The Effects of Stimulation and Sleep on Neural Circuit Connections

Project Summary/Abstract Defects in neural circuit plasticity and its modulation by sleep are thought to underlie devastating neurological disorders, including schizophrenia and dementia. Here we propose to uncover molecular pathways and circuit responses that allow sensory activity and sleep to sculpt the juvenile and adult nervous systems. Sensory signaling can affect functional plasticity via regulation of neurotransmitter release and receptor levels, however the molecular mechanisms by which sensory activity affects structural plasticity is poorly understood. We discovered that C. elegans have a burst of chemosensory activity-dependent sensory synapse formation immediately before their first bout of developmentally timed sleep. We also discovered that adult animals sleep after olfactory training and this sleep is required for long-term memory and structural synaptic modulation. Here, we will investigate how sensory activity and sleep affect neuronal circuits and behavioral plasticity. The neuroanatomical simplicity and optical transparency of C. elegans enable a multidisciplinary approach, combining tools to visualize structural and functional plasticity, with environmental modulation, genetic mutations, and optogenetic techniques in live, behaving organisms. In Aim 1, we will elucidate the mechanisms by which sensory activity and sleep affect structural plasticity during development. Aim 1A: We will test the prediction that chemosensory activity instructs the level of sensory synaptogenesis by assessing whether synapses, visualized with the split GFP-based marker NLG-1 GFP Across Synaptic Partners (GRASP), are increased. Aim 1B: To discover molecules that act downstream to instruct the burst, we will use genetic techniques to test molecules with previously described roles in developmental synaptogenesis. Aim 1C: To determine how chemosensory activity drives synapse assembly, we will visualize pre- and postsynaptic molecules to determine the timeline of assembly. Aim 1D: We will determine whether sleep at the end of the first larval stage slows the burst of sensory synapse formation using time course and sleep-manipulation experiments. In Aim 2, we will reveal mechanisms by which olfactory training and post-training sleep sculpt the adult nervous system. Aim 2A: To identify cells that carry out phagocytosis required for long-term memory, we will conduct cell-specific rescue experiments. Aim 2B: To determine if phagocytosis is required during sleep for long-term memory, we will inactivate the phagocytosis machinery during the sleep period. Aim 2C: To test if glial cells are required for long-term memory and synapse reduction during consolidation, we will inactivate glia during training and consolidation. Here, we seek to identify the cellular and molecular mechanisms by which neural circuits are modified by sensory activity and sleep. Such plasticity is required for perception, learning and memory, and its dysregulation underlies neurological disorders, such as schizophrenia and dementia. These studies will provide insights that will inform the development of future therapeutic strategies.