Effects of hypothalamic peptides on the aging brain.

The hypothalamic peptide hormones, TRH, LHRH (GnRH), CRH, GHRH, and GHIRH (somatostatin), influence the release of the anterior pituitary hormones, which in turn promote the release of target endocrine gland hormones and other metabolites. These latter compounds feed back to the brain to help control the secretion of the hypothalamic hormones. This is a dynamic interaction that is influenced by the aging process: Most of these hormones systems become less responsive with advancing age, due to decreased function of peptide-containing secretory neurons, a loss of hormone receptor sensitivity, and/or a reduction in the output of the target endocrine glands. That the hypothalamic peptides themselves can influence brain function is supported by the fact that most are found in areas of the brain other than the hypothalamus and that receptors for them exist in these other areas. For example, CRH is contained in a number of central neural systems that can influence behavior, including limbic areas, the hypothalamus, locus coeruleus, median raphé nuclei, and cortical interneurons. CRH has been shown to be anxiogenic in animal models, and its effect can be blocked by CRH receptor antagonists. CRH content in the locus coeruleus is particularly increased by stress and may influence norepinephrine neurotransmitter function in this structure. In aging there is a gradual reduction of the sensitivity of the brain to the negative feedback of corticosteroids, such that CRH secretion becomes somewhat increased under basal conditions. The behavioral effects of this change are unclear, however, as is the influence of stress-related activation of CRH, ACTH, and glucocorticoid secretion on behavior in the elderly. Other hypothalamic peptides have different patterns of change with aging, and some are markedly altered in pathological conditions; for example, in Alzheimer's disease the content of CRH and somatostatin in certain brain areas is decreased. However, whether the changes in hypothalamic peptides precede or follow the pathological behavioral changes, and how they participate in the changes, is still unclear.