Upon exposure to stress, neurons in the hypothalamic paraventricular nucleus (PVN) secrete corticotropin-releasing hormone (CRH) from nerve terminals in the median eminence into the hypothalamo-hypophyscal

portal circulation, which stimulates the production and release of adrenocorticotropin (ACTH) from the anterior pituitary. ACTH in turn stimulates the release of glucocorticoids from the adrenal cortex. Glucocorticoids modulate metabolism as well as immune and brain function, thereby orchestrating physiological and organismal Inhibitors,research,lifescience,medical behavior to manage stressors. At the same time, several brain pathways modulate HPA axis activity. In particular, the hippocampus and prefrontal cortex (PFC) inhibit, whereas the amygdala and aminergic brain stem neurons stimulate, CRH neurons in the PVN. In addition, glucocorticoids exert negative feedback control of the HPA axis by regulating hippocampal and PVN neurons. Sustained glucocorticoid exposure has adverse effects on hippocampal neurons, Inhibitors,research,lifescience,medical including reduction in Inhibitors,research,lifescience,medical dendritic branching, loss of dendritic spines, and impairment of neurogenesis.3-5 Figure 1. The hypothalamic-pituitary-adrenal axis is the body’s major response system for stress. The hypothalamus secretes CRH, which binds to receptors on pituitary cells, which produce/release ACTH, which is transported to the adrenal gland where

adrenal hormones … Although stressors as a general rule activate the HPA axis, studies in combat veterans with PTSD demonstrate decreases in Cortisol concentrations, as detected in Inhibitors,research,lifescience,medical urine or blood, compared with healthy controls and other com parator groups. This surprising finding,

though replicated in PTSD patients from other populations including Holocaust survivors, refugees, and abused persons, is not consistent across all studies.6 It has been suggested that inconsistent findings may result from differences in the severity and timing of psychological trauma, the patterns of signs/symptoms, comorbid conditions, personality, and genetic makeup.7 Studies Inhibitors,research,lifescience,medical using low-dose dexamethasone suppression testing suggest that hypocortisolism in PTSD occurs due to Chlormezanone increased negative feedback sensitivity of the HPA axis. Sensitized negative feedback selleck inhibition is supported by findings of increased glucocorticoid receptor binding and function in patients with PTSD.6 Further, sustained increases of CRH concentrations have been measured in cerebrospinal fluid (CSF) of patients with PTSD. As such, blunted ACTH responses to CRH stimulation implicate a role for the downregulation of pituitary CRH receptors in patients with PTSD.6 In addition, reduced volume of the hippocampus, the major brain region inhibiting the HPA axis, is a cardinal feature of PTSD.8 Taken as a whole, these neuroendocrine findings in PTSD reflect dysregulation of the HPA axis to stressors.