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Stress, Neuroendocrinology and Immunology

There is a hierarchical control for the control of metabolic glandular function that begins in the brain.  This occurs through the secretion of chemical release factors that arrive from the hypothalamus to the pituitary gland via venous portal channels that in turn, secrete chemical messengers to the visceral organs causing them to release appropriate basal and stress levels of hormones. Feedback regulatory processes operate at various levels in this hierarchy to assure precise metabolic functioning. Deficient function of any of these processes can lead to dysregulation of body metabolism.

The sympathetic adrenal neuroendocrine system is the prototypical neuroendocrine system that maintains normal and stress levels of the circulating catecholamine epinephrine and norepinephrine. Epinephrine is a hormone in the traditional sense, released by the adrenal gland proper, while norepinephrine is primarily a neurotransmitter released from axonal terminals of sympathetic postganglionic neurons. Both are deposited directly at their innervated target cells and organs, mediating rapid communication between sympathetic components of the autonomic nervous system and visceral organs. These trigger hemodynamic and metabolic actions that directly impact upon the metabolism of lipids, proteins, and carbohydrates. 

Altered sympathetic adrenal activity has a major role in the pathophysiology underlying common human diseases. One particular disorder, orthostatic (postural) hypotension leads to an abrupt fall in systolic blood pressure upon standing or tilting. This is due to disturbed sympathetic neural reflexes initiated by baroreceptors that fail to increase peripheral vascular resistance. It is the failure to release the approximately two-fold needed increase in plasma norepinephrine from sympathetic postganglionic neurons that underlies this disturbed reflex. Another condition termed, postural orthostatic tachycardia (POTS), presents with acceleration of the heart rate upon tilting or standing, but without hypotension, the cause of which is less well understood but also under neural control.
There is increasing recognition of the relationship between the neuroendocrine control of body metabolism in response to infection, inflammation, and tissue injury.  Immune reactions arise in the central nervous system response to peripheral immune stimuli through the action of activated immunocompetent cells such as monocytes, lymphocytes, and macrophages that cross the blood-brain barrier and take up residence in the brain. There, they secrete a full range of cytokines and other inflammatory mediators as do activated brain microglia and endothelial and smooth muscle cells. Activation of three cytokines, interleukin (IL)-1 and -6, and tumor necrosis factor (TNF)-a, account for most of the stimulating activity of the hypothalamic pituitary-adrenal (HPA) axis, which in concert with the systemic adrenal sympathetic system, function as the main components of the peripheral stress system, maintaining basal and stress-related hormone levels. 

A change in personality, behavior, coping style, and one’s emotional state may be the first clue to abnormalities in immune neuroendocrine regulatory function due to activation of cytokines in the brain. Unrecognized and thus untreated, there may be potentially disastrous consequences ranging from mental changes to permanent neural injury. The neuropathological effect of certain viruses and bacteria that do not directly invade neurons such as Borrelia burgdorferi, the spirochete agent responsible for Lyme disease, and human immune deficiency virus (HIV), the agent of the acquired immune deficiency syndrome (AIDS), both appear to be mediated by cytokines produced by activated glial and immune cells that enter the brain from the systemic circulation. 

It is becoming clear that inadequate activation and therefore, reduced responsiveness by the HPA axis due to an underlying brain disturbance, may impact on an individual's capacity to withstand infectious invasions or a developing autoimmune disorder. These observations, and others relevant to maintaining optimal brain health during conditions at rest and with stress, are important topics for future research.