A Common Substrate for Prefrontal and Hippocampal Inhibition of the Neuroendocrine Stress Response

Abstract

A network of interconnected limbic forebrain cell groups, including the medial prefrontal cortex (mPFC) and hippocampal formation (HF), is known to shape adaptive responses to emotionally stressful experiences, including output of the hypothalamo-pituitary-adrenal (HPA) axis. While disruption of limbic HPA-inhibitory systems is implicated in stress-related psychiatric and systemic illnesses, progress in the field has been hampered by a lack of a systems-level understanding of the organization that provides for this regulation. Using rats, we first localized cell groups afferent to the paraventricular hypothalamic nucleus (PVH) (the initiator of HPA responses to stress) whose engagement following acute (30 min) restraint was diminished by excitotoxin lesions of the ventral subiculum, a component of the HF. This identified a candidate relay for imparting HF influences in a circumscribed portion of the anterior bed nucleus of the stria terminalis (aBST), which we previously identified as a GABAergic relay subserving mPFC inhibition of the stress axis. Anatomical tracing experiments then indicated that extrinsic projections from HF and mPFC converge onto regions of aBST that contain neurons that are both stress sensitive and PVH projecting. Two final experiments provided evidence that (1) HPA-inhibitory influences of mPFC and HF are additive and (2) aBST plays a more prominent inhibitory role than ventral subiculum over stress-induced HPA endpoints. These findings support the view that stress-inhibitory influences of mPFC and HF are exerted principally via convergence onto a common relay, as opposed to a serial, parallel, or more complex multisynaptic network.