Subcellular plasticity mechanisms of hippocampal-dependent memory formation and consolidation

PROJECT SUMMARY/ABSTRACT Episodic memories formed from a single experience can be used to guide behavior throughout the lifetime. Memories are thought to be encoded during ‘online’ periods of awake exploration and subsequently consolidated during sleep. In the mammalian brain, the initial formation and consolidation of episodic memories rely on the CA1 region of the hippocampus. Pyramidal neurons in CA1 (CA1PNs) form spatially selective firing fields (place fields, PFs), which serve as the cellular basis for memory encoding. Despite decades of research, subcellular mechanisms underlying memory encoding (Aim 1, F99 phase) and consolidation (Aim 2, K00 phase) remain poorly understood. CA1PNs receive excitatory synaptic inputs that interact through somatic action potentials that backpropagate into the dendrites (bAPs) and dendritic plateau potentials (PPs) that initiate in distal dendrites. Recent evidence suggests that PFs in CA1PNs are formed through behavioral timescale synaptic plasticity (BTSP) by generating conjunctive PPs and bAPs. These plateau-burst (PP-bAP) events are robust signals for synaptic plasticity (SP). While BTSP is emerging as a critical cellular mechanism driving PF formation, a significant knowledge gap exists concerning whether and how bAPs and PPs differentially contribute to BTSP. To address this major knowledge gap, in the F99 phase, I will test the hypothesis that synaptic plasticity requires the interaction of bAPs and PPs during BTSP by measuring SP at single synapses after decoupling somatic and dendritic activity using a combination of tools that allow electrophysiological manipulation of somatic membrane potential and optogenetic manipulation of afferent inputs to distal dendrites in behaving mice. For my postdoctoral work in the K00 phase, I will study the subcellular mechanisms responsible for refining and consolidating the plasticity acquired during awake conditions into long-term memory during sleep. To study this, I will build on my skills gained in the F99 phase, by combining intracellular recordings and dendritic imaging with extracellular physiology and modeling to relate single-cell activity to different sleep states. Ultimately, I aim to provide a deeper understanding of fundamental mechanisms controlling dendritic integration of synaptic activity and develop direct experimental approaches linking sleep-specific dendritic activity to memory consolidation. These goals directly align with the BRAIN Initiative objective of linking neural function and behavior by combining new electrophysiological and imaging technologies to image single cells at high resolution across time. These experiments will deepen our understanding of how physiological signals are produced and transmitted in dendrites and will also help to identify key mechanisms behind neuronal diseases such as Alzheimer's and other pathological memory-related disease states. The support of the DSPAN F99/K00 award will allow me to merge techniques spanning multiple fields in neuroscience to further our understanding of memory formation and consolidation, and ultimately provide me with the necessary training to achieve my long-term goal of becoming an independent investigator.