Perhaps the fundamental property of a neuron is its ability to integrate and transform diverse inputs into a singular train of action potential output. This capacity is what enables circuits of neurons to combine environmental features and internal states to drive an organism?s behavior. Dendrites, the primary sites of synaptic input integration, are capable of generating local regenerative events known as dendritic spikes. Recent in vivo work points to the importance of dendritic spiking to behavior and has demonstrated a role for these events in synaptic plasticity, feature selectivity, and learning in cortical and non-cortical areas. In particular, there has been significant recent progress connecting the dynamics of dendritic spiking in CA1 pyramidal cells (CA1 PCs) during active exploration to the formation and maintenance of CA1 PC spatial tuning. It has therefore become clear that an understanding of in vivo dendritic dynamics in CA1 PCs is critical for elucidating the computational roles of CA1 PCs in hippocampal spatial memory function. In parallel, the role of CA1 network activity in spatial memory function during immobility is also recently being actively explored. Sharp-wave ripples (SWRs), the predominant network event during awake immobility, are thought to enable synaptic potentiation in CA1 PCs previously co-active during exploration. Through this mechanism, SWRs have been implicated in memory consolidation and spatial learning. A major knowledge gap remains concerning how these population-level network states alter dendritic dynamics in CA1 PCs. The goal of the proposed research is to connect CA1 network dynamics to the dendritic dynamics determining cellular participation in spatial navigation and memory tasks. This proposal implements several recent advances in optical imaging and extracellular electrophysiology methods in the mouse, allowing us to longitudinally monitor the activity of the dendrites and cell bodies of hippocampal neurons with submicron resolution while simultaneously recording network oscillations over many days as the animal engages in various navigation and learning behaviors. Using these methods, I will address the central hypothesis of this application, that SWRs persistently alter the mode of dendritic integration of recruited CA1 PCs and that these mode changes will in turn determine the cell?s spatial memory function.
Aim 1 will test whether the activity of dendrites active during SWRs are stabilized, and if this has an impact on the day to day stability of CA1 PC spatial tuning.
Aim 2 will examine how dendritic activity during SWRs shapes the way CA1 PC spatial tuning is altered by rewards in a spatial learning task. In summary, this work will use chronic extracellular electrophysiology and simultaneous multiplane two-photon imaging of CA1 PC dendritic and somatic activity during learning in the awake rodent to further our understanding of the interplay of network and dendritic dynamics on hippocampal spatial memory function.
Normal network and subcellular function within the hippocampal formation are critical for the processes of learning and memory. Although these functions are impaired in a variety of neurological disorders, such as epilepsy and Alzheimer?s disease, we know little about their precise relationship to the cellular basis of learning and memory. By working to better understand the impact of network activity on dendritic computation in hippocampal neurons during learning and memory, this proposal will elucidate the means by which aberrant network and subcellular processes contribute to pathology.
