Compartment-Specific Synaptic Organization and Plasticity During Learning

ABSTRACT Neurons serve as foundational units underlying neural computations. The computational capacity of individual neurons arises, in part, from their extensive dendritic arbors that are capable of nonlinearly integrating and transforming synaptic inputs. However, dendrites are not uniform and can be categorized into discrete compartments that have distinct anatomical and biophysical properties that influence how synaptic inputs are integrated to regulate somatic activity. As a result, different dendritic compartments may favor distinct synaptic organization motifs that confers them with unique computational properties. Yet, our understanding of how synapses are functionally organized along different compartments of the dendritic arbor in the intact brain remains limited, presenting a gap in our comprehension of how synaptic and dendritic function contribute to neural computation. To address this gap, the research proposed here will use cutting-edge imaging approaches and causal manipulations to investigate the compartment-specific functional organization of synaptic inputs along the dendrites of layer 2/3 pyramidal neurons in behaving animals, as well as the mechanisms that shape this organization over the course of learning. Specifically, Aim 1 will characterize how synapses from different input regions are spatially and functionally organized along apical and basal dendrites in behaving animals. Next, Aim 2 will determine the activity-dependent rules shaping synaptic plasticity in apical and basal dendrites as animals undergo learning. Lastly, Aim 3 will examine how the spatiotemporal dynamics of neuromodulatory signaling conveying behaviorally relevant information interacts with ongoing synaptic and neural activity to regulate synaptic plasticity along the apical and basal dendrites during behavior. Accomplishing the proposed work will provide important insights into how different dendritic compartments integrate and transform incoming inputs to perform neural computations and how these processes adapt through learning. In addition, the applicant will receive extensive technical training in state-of-the-art in vivo two-photon, confocal, and electron microscopy methods, as well as genetic and optogenetic manipulations, under the guidance of his primary mentor Dr. Takaki Komiyama and his external advisory committee consisting of Drs. Mark Ellisman, Byungkook Lim, Mikio Aoi, and Thomas Hnasko. This strong mentorship in combination with the numerous professional development resources and rich research environment at the University of California, San Diego will benefit the applicant’s research and transition to an independent research program focused on the dendritic and synaptic mechanisms underlying neural computation in health and disease.