Cell-type and projection-specific dissection of the bed nucleus of the stria terminalis in the mediation of social behavioral deficits induced by early life adversity

项目总结

PROJECT SUMMARY Nearly one percent of children in the US experience childhood abuse or neglect, which can induce life-long behavioral deficits including social behavior disorders like social anxiety, attachment disorders, difficult peer relations, and externalizing behaviors. Investigations into the neural mechanisms mediating early life adversity- induced behavioral impairments have largely focused on dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and its release of the stress hormone corticotropin-releasing factor (CRF), which account for aspects of altered anxiety and responsiveness to stress induced by early life adversity. However, social interaction involves coordination between neural circuits promoting reward and circuits inhibiting anxiety, and thus neural substrates mediating early life adversity-induced social deficits likely extend beyond HPA axis dysfunction, but this has not been systematically investigated. Our proposed studies will address the extent to which early adversity-induced social deficits are driven by dysfunction in anxiety versus reward circuits, critical for effectively treating disorders spurred by childhood abuse and neglect. Our lab uses mouse maternal separation with early weaning (MSEW) to model early life adversity, which robustly reduces social interaction and increases anxiety- like behavior, recapitulating effects of childhood abuse and neglect. Our preliminary studies evidenced a central regulatory role for the anterior bed nucleus of the stria terminalis (aBNST) in MSEW-induced social deficits, so the critical next step is to explicate cell-type and projection-specific aBNST mechanisms governing MSEW- induced social deficits. First we will investigate the relationship between MSEW-induced social deficits and anxiety and reward mechanisms using a small battery of robust behavioral assays to determine whether social motivation and vigilance correlate with measures of social reward or anxiety-like behavior in MSEW and control mice. Next we will determine how CRF-expressing neurons in the aBNST, as well as aBNST projections to the paraventricular nucleus of the hypothalamus (PVN) or ventral tegmental area (VTA) contribute to anxiety- and reward-related mechanisms underlying MSEW-induced social deficits using a multiplexed approach that includes in vivo electrophysiology, combined retrograde labeling and immunofluorescence imaging, and projection-specific chemogenetic manipulation experiments. Notably, prior work in this field has mostly neglected female subjects, so we will include sex as a biological variable to enhance the rigor and translatability of our findings. Proposed studies will be conducted exclusively by undergraduate students in the PI's lab who are regularly trained on each method proposed here. Studies here are in line with the NIMH's mission to understand mental illness through basic research, will expose undergraduates to primary biomedical research, and will enhance the research environment at Santa Clara University.