Investigating the role of early postnatal neuromodulation in cerebellar development

About This Grant

Abstract This study seeks to elucidate the impact of early postnatal oxytocin signaling on cerebellar development and function. The cerebellum shapes motor behavior, cognition, and emotion and, in consequence, its functional disruption during early development is one of the highest risk factors for neurodevelopmental disorders. Due to its protracted development, anatomical location, and dense vascularization, the cerebellum is highly susceptible to perinatal insults. The process of parturition for instance exposes the infant cerebellum to high levels neurohormones like oxytocin. Previous studies suggest that neonatal oxytocin exposure contributes to functional maturation of cortical and hippocampal circuits, but the impact of those hormone surges on cerebellar development remain unknown. Recent transcriptomic profiling of the developing mouse cerebellar cortex revealed that GABAergic progenitors transiently express oxytocin receptor mRNA, peaking around postnatal day 4, and then steeply declining. My goal is to determine the role of oxytocin signaling in the development of GABAergic neurons and cerebellar circuit formation. I will use a combination of molecular, functional, and genetic approaches in mice. In aim 1, I will use gene expression analysis and receptor labeling to determine the timing of Oxtr and OTR expression in molecularly identified cell types. In aim 2, I will use in vitro electrophysiology to identify the impact of oxytocin on the activity of immature GABAergic neurons and the GABA functional switch from excitatory to inhibitory. In aim 3, I will probe how oxytocin regulates emerging excitatory and inhibitory connectivity across development and probe the long-term impact of oxytocin on synaptic plasticity. Completion of this study will provide mechanistic insight into how transient oxytocin receptor signaling shapes circuit development.