate the formation of learning-related CA1 place cell representations

Spatial learning depends on hippocampal CA1 place cell representations, which form rapidly through behavioral timescale synaptic plasticity (BTSP). BTSP is driven by dendritic plateau potentials proposed to arise from the interaction of an excitatory target signal from entorhinal cortex layer 3 (EC3) and inhibitory feedback reflecting the current CA1 population state. However, the cellular source of this feedback has remained unknown. Using two-photon Ca2+ imaging in mice during spatial learning, we found that dendrite-targeting oriens-lacunosum moleculare (OLM) interneurons increased their activity at behaviorally salient locations in a manner consistent with previously described environment-specific CA1 representations and EC3 target signals. Causal manipulations revealed that silencing a genetically defined subset of OLM interneurons late in learning enhanced BTSP and place field formation, whereas activating them early suppressed place field formation. These findings identify OLM interneurons as a key inhibitory feedback element regulating BTSP and the formation of hippocampal representations during learning.

neuroscience↗

bioRxiv2025

Memory traces bias new learning for hippocampal generalization

The ability to use generalized prior experience to guide behavior in novel situations is a fundamental cognitive function1. While recent evidence suggests that the hippocampus supports generalization how this is accomplished is poorly understood2-9. Here we combined longitudinal optical imaging in head-fixed mice with computational modeling to examine generalization in hippocampal area CA1. We found that prior training accelerated behavioral adaptation to a novel environment and that this was accompanied by highly stable hippocampal representations. We identified putative memory traces from prior experience that enabled this generalization at multiple levels. At the population level, novel-context network dynamics rapidly aligned with low-dimensional neural subspaces10 established during prior experience. At the cellular level, spatially-informative weak "residual" activity reflecting generalizable information about the task structure appeared to bias which neurons form place fields (PFs) and where via behavioral timescale synaptic plasticity (BTSP)11,12. Finally, this was an active process as many PFs changed their reference frame in the novel environment to reflect the consistent task structure. In sum, the influence of memory traces on new PF formation may allow past experience to guide new learning such that representations are based on generalizable features, thus enabling rapid adaptive behavior in new contexts.

neuroscience↗

bioRxiv2025

Rapid neocortical network modifications via dendritic plateau potential induced plasticity

Learning in brains is associated with changes in neuronal network activity thought to be driven by synaptic plasticity. While recent work in the hippocampus has revealed some of the mechanisms involved there, less is known about how neocortical circuits adapt, especially during behavior. Here to determine if neocortical areas possess rapid plasticity mechanisms that could support online adaptations we used optical imaging and intracellular membrane potential (Vm) recordings to examine the activity of layer V neurons in a higher visual area of mice learning a task. The introduction of a novel rewarded stimulus resulted in a rapid modification of population activity that featured abrupt alterations in single neuron selectivity. Vm recordings revealed that both naturally occurring and experimentally-induced dendritic calcium plateau potentials (plateaus) rapidly alter the action potential (APs) output and Vm dynamics of neurons over many seconds of time around the plateau, in some cases from one trial to the next. Trains of high frequency APs had no effect. Finally, experimental inhibition during learning of the distal dendritic region responsible for initiating plateaus reduced the rate of population level adaptation. Our findings suggest that the deep layers of higher order visual cortex possess a rapid learning mechanism mediated by plateau-induced synaptic plasticity.

neuroscience↗

bioRxiv2023

Experience-dependent place-cell referencing in hippocampal area CA1

CA1 hippocampal place cells (PCs) are known for using both self-centric (egocentric) and world-centric (allocentric) reference frames to support a cognitive map1,2. The mechanism of PC referencing and the role of experience in this process, however, remain poorly understood3-5. Here we longitudinally recorded the activity of CA1 PCs while mice performed a spatial learning task. In a familiar environment, the CA1 representation consisted of PCs that were referenced to either spatial locations (allocentric PCs) or mouse running (egocentric PCs) in approximately equal proportions. In a novel environment, however, the CA1 representation became predominately egocentrically referenced. Notably, individual allocentric PCs in a familiar environment adaptively switched reference frames to become egocentric in a novel environment. In addition, intracellular membrane potential recordings revealed that individual CA1 neurons simultaneously received both ego- and allo-centric synaptic inputs, and the ratio of these two input streams correlated with the level of individual PC referencing. Furthermore, behavioral timescale synaptic plasticity6,7 (BTSP) was an active participant in shaping PC referencing through the rapid adjustment of synaptic weights on many PCs. Together, these results suggest that experience-dependent adjustment of synaptic input shapes ego and allocentric PC referencing to support a flexible cognitive map in CA1.

neuroscience↗

bioRxiv2023

Mechanisms of memory storage and retrieval in hippocampal area CA3

Hippocampal area CA3 is thought to play a central role in memory formation and retrieval. Although various network mechanisms have been hypothesized to mediate these computations, direct evidence is lacking. Using intracellular membrane potential recordings from CA3 neurons and optogenetic manipulations in behaving mice we found that place field activity is produced by a symmetric form of Behavioral Timescale Synaptic Plasticity (BTSP) at recurrent synaptic connections among CA3 principal neurons but not at synapses from the dentate gyrus (DG). Additional manipulations revealed that excitatory input from the entorhinal cortex (EC) but not DG was required to update place cell activity based on the animals movement. These data were captured by a computational model that used BTSP and an external updating input to produce attractor dynamics under online learning conditions. Additional theoretical results demonstrate the enhanced memory storage capacity of such networks, particularly in the face of correlated input patterns. The evidence sheds light on the cellular and circuit mechanisms of learning and memory formation in the hippocampus. One Sentence SummaryEvidence from behaving mice points to cellular and circuit mechanisms that underlie observed attractor dynamics in area CA3.

neuroscience↗

bioRxiv2023

A critical role for CaMKII in behavioral timescale synaptic plasticity in hippocampal CA1 pyramidal neurons.

Behavioral timescale synaptic plasticity (BTSP) is a type of non-Hebbian synaptic plasticity reported to underlie place field formation in the hippocampal CA1 neurons. Despite this important function, the molecular mechanisms underlying BTSP are poorly understood. The -Calcium-calmodulin-dependent protein kinase II (CaMKII) is activated by synaptic transmission-mediated calcium influx and its subsequent phosphorylation is central to synaptic plasticity. Because the activity of CaMKII is known to outlast the event triggering phosphorylation, we hypothesized it could be involved in the extended timescale of the BTSP process. To examine the role of CaMKII in BTSP, we performed whole-cell in-vivo and in-vitro recordings in CA1 pyramidal neurons from mice engineered to have a point mutation at the autophosphorylation site (T286A) causing accelerated signaling kinetics. Here we demonstrate a profound deficit in synaptic plasticity, strongly suggesting that CaMKII signaling is required for BTSP. This study elucidates part of the molecular mechanism of BTSP and provides insight into the function of CaMKII in place cell formation and ultimately learning and memory. TeaserThe molecular mechanisms of BTSP have been revealed to require the autophosphorylation of CaMKII.

neuroscience↗

bioRxiv2023

The formation of an expanding memory representation in the hippocampus

How brain networks connected by labile synapses store new information without catastrophically overwriting previous memories remains poorly understood1,2. To examine this, we tracked the same population of hippocampal CA1 place cells (PC) as mice learned a task for 7 days. We found evidence of memory formation as both the number of PCs maintaining a stable place field (PF) and the stability of individual PCs progressively increased across the week until most of the representation was composed of long-term stable PCs. The stable PCs disproportionately represented task-related learned information, were retrieved earlier within a behavioral session, and showed a strong correlation with behavioral performance. Both the initial formation of PCs and their retrieval on subsequent days was accompanied by prominent signs of behavioral timescale synaptic plasticity (BTSP), suggesting that even stable PCs were re-formed by synaptic plasticity each session. Further experimental evidence supported by a cascade-type state model indicates that CA1 PCs increase their stability each day they are active eventually forming a highly stable population. The results suggest that CA1 memory is implemented by an increase in the likelihood of new neuron-specific synaptic plasticity, as opposed to extensive long-term synaptic weight stabilization.

neuroscience↗

bioRxiv2021

Entorhinal cortex directs learning-related changes in CA1 representations

Learning-related changes in brain activity are thought to underlie adaptive behaviors1,2. For instance, the learning of a reward site by rodents requires the development of an over-representation of that location in the hippocampus3-6. However, how this learning-related change occurs remains unknown. Here we recorded hippocampal CA1 population activity as mice learned a reward location on a linear treadmill. Physiological and pharmacological evidence suggests that the adaptive over-representation required behavioral timescale synaptic plasticity (BTSP)7. BTSP is known to be driven by dendritic voltage signals that we hypothesized were initiated by input from entorhinal cortex layer 3 (EC3). Accordingly, the CA1 over-representation was largely removed by optogenetic inhibition of EC3 activity. Recordings from EC3 neurons revealed an activity pattern that could provide an instructive signal directing BTSP to generate the over-representation. Consistent with this function, exposure to a second environment possessing a prominent reward-predictive cue resulted in both EC3 activity and CA1 place field density that were more elevated at the cue than the reward. These data indicate that learning-related changes in the hippocampus are produced by synaptic plasticity directed by an instructive signal from the EC3 that appears to be specifically adapted to the behaviorally relevant features of the environment.

neuroscience↗

bioRxiv2020

Bidirectional synaptic plasticity rapidly modifies hippocampal representations independent of correlated activity

Learning requires neural adaptations thought to be mediated by activity-dependent synaptic plasticity. A relatively non-standard form of synaptic plasticity driven by dendritic plateau potentials has been reported to underlie place field formation in hippocampal CA1 neurons. Here we found that this behavioral timescale synaptic plasticity (BTSP) can also reshape existing place fields via bidirectional synaptic weight changes that depend on the temporal proximity of plateau potentials to pre-existing place fields. When evoked near an existing place field, plateau potentials induced less synaptic potentiation and more depression, suggesting BTSP might depend inversely on postsynaptic activation. However, manipulations of place cell membrane potential and computational modeling indicated that this anti-correlation actually results from a dependence on current synaptic weight such that weak inputs potentiate and strong inputs depress. A network model implementing this bidirectional synaptic learning rule suggested that BTSP enables population activity, rather than pairwise neuronal correlations, to drive neural adaptations to experience.

neuroscience↗

bioRxiv2019

Synaptic mechanisms of context-dependent sensory responses in the hippocampus

As animals navigate, they must identify features in context. The hippocampus-a structure critical for navigation-exhibits a different code for each environment, uniquely representing locations and objects within each environment in the firing rates of its neurons. It is unknown how or where these context-specific codes emerge. For example, it is unknown whether pyramidal neurons in the CA1 subregion produce these codes (by combining separate inputs from local sensory cues and the environmental context) or inherit conjunctive codes from upstream brain areas. We performed electrical recordings in the hippocampus as mice navigated in two distinct virtual environments. In CA1, subthreshold synaptic responses to a visual cue in one environment were absent when the same cue occurred in the second environment. In CA3, cue-driven spiking also strongly depended on environmental context. These results indicate that context-dependent sensory coding in CA1 is inherited from its CA3 input.

neuroscience↗