However, despite this habituation, the neuroendocrine system is maintained alert and can respond to unexpected stressors, such as exposure to an unfamiliar environment (Enthoven et al., 2008). learn more The dissociation between habituation to a predictable chronic stress, and stimulation by an unpredictable acute stress reflects the astonishing plasticity of the HPA axis that depends on molecular processes in different brain regions. For instance, while GR forebrain overexpression during development alters HPA negative feedback and induces sensitization to acute stress (Hebda-Bauer et al., 2010), GR deficiency in the pituitary induces resilience to chronic social stress in adulthood (Wagner et al., 2011). Mechanistically, HPA axis
(re)programming by maternal care is complex. It involves transcriptional regulation such as changes in binding of the transcriptional repressor neuron-restrictive silencer factor (NRSF) to CRH promoter in hypothalamic neurons (Korosi et al., 2010) and epigenetic mechanisms (McGowan et al., 2011).
HPA axis (re)programming also recruits learning EPZ5676 solubility dmso mechanisms, such as LC/NAd-dependent pathways that are hyperfunctional in neonates and favor maternal attachment (Landers and Sullivan, 2012). Observations that poor maternal care disrupts the HPA axis in animals are consistent with the link between childhood maltreatment, social adversity, emotional neglect, and lower cortisol in humans (Dietz et al., 2011). It is therefore important to better understand the mechanisms of HPA axis (re)programming. Several brain regions have been causally associated with this process, in particular the hippocampal formation and the mPFC. The hippocampus is one of the major brain areas that exert strong regulatory control over the HPA axis. It from is also itself modulated by stress hormones. The hippocampus has direct and indirect polysynaptic connections to the PVN, and it negatively influences the HPA axis via GR-dependent negative feedback (see Figure 3). In rats and humans, hippocampus stimulation
decreases glucocorticoid secretion while hippocampal lesion elevates basal glucocorticoid level, especially during the stress recovery phase, which is the most reliant on negative feedback (Jankord and Herman, 2008). Facilitated glutamatergic plasticity in the dentate gyrus (DG) enhances exploratory activity in mice (Saab et al., 2009). In humans, dysfunctions of glutamatergic neurotransmission, maladaptive structural and functional changes in hippocampal circuitry, and decreased hippocampal volume have been associated with stress-related conditions such as MDD. The glutamate hypothesis for depression, for which hippocampus dysfunction is a major component, is well accepted (Sanacora et al., 2012). Glutamate and AMPA Receptors. Both pre- and postsynaptic components of hippocampal glutamatergic neurotransmission are linked to stress responsiveness and HPA axis regulation ( Popoli et al., 2012).