The orexin system as a novel mediator of depression-like outcomes in female rats exposed to an endocrine disrupting compound during the peripubertal period

Project Summary Age of puberty is one the most reliable predictors of later mental health outcomes in girls, with early menarche greatly increasing the risk of depression in early adulthood. Environmental exposure to endocrine disrupting compounds (EDCs) has been linked with early puberty onset in girls. Despite this, the neurobiological consequences of EDC exposure, and how they might predispose to depression, remain poorly understood. In a series of preliminary studies, we showed that peripubertal exposure to a model EDC, bisphenol-A (BPA), accelerates puberty onset in female rats, and predisposes to behaviors in early adulthood that are reminiscent of anhedonia, a core symptom of clinical depression. These changes were associated with a persistent impairment in the functioning of the orexin neuropeptide system, the activity of which is normally important for translating motivational states into reward behaviors. Specifically, BPA was associated with reduced reactivity of orexin neurons to reward-predictive stimuli, as well as reduced orexin terminals in ventral tegmental area (VTA), a key region through which orexins initiate reward-directed actions. Based on these data, we hypothesize that: at doses that promote early puberty onset, BPA produces a persistent impairment in the functioning of the orexin-VTA circuit. We predict that these changes are causally linked to the anhedonia-like phenotype observed in early adulthood in BPA-exposed rats. Here, we propose three distinct, yet interrelated aims to begin testing our hypothesis. In Aim 1, we will characterize the baseline activity (using electrophysiology) of VTA-projecting orexin neurons in BPA-exposed rats and determine how this is related to the expression of anhedonia-like behavior in early adulthood. In Aim 2, we will use fiber photometry recordings of a novel orexin sensor to measure orexin signaling in VTA in response to reward-predictive stimuli. Finally, in Aim 3, we will use chemogenetics to stimulate the orexin-VTA circuit to test its causal role in the expression of anhedonia-like behavior following BPA. These studies will be the first to determine the effect of EDC exposure on orexin neurons and their circuits, and will determine their mechanistic involvement in depression outcomes in a model of early puberty onset. The proposed project is thus highly relevant to the goal of NIEHS to understand the impact of environmental chemical exposures on psychiatric illness. Moreover, these studies are a critical first step for developing novel strategies to improve mental health outcomes in young women.