Experience-dependent regulation of dendrite morphogenesis and plasticity

National Institute Of Neurological Disorders And Stroke

Investigators

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Abstract

Over the past few years, our research has uncovered critical roles for cholinergic receptor signaling and neuron-glia lipid trafficking in synapse maturation, dendrite development, and adaptive responses to changes in neuronal activity. Building on these findings, we are now integrating multi-omics analyses with genetic and imaging approaches to systematically understand how the nervous system adapts to dynamic internal and external environments. Our current investigations focus on three main areas. First, we study the organization, development, and plasticity of central cholinergic synapses. Using a chemical-genetics proximity labeling approach, we have identified proteins near two nAchR subunits, enabling us to map the molecular composition of postsynaptic compartments in central cholinergic synapses with high spatial resolution. A subset of newly identified synaptic proteins is being characterized in cellular and functional assays to evaluate their roles in activity-dependent structural and functional plasticity. Second, our genetic studies have uncovered novel lipid-binding proteins highly expressed in Drosophila CNS glia. These discoveries provide unique opportunities to monitor and manipulate lipid trafficking in both developing and aging brains. By characterizing these proteins in vivo, we aim to elucidate the structural mechanisms underlying ligand binding and release, investigate the cellular processes governing intra- and intercellular lipid trafficking, and explore their contributions to brain lipid and redox homeostasis under physiological and pathological conditions. Third, we are investigating the molecular machinery controlling neuropeptide trafficking and release, and how neuromodulation shapes behavioral plasticity. Our larval LNv neurons, which produce and release the wake-promoting neuropeptide PDF, provide a tractable model for these studies. By combining genetics, imaging, and behavioral analyses, we are elucidating the molecular machinery underlying the circuit-specific and state-dependent control of neuropeptide release. In summary, our overarching goal is to uncover the cellular and molecular mechanisms that allow the brain to adjust its structure and function while maintaining stable output. Beyond identifying shared organizational principles of synapse and circuit development across species, we have also revealed unique molecular adaptations in the Drosophila genome, giving rise to proteins with distinctive functions that hold promise for both basic research and therapeutic applications.