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.