Biology subjects

Zhang, T. R.

Publications and source records attributed to Zhang, T. R..

4 recordsLinked to original sources

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

Chronic electroconvulsive shock disrupts hippocampal physiology and impairs associative memory in mice

Electroconvulsive therapy (ECT) is a highly effective treatment for depression but it has undesirable side effects on various aspects of cognition, including memory. Patients might display retrograde amnesia for autobiographical events and anterograde amnesia in tests of recall and recognition memory. These amnestic effects are likely to depend, at least in part, on changes in the hippocampus. ECT-induced volume increases in the hippocampus, and dentate gyrus subregion in particular, correlate with the cognitive deficits. However, the precise cellular and behavioral effects of ECT remain poorly understood. Here, we therefore subjected male and female mice to chronic electroconvulsive shock (ECS) and examined effects on hippocampal physiology and memory. Perforant path inputs onto dentate gyrus neurons were examined using whole cell patch clamp recordings in hippocampal slices. In the intact slice, perforant path stimulation did not result in any synaptic or spiking differences in mice given sham vs ECS treatments. However, GABAA blockade increased depolarization and spiking in sham, but not ECS-treated, mice. Voltage clamp recordings further revealed weaker perforant path excitation of dentate gyrus neurons in ECS-treated mice. Extrapolating these findings to the intact animal, we then used Fos expression as a proxy for neural activity, and found that ECS blunted exploration-induced hippocampal activation, which was most pronounced in the dentate gyrus. Finally, recognition memory tasks revealed that ECS impaired memory for object-context associations but not memory for objects or locations. Collectively, these experiments reveal that a clinically relevant schedule of ECS disrupts synaptic and circuit functions of the hippocampus and causes anterograde amnesia in a test of episodic-like associative memory.

neuroscience↗

bioRxiv2024

Diminished social memory and hippocampal correlates of social interactions in chronic social defeat stress susceptibility

BackgroundThe susceptibility to chronic stress has been associated with depression, a mood disorder which highly implicates the hippocampus. Hippocampal contribution to stress susceptibility has been supported by findings in mice following chronic social defeat stress (CSDS). However, little is known of the role of hippocampal activity in determining the development of stress susceptibility. MethodsWe used the UCLA miniscope to longitudinally measure the activity of dorsal CA1 hippocampal neurons across CSDS. Apart from examining the representation of social information by these neurons, we also compared social memory in mice that were susceptible or resilient to CSDS. ResultsWe observed more stable dCA1 correlates of social interaction and social memory in CSDS resilience. Such changes were absent in CSDS susceptible mice and accompanied by greater social memory impairments. ConclusionsCSDS susceptibility may be supported by hippocampal social cognitive processes, reflected in diminished hippocampal representations of social information and a greater impairment in social memory.

neuroscience↗

bioRxiv2018

Negative memory engrams in the hippocampus enhance the susceptibility to chronic social defeat stress

The hippocampus has been highly implicated in depression symptoms. Recent findings suggest that the expression and susceptibility of depression symptoms are related to the enhanced functioning of the hippocampus. We reasoned that hippocampal engrams, which represent ensembles of neurons with increased activity after memory formation, could underlie some contributions of the hippocampus to depression symptoms. Using the chronic social defeat stress (CSDS) model, we examined social defeat-related hippocampal engrams in mice that are either susceptible or resilient to the stressor. TetTag mice were used to label social defeat-related hippocampal ensembles by LacZ. Engram cells correspond to ensembles that were reactivated by the same stressor.\n\nCompared to resilient and non-stressed control mice, we found that in both the dorsal and ventral hippocampal CA1 regions, susceptible mice exhibited a higher reactivation of social defeat-related LacZ-labeled cells (i.e. engram cells). The density of CA1 engram cells correlated with the level of social avoidance. Using DREADD to reactivate social defeat-related but not neutral contextual stimuli-related CA1 engram cells decreased social interaction. Increased engram cells in susceptible mice were region specific and could not be found in the dentate gyrus. Susceptible mice exhibited more negative stimuli-, but not neutral stimuli-, related CA1 engram cells than resilient mice in the dorsal hippocampus. Finally, chronic, but not a short and subthreshold, social defeat protocol was necessary to increase CA1 engram cell density. Together, our findings reveal that the susceptibility to CSDS is regulated by hippocampal CA1 engrams for negative memory. Hippocampal engrams for negative memory may underlie the vulnerability and expression of cognitive symptoms in depression.\n\nSignificance statementWe provided evidence that negative memory hippocampal engrams contribute to the susceptibility to developing depression-related behavior after chronic social defeat stress. The activation of positive memory engrams have been shown to alleviate depression-related behaviors, while our findings reveal the pathological roles of negative memory engrams that could lead to those behaviors. Increased negative memory engrams could be a downstream effect of the reported high hippocampal activity in animal models and patients with depression. Unlike affective symptoms, we know much less about the cellular mechanisms of the cognitive symptoms of depression. Given the crucial roles of hippocampal engrams in memory formation, enhanced reactivation of negative memory engrams could be an important cellular mechanism that underlies the cognitive symptoms of depression.

animal behavior and cognition↗