Chronic stress causes a marked reorganization of the central components of the HPA axis. Numerous studies document increases in CRH and AVP expression in parvocellular PVN neurons (Herman et al., 1995; Makino et al., 1995), consistent with increased response capacity of the central limb of the HPA axis. Chronic stress also causes marked structural plasticity in CRH neurons. Glutamatergic and NE terminal appositions on CRH somata and dendrites increase with chronic stress, consistent with enhanced excitatory drive (Flak et al., 2009). There is also evidence that PVN GABAergic signaling is impaired following chronic stress. Chronic variable stress exposure causes decreases in GABA-A receptor subunit mRNAs, which would be predicted to diminish the potential for inhibition of the HPA axis (Cullinan, 2000). At the synaptic level, chronic stress decreases miniature inhibitory post-synaptic potentials in PVN neurons (Verkuyl et al., 2004), consistent with decreased inhibitory innervation. In addition, recent studies suggest that stress causes a reversal of the cellular chloride gradient in parvocellular PVN neurons (Hewitt et al., 2009), essentially negating the inhibitory impact of GABA on post-synaptic neurons. Neuroplastic responses likely reflect increased demand upon the CRH neurons, serving to maintain response capacity if confronted with additional stressors.
