Grant: Foundation Grant

Activity-Dependent; Axon; Circuit Refinement; Developmental Plasticity; Electrophysiology; In Vivo Imaging; Retinotectal; Synaptic Plasticity; Two-Photon; Visual System

<html> <body> <p>During critical periods in development, activity in the brain instructs the fine-tuning of circuits (1,2). Neurodevelopmental disorders, such as schizophrenia and autism, involve mutations that impair the brain's ability to use patterned activity to refine connections (3). The detailed mechanisms by which activity mediates circuit refinement remain elusive.<strong><em>The overarching goal of my lab is to explain how neural activity instructs the structural and functional refinement of developing neural circuits and how this may go awry in neurodevelopmental disease.</em></strong> <br> <br> <strong><em>The specific patterns and timing of neural activity instruct circuit refinement.</em></strong> This idea, proposed by Hebb in 1949, has deeply influenced neuroscience (4-6). But only in recent years with advances in <em>in vivo</em> microscopy has it become possible to directly scrutinize this hypothesis. Using translucent animal models like zebrafish and albino Xenopus tadpoles, my lab has pioneered a novel experimental approach that <em>for the first time</em> allows us to precisely manipulate the firing of different cells in the network while simultaneously observing structural remodeling and measuring synaptic strengths of these same cells <em>in the intact animal</em> (7)<em>. <strong>Objective 1 of this grant describes our plans to exploit this powerful new experimental approach to uncover the cellular and molecular mechanisms by which activity patterns encode instructions for circuit remodeling</strong> to yield proper wiring in the developing brain.</em> <br> <br> An additional advantage of working in the intact animal, is that one immediately appreciates that neurons are not the only cells participating in these processes. The significance of neuron-glia interactions in synaptic function has become increasingly appreciated in recent years. <strong><em>Objective 2 will further explore the various contributions of neuron-glia interactions to proper development</em></strong><em>, and specifically for activity-dependent processes.</em> <br> <br> Moving beyond individual cell-cell interactions, it is evident that experience-dependent plasticity can propagate throughout the entire interconnected neural network, such that the exact same sensory stimulus presented at different times may evoke distinct percepts, population neuronal responses and behaviors, depending on the past sensory experience of the animal. Recent genetic and imaging advances make it possible to monitor the evolving responses of the entire network to specific stimuli over time. <em>In</em> <em><strong>Objective 3</strong> we will <strong>extend our understanding of the rules governing activity-dependent plasticity</strong> beyond the synapse, axon and dendrite, <strong>to how entire networks evolve in response to prior experience.</strong></em> <br> <br> Over the years my team has tenaciously worked to build and assemble the tools and expertise to tackle this fundamental problem in developmental neuroscience. In addition to the decades of live imaging and neurophysiology research that have established us as leaders in the field of activity-dependent development, we have also nurtured collaborations with leading experts in areas ranging from synaptogenesis to optogenetics to image analysis, each of whom brings innovative approaches to this program.<br> <br> This international team of collaborators will interact closely with my lab, through trainee exchanges, workshops and the sharing of tools and data, to apply creative solutions to unraveling how early sensory experience guides the construction of precise neuronal networks, and how this may go wrong in certain neurodevelopmental disorders.</p> </body> </html>