The stress system in depression and neurodegeneration: focus on the human hypothalamus

Abstract

The stress response is mediated by the hypothalamo-pituitary-adrenal (HPA) system. Activity of the corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) forms the basis of the activity of the HPA-axis. The CRH neurons induce adrenocorticotropin (ACTH) release from the pituitary, which subsequently causes cortisol release from the adrenal cortex. The CRH neurons co-express vasopressin (AVP) which potentiates the CRH effects. CRH neurons project not only to the median eminence but also into brain areas where they, e.g., regulate the adrenal innervation of the autonomic system and affect mood. The hypothalamo-neurohypophysial system is also involved in stress response. It releases AVP from the PVN and the supraoptic nucleus (SON) and oxytocin (OXT) from the PVN via the neurohypophysis into the bloodstream. The suprachiasmatic nucleus (SCN), the hypothalamic clock, is responsible for the rhythmic changes of the stress system. Both centrally released CRH and increased levels of cortisol contribute to the signs and symptoms of depression. Symptoms of depression can be induced in experimental animals by intracerebroventricular injection of CRH. Depression is also a frequent side effect of glucocorticoid treatment and of the symptoms of Cushing's syndrome. The AVP neurons in the hypothalamic PVN and SON are also activated in depression, which contributes to the increased release of ACTH from the pituitary. Increased levels of circulating AVP are also associated with the risk for suicide. The prevalence, incidence and morbidity risk for depression are higher in females than in males and fluctuations in sex hormone levels are considered to be involved in the etiology. About 40% of the activated CRH neurons in mood disorders co-express nuclear estrogen receptor (ER)-alpha in the PVN, while estrogen-responsive elements have been found in the CRH gene promoter region, and estrogens stimulate CRH production. An androgen-responsive element in the CRH gene promoter region initiates a suppressing effect on CRH expression. The decreased activity of the SCN is the basis for the disturbances of circadian and circannual fluctuations in mood, sleep and hormonal rhythms found in depression. Neuronal loss was also reported in the hippocampus of stressed or corticosteroid-treated rodents and primates. Because of the inhibitory control of the hippocampus on the HPA-axis, damage to this structure was expected to disinhibit the HPA-axis, and to cause a positive feedforward cascade of increasing glucocorticoid levels over time. This 'glucocorticoid cascade hypothesis' of stress and hippocampal damage was proposed to be causally involved in age-related accumulation of hippocampal damage in disorders like Alzheimer's disease and depression. However, in postmortem studies we could not find the presumed hippocampal damage of steroid overexposure in either depressed patients or in patients treated with synthetic steroids.