Role of Paraventricular Nucleus Glutamate Signaling in Regulation of HPA Axis Stress Responses

The hypothalamus-pituitary-adrenal (HPA) axis is the main neuroendocrine arm of the stress response, activation of which leads to the production of glucocorticoid hormones. Glucocorticoids are steroid hormones that are secreted from the adrenal cortex, and have a variety of effects on the body, including modulation of the immune system, suppression of reproductive hormones maintenance of blood glucose levels, and maintenance of blood pressure. Glutamate plays an important role in coordination of HPA axis output. There is strong evidence that glutamate drives HPA axis stress responses through excitatory signaling via ionotropic glutamate receptor signaling. However, glutamate signaling via kainate receptors and group I metabotropic receptors inhibit HPA drive, probably via presynaptic inhibitory mechanisms. Notably, kainate receptors are also localized in the median eminence, and appear to play an excitatory role in control of CRH release at the nerve terminals. Finally, glutamate innervation of the PVN undergoes neuroplastic changes under conditions of chronic stress, and may be involved in sensitization of HPA axis responses. Altogether, the data suggest that glutamate plays a complex role in excitation of CRH neurons, acting at multiple levels to both drive HPA axis responses and limit over-activation.