Toward a limbic cortical inhibitory network: implications for hypothalamic-pituitary-adrenal responses following chronic stress

A network of interconnected cell groups in the limbic forebrain regulates hypothalamic-pituitary-adrenal (HPA) axis activation during emotionally stressful experiences, and disruption of these systems is broadly implicated in the onset of psychiatric illnesses. A significant challenge has been to unravel the circuitry and mechanisms providing for regulation of HPA output, as these limbic forebrain regions do not provide any direct innervation of HPA effector cell groups in the paraventricular hypothalamus (PVH). Recent evidence will be highlighted that endorses a discrete region within the bed nuclei of the stria terminalis serving as a neural hub for integrating and relaying HPA-inhibitory influences to the PVH during emotional stress, whereas the prevailing view has involved a more complex organization of mulitple cell groups arranged in parallel between the forebrain and PVH. A hypothesis will be advanced that accounts for the capacity of this network to constrain the magnitude and/or duration of HPA axis output in response to emotionally stressful experiences, and for how chronic stress-induced synaptic reorganization in key cell groups may lead to an attrition of these influences, resulting in HPA axis hyperactivity.