Glucocorticoid regulation of dopamine circuit function

Project Summary Stress during adolescence is a significant risk factor for the development of numerous psychiatric disorders, including major depressive disorder (MDD), in adulthood. Adolescence is a critical period of development for multiple neural systems in the brain, including the dopaminergic system. The dopaminergic system is crucial for reward-guided motivation, a process which is impaired in individuals with MDD. Clarifying how adolescent stress alters the dopaminergic system to impair reward-guided motivation in adulthood may lead to the discovery of novel therapeutic targets for MDD. Recent studies have shown that adolescent stress can alter population activity and synaptic plasticity of dopamine neurons in adulthood. Importantly, astrocytes regulate neuronal population activity throughout the brain and have recently been shown to modulate VTA dopamine neuron activity. Therefore, adolescent stress may impair reward-guided behaviors in adulthood by altering the activity dynamics of VTA astrocytes and dopamine neurons. The long-term goal of this proposal is to elucidate how adolescent stress alters the endogenous activity dynamics of VTA astrocytes and dopamine neurons to drive reward-related behavioral deficits in adulthood. In Aim 1, we will use cellular resolution microendoscopic calcium imaging to determine how adolescent stress alters the endogenous activity dynamics of VTA astrocytes and dopamine neurons during reward-guided operant conditioning in adulthood. In Aim 2, we will assess how chemogenetic modulation of VTA astrocytes alters the endogenous activity dynamics of VTA astrocytes and dopamine neurons to change reward-guided operant conditioning in mice exposed to adolescent stress. The results of these studies will provide the first characterization of the endogenous activity dynamics of VTA astrocytes and dopamine neurons during reward-guided behaviors and will provide a framework for understanding how adolescent stress influences astrocyte-dopamine neuron interactions to impair reward-related behaviors in adulthood. Under this award, the applicant will work with her mentorship team to develop technical skills in cellular resolution calcium imaging and chemogenetics. Moreover, the applicant will engage in professional development to hone her skills in leadership, mentorship, and teaching. Collectively, the training under this award will prepare the applicant to pursue an independent investigator position at a research-intensive institution.