Activity-dependent neuronal transcription and its importance in brain development and function

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Neuronal activity stimulates activity-dependent signaling networks and gene expression to modify synapse development and plasticity. My research program asks two fundamental questions: How is activity-dependent neuronal transcription regulated? How does this process contribute to neuronal development and function? Our long-term objective is to understand the regulation of activity-dependent transcription in different neurons and its effects on the physiology of these neurons. This includes the identification of activity-dependent genes, cellular signaling networks and transcriptional regulators, and neuronal subtype-specific outcomes. Currently, my research is centered on the role of a transcriptional regulator, named capicua, in activity-dependent neuronal transcription. Capicua acts downstream of the RAS-mitogen-activated protein kinase (MAPK) pathway to regulate gene expression. The RAS-MAPK signaling is important for neuronal activity-dependent transcription, but whether capicua plays a role in this process is unknown. In this proposal, we focus on a cluster of neurons in the hypothalamus, the paraventricular nucleus (PVN), because these neurons can be reliably and selectively stimulated by multiple approaches, providing an accessible way to study activity-dependent transcription. Our short-term objective is to investigate the role of capicua in the regulation of activity-dependent transcription of PVN neurons. PVN neurons produce oxytocin (Oxt) and arginine vasopressin (Avp), two crucial neuropeptide regulators of physiology and behavior. We can monitor the effects of activity-dependent transcription in PVN and understand the significance of this process in modulating adaptive behavior. Based on our exciting preliminary data, we hypothesize that capicua regulates activity-dependent neuronal transcription in the PVN. In the proposed studies, we will define the role of capicua in RAS-MAPK signaling in the PVN (Aim 1). We will identify genome-wide capicua-regulated activity-dependent transcription in the PVN (Aim 2). Lastly, to assess the importance of this process on the physiology and function of PVN neurons, we will investigate the impact of activity-dependent transcription on the physiology of PVN neurons. (Aim 3). Our studies will shed light on the role of capicua in regulation of activity-dependent transcription. Importantly, we will begin to understand the complexity of this process in neurons-how the cellular signaling pathways are kept in check by feedback regulation. The list of capicua-regulated activity-dependent genes will broaden our understanding of the networks of genes and proteins important for normal function of the PVN neurons. Our work will shed light on the regulation of the synthesis of Oxt and Avp, two physiologically important hormones, and provide insight into normal neuronal development and the regulation of adaptive neurobehaviour.