Hyperactivity of the PVN may be linked to alterations in glucocorticoid feedback in brain. Numerous studies indicate that chronic stress decreases expression of GR in the prefrontal cortex (PFC) and hippocampus (Mizoguchi et al., 2003; Chiba et al., 2012). Lesion and stimulation studies indicate that both of these regions play a key role in inhibition of HPA axis stress responses, working by way of excitation of inhibitory relays into the PVN [e.g., in the bed nucleus of the stria terminalis (BST), dorsomedial hypothalamus and peri-PVN regions, among others] (Herman et al., 2003; Ulrich-Lai and Herman, 2009). Local administration of glucocorticoids into the PFC reduce HPA axis responses to stress (Diorio et al., 1993), also consistent with an important role in feedback regulation. This conclusion is further supported by studies demonstrating that forebrain deletion of the GR (including the PFC and hippocampus) (Boyle et al., 2005; Furay et al., 2008) or local knock-down of GR in the PFC (McKlveen et al., 2013) enhance HPA axis stress responses. Thus, chronic stress-induced reductions in PFC and hippocampal GR may remove an important brake on the HPA axis, resulting in down-stream changes in PVN excitability.
