Thursday, June 5, 2025
6/5/2025
Maturation of frontal cortico-thalamic circuitry in control of social behavior - Impaired social processing is one of key hallmarks of many neurodevelopmental and psychiatric disorders including autism spectrum disorders (ASDs). As the social deficits tend to emerge during early childhood and adolescence, characterization of developmental trajectories is vastly important for understanding and treating underlying disruptions. The objective of our study is to identify the developmental mechanisms and windows when circuits responsible for social processing are sensitive to modulation by aberrant social experience or genetic risk of disorders. Such information will point toward therapeutic targets that allow amelioration of social deficits. During the prior funding period, we demonstrated that corticothalamic projections from medial prefrontal cortex (mPFC) to paraventricular nucleus of thalamus (PVT) (mPFC->PVT), which relays signals to various components of the classical reward circuitry, is causally necessary for proper sociability, but is dysregulated by juvenile social isolation in adult mice. Our preliminary study further revealed that mPFC->PVT neurons are also dysregulated by the deletion of several ASD related genes including Fmr1. These findings prompt new pressing questions: When and how the circuit and behavior deficits emerge across development? Can these vulnerability windows serve as windows for preventing sociability deficits? Even if these windows are missed, to what extent adult amelioration is possible later in life? In this competitive renewal, we propose to address these questions by testing a hypothesis that juvenile social isolation or genetic risk of ASD (Fmr1 deletion) convergingly dysregulates the maturation of mPFC->PVT projection neurons and sociability yet differentially impact the circuit at different developmental windows. We will also test that these developmental windows of vulnerability also serve as windows for interventions to prevent sociability deficits, while adult reversal is also possible by circuit- based interventions. We will test this hypothesis by integrating techniques to measure (fiber photometry imaging, patch-clamp/ in vivo electrophysiology) and manipulate (optogenetics/chemogenetics) the activities of selective circuits during social behavior in male/female mice.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).