Tuesday, April 30, 2024
4/30/2024
7. Project Summary/Abstract Adverse experiences during childhood and adolescence, especially social isolation and/or disrupted peer interactions, are major risk factors for the emergence of anxiety and depressive disorders in adulthood. However, the neural mechanisms through which adolescent social isolation increases the risk for developing mental illnesses remain poorly understood. The NIMH has established a Research Domain Criteria matrix to identify molecular and neural mechanisms of various domains of mental function. In this proposal, we utilize the domain of negative valence systems (NVS; specifically, the constructs of potential/acute threat and loss) to investigate mechanisms of stress-related problems that are seeded during adolescence. The prefrontal cortex (PFC), nucleus accumbens (NAc), and basolateral amygdala (BLA), and especially serotonergic innervation of these regions from the dorsal raphe nucleus (DR), are all strongly implicated in the dysregulation of NVS. The DR itself is modulated by corticotropin-releasing factor (CRF) projections, including from the bed nucleus of the stria terminalis (BNST), which regulates stress responses. Our previous studies demonstrate that socially isolating animals during a critical juncture in development, from early to mid- adolescence (postnatal day (P) 21 to P42) followed by re-socialization, significantly increases hyper-reactivity to aversive stimuli in adulthood. We also find that the deleterious effects of adolescent social isolation (ASIR) are attenuated by CRF receptor antagonism within DR, and that ASIR up-regulates CRF2 receptor expression in the DR, resulting in prolonged serotonin (5-HT) release in the NAc. ASIR also enhances stress-related activity in NVS-related subregions of the DR which project to PFC, NAc and BLA. Together, these findings support the proposal that isolation- induced dysregulation of NVS could result from CRF mechanisms in the DR and activation of specific DR serotonergic outputs. In Aim 1, we will investigate the role of CRF input to the DR on ASIR. We hypothesize that optogenetic inhibition of CRF outputs within the BNST-DR circuit of isolation-reared Crh-Cre rats will decrease reactivity to aversive stimuli. In Aim 2, we will determine how ASIR alters neuronal properties and CRF receptors in key DR output circuits (DR-PFC, DR-NAc, DR-BLA) associated with NVS. We predict that isolation-reared rats will exhibit altered intrinsic and synaptic excitability, and greater CRF enhancement of firing (measured with ex vivo brain slice electrophysiology) along with alterations in CRF receptor mRNA expression in DR-PFC, DR-NAc, and DR-BLA neural circuits. Overall, the studies proposed here will identify critical neuronal circuit(s) and signaling mechanisms that mediate expression of dysregulated NVS after ASIR.
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