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.
