Jason J. Radley, Kristin L. Gosselink, Paul E. Sawchenko

Complementing its roles in cognitive and affective information processing, the medial prefrontal cortex (mPFC) is a nodal point of a limbic forebrain circuit that modulates stress-related homeostatic mechanisms, including the hypothalamic-pituitary-adrenal (HPA) axis. mPFC influences on HPA output are predominantly inhibitory and emanate from the prelimbic and/or dorsal anterior cingulate cortical fields (PL and ACd, respectively). mPFC projections do not target HPA effector neurons in the paraventricular hypothalamic nucleus (PVH) directly, distributing instead to nearby forebrain regions, including some that house GABAergic neurons implicated in inhibitory PVH control. To identify pathway(s) subserving HPA-inhibitory mPFC influences, an initial screen for sources of GABAergic input to PVH whose sensitivity to an acute emotional (restraint) stress was diminished by PL/ACd lesions identified a discrete region of the anterior bed nucleus of the stria terminalis (aBST) as a candidate for fulfilling this role. Anatomical tracing experiments confirmed projections from PL (but not ACd) to implicated aBST cell groups, and from these to PVH. Finally, selective immunotoxin-mediated ablation of GABAergic aBST neurons recapitulated the effects of PL/ACd lesions on acute stress-induced activation of HPA output. The identification of a proximate mediator of HPA-inhibitory limbic influences provides a framework for clarifying how inhibitory neural and hormonal controls of HPA output are integrated, adaptations of the axis to chronic stress are effected, and how endocrine abnormalities may contribute to stress-related psychiatric illnesses in which mPFC dysfunction is implicated.