The role of development of glutamatergic inputs to the nucleus accumbens in adolescent behavior

About This Grant

PROJECT SUMMARY/ABSTRACT Adolescence is a postnatal developmental period observed across many species, marked by large changes in behavior driven by extensive remodeling of neural circuitry. It is critical to elucidate how the brain changes in this transient period between childhood and adulthood: the adolescent brain is powerfully dynamic, but this plasticity induces high sensitivity to both beneficial and adverse alterations, including onset of neuropsychiatric disorder. Despite this necessity for scientific understanding to improve neuropsychiatric health outcomes, the biological drivers of adolescent behavior are only partially understood, in part due to limits of human neuroimaging studies and the short duration of adolescence in model species. A plethora of behavioral work emphasizes adolescent hypersensitivity to rewards, resulting in heightened risk-taking and novelty-seeking; a smaller body of evidence suggests adolescents also show altered sensitivity to aversive outcomes. These studies are often limited in interpretation due to risk/reward tradeoff task designs, from which it is difficult to parse out pure reward versus aversion signals. The neural circuitry that underlies sensitivity to both reward and aversion outcomes critically includes the nucleus accumbens (NAc), a region necessary for motivation and decision-making. Two vital regions sending glutamatergic projections to the NAc are the amygdala, known to receive and send signals for affective processing and fear encoding, and the prefrontal cortex (PFC), which is critically involved in executive function and decision-making. High level changes to these systems are well-characterized in the context of adolescent development; however, these changes are most certainly driven mechanistically by alterations at the level of individual synapses. Mechanistic studies at high resolution are necessary to build an accurate model of adolescent behavior and understand how synaptic development drives the transition from childhood to adulthood in both typical and atypical states. With the goal of uncovering the synaptic developmental mechanisms that define adolescent sensitivity to aversive behavioral outcomes, this proposal will use a combination of superresolution histology, ex vivo electrophysiology, behavior, fiber photometry, and optogenetic approaches. The proposed study will test the central hypothesis that different developmental timeframes of synaptic connectivity from two glutamatergic inputs to NAc neurons, the amygdala and the PFC, underlie age-specific sensitivities to aversive outcomes. In addition to providing description of the exceptional training environment and resources available to complete this work, the fellowship training plan in this proposal details specific scientific training goals in histological interrogation of synaptic biology, ex vivo whole-cell patch clamp electrophysiology to quantify functional connectivity, and in vivo studies of synaptic function using fiber photometry. Additionally, the training goals include development of mentorship and pedagogical skills in the laboratory.