Activity Dependent Changes in the Contextual Memory Engram

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Project Summary The goal of this project is to determine the activity-dependent mechanisms involved in contextual memory formation in the hippocampal circuit of the CA3. Encoding memory requires activity-dependent changes to neuronal properties and circuits, and improper function of these processes is thought to contribute to many cognitive disorders. Contextual memory, in particular, requires the storage of environmental information accompanying a salient stimulus to encode the context in which an experience occurred. The CA3 region of the hippocampus is known to play a critical role in contextual memory due to extensive connections between its pyramidal neurons, the principal excitatory neurons of the circuit. Changes in the CA3 circuit during learning and memory, however, remain poorly understood. An emerging strategy in identifying active neuronal ensembles during learning and memory is through detecting expression of immediate early genes. Known to rapidly turn on upon the detection of cellular activity, immediate early gene expression is heterogenous across neuronal populations. The transcription factor Npas4, an IEG expressed upon neuronal depolarization, has recently been shown to activate during contextual memory tasks. Moreover, conditional knockout of Npas4 in the CA3 region impairs contextual memory recall, suggesting that activity in the Npas4+ neuronal ensemble in this circuit is required for proper contextual memory function. Recent evidence strongly suggest that contextual fear conditioning induces changes at dentate granule cell to Npas4+ CA3 pyramidal neuron synapses. The full extent to how CA3 pyramidal neurons in the Npas4+ ensemble changes through activity, however, remains unknown. Previous evidence in areas such as CA1 and sensory cortices suggest that Npas4+ neurons exhibit changes in both excitatory and inhibitory drive through synapse formation and elimination. To study the changes in neuronal function and circuit activity in the CA3 in the Npas4+ ensemble, an Npas4-specific Robust Activity Marking system (NRAM) will be employed to identify neurons active during a contextual memory task. Neurons recruited to the Npas4 ensemble will be assessed through electrophysiology and structural studies to determine changes in synaptic transmission, morphology, and intrinsic properties that contribute to memory formation. Changes in connectivity and circuit function will also be surveyed to determine larger scale changes to the CA3 network in the encoding of contextual memory. Finally, the necessity and sufficiency of the Npas4 neuronal ensemble, as well as its relevance in other cognitive functions will be determined. The work proposed will elucidate mechanisms of learning in the CA3 circuit, and provide a foundation in uncovering the molecular basis of memory.