Neuronal Activity-Induced IEG Transcription Factors in Neurodevelopment and Plasticity - Project Summary: Neural circuits are continually shaped and reshaped during development and throughout life in response to ongoing experience. In addition to short-term changes in synaptic strength, sensory-driven neuronal activity drives long-lasting circuit adaptations that are critical for learning, memory, and behavior, but the mechanisms that underlie these long-lasting changes in neural circuitry have been challenging to discern. We discovered that neuronal activity induces gene programs that mediate various aspects of synaptic development, including dendritic outgrowth, spine and synapse maturation, synaptic pruning, myelination, and excitatory/inhibitory balance. And we demonstrated that these gene networks are required for learning, memory, and behavior in mice, and have linked these gene programs to multiple neurodevelopmental disorders in humans. These findings underscore the critical role these gene networks play in human cognitive development and function. While highly context- and cell-type-specific, neuronal activity-dependent gene responses exhibit a standard architecture in which neurotransmitter release at synapses drives the transcription of a largely common set of immediate-early genes (IEGs) that encode sequence-specific transcription factors (TFs), including FOS and the neuronal-specific TF NPAS4. These IEG-encoded TFs (IEG TFs), in turn, induce the expression of diverse cell-type-specific lateresponse gene programs that encode neuropeptides and other secreted factors that regulate circuit plasticity, and are tailored to the functions of each neuronal subtype. While the induction of FOS has been routinely employed as a proxy marker of activated neurons, whether FOS is a marker or a mediator of synaptic plasticity has only recently been addressed, and many questions regarding IEG TF regulation and function in the brain remain unanswered. In this application we propose to use advanced genetic, biochemical, transcriptomic and epigenomic, electrophysiological, and behavioral approaches to further probe the regulation and function of activity-induced TFs and their downstream genomic targets during neuronal maturation and plasticity. Building upon our prior advances, our goals under the auspices of this R35 proposal are: 1) to determine how distinct IEG TFs contribute mechanistically to different aspects of activity-induced gene regulation; 2) to elucidate the roles of IEG TFs in sensory-mediated circuit reorganization; 3) to determine how a common set of IEG TFs regulate context-specific late-response gene programs; 4) to determine how specific IEG TF target genes contribute to activity-dependent circuit plasticity; 5) to test the role of IEG TFs in stable neuronal ensemble formation that underlies learning, memory, and behavior; and 6) to train and mentor the next generation of neuroscientists, with an emphasis on rigor, creativity, collaboration, diversity, and inclusion. These advances will reveal mechanisms underlying key aspects of sensory experience-dependent circuit maturation and refinement, provide insight into how dysregulation of these mechanisms contributes to human neurodevelopmental and neuropsychiatric disorders, and help to train and prepare the neuroscientists of the future.
