Thyroid hormone mediated reprogramming of the basolateral amygdala by adolescent social deprivation

PROJECT SUMMARY Social disconnection in humans, particularly during adolescence, is associated with substance use disorder vulnerability. In mice, adolescent social isolation profoundly alters reward processing in adulthood; increasing the preference for drugs of abuse, enhancing associative learning, altering dopaminergic signaling and transcription within the BLA and extended reward circuitry. Intriguingly, these phenomena are all also associated with thyroid hormone signaling. Further, dysregulation of thyroid hormone in early life is associated lifetime risk for reward-related mood disorders and altered development of monoaminergic systems. In adults, thyroid hormone dysregulation is associated with substance- and alcohol use disorders. Therefore, we propose that the persistent impacts of adolescent social isolation result from transient dysregulation of thyroid hormone signaling during the sensitive period of adolescence. Thyroid hormones, when bound to their receptors, are transcription factors that mediate various epigenetic processes and regulate gene expression. Aberrant thyroid hormone signaling at critical developmental periods persistently alters transcription in other tissues through epigenetic reprogramming of thyroid hormone sensitive genes. Despite its critical role in neurodevelopment and its link to substance use disorder, the consequences of thyroid hormone dysregulation in adolescence, a key period for reward circuitry development and substance use disorder vulnerability, is virtually unknown. Our preliminary data suggest that circulating thyroid hormones and expression of its receptors are transiently disrupted in adolescence by social isolation and this is associated with enhanced expression of GABAergic neuronal markers in the adult basolateral amygdala (BLA), a key reward-related brain region Here, we will test the hypothesis that thyroid hormone is critical for development of the basolateral amygdala (BLA) during adolescence and that isolation-induced disruptions to the thyroid hormone system result in lasting epigenetic reprogramming of the reward circuitry to increase cocaine sensitivity. First, we will determine how adolescent social isolation impacts thyroid hormone-mediated transcription in the BLA (Aim 1). Then we will determine if thyroid hormone dysregulation induced by adolescent isolation disrupts cell-type specific transcriptional profiles within the BLA (Aim 2). Finally, we will disrupt thyroid hormone receptor beta levels specifically during adolescence to determine its role in reward-related behavior in (Aim 3). Together, these foundational studies will establish a role for thyroid hormone-mediated programming of the BLA and uncover novel mechanisms of isolation-induced reprogramming of SUD vulnerability during adolescence - an endpoint that has become even more urgent given the known reductions in social interactions due to the mitigation of Covid-19 for the current generation of adolescents.