Neuroendocrinology

Neuroendocrinology studies the relationships between the endocrine system and the brain. The endocrine system produces a variety of hormones, which are chemical messengers that signal changes that the body needs to make to adapt to new situations. The brain controls the endocrine system through the hypothalamus and pituitary gland, and the secretions of the gonads, adrenals, and thyroid act on tissues throughout the body, and on the brain and pituitary, to produce a wide variety of effects. Some hormone effects occur during development and are generally long lasting and even permanent for the life of the individual. Other hormone actions take place in the mature nervous system and are usually reversible. Still other hormone actions in adult life are related to permanent changes in brain function associated with disease processes or with aging.

Nerve cells in the hypothalamus produce hormones, called releasing factors, which are released into a portal blood supply and travel to the anterior pituitary gland where they trigger the release of trophic hormones such as adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, and growth hormone. These hormones, in turn, regulate endocrine responses -- for example, ACTH stimulates glucocorticoid secretion by the adrenal cortex; TSH, thyroid hormone secretion; and LH, sex hormone production. Other hypothalamic neurons produce the hormones vasopressin and oxytocin and release these hormones at nerve terminals located in the posterior lobe of the pituitary gland. Brain activity stimulates the secretion of these hormones; for example, oxytocin and prolactin release are stimulated by suckling, and the sight and sound of an infant can stimulate "milk letdown" in the mother; ACTH is driven by stressful experiences and by an internal clock in the brain that is entrained by the light-dark cycle; and LH and FSH secretion are influenced by season of the year in some animals.

Thyroid hormone and sex hormones act early in life to regulate development and differentiation of the brain, whereas the activity of the stress hormone axis is programmed by early experiences via mechanisms which may depend to some degree on the actions of glucocorticoid hormones.

For thyroid hormone, both excesses and deficiencies of thyroid hormone secretion are associated with altered brain development; extremes in thyroid hormone secretion lead to major deficiencies in cognitive function (e.g., cretinism), whereas smaller deviations in thyroid hormone secretion are linked to more subtle individual variations in brain function and cognitive activity.

For sex hormones, the story is more complicated in that testosterone secretion during midgestation in the human male and then again during the first two years of postnatal life alters brain development and affects cognitive function as well as reproductive function. There are comparable periods of testosterone production in early development in other mammals. Absence of testosterone in females leads to the female behavioral and body phenotype; and absence of androgen receptors or the lack of normal androgen secretion in genetic males leads to a feminine phenotype, whereas exposure of genetic females to androgens early in development produces a masculine phenotype. Sexual differentiation of the brain has been investigated in animals, and there are subtle sex differences in a variety of brain structures, ranging from the hypothalamus (which governs reproduction) to the HIPPOCAMPUS and CEREBRAL CORTEX (which subserve cognitive function). There are also indications for structural and functional sex differences in the human brain that are similar to those found in lower animals. For example, in both animals and humans, sex differences are found in the strategies used for spatial learning and memory, with males using the more global spatial cues and females relying upon local contextual cues.

For stress hormones, early experience has a profound role in shaping the reactivity of the stress hormone axis and the secretion not only of ACTH and glucocorticoids but also the activity of the autonomic nervous system. Prenatal stress and certain types of aversive experience in infant rodents (e.g., several hours of separation from the mother) increase reactivity of the stress hormone axis for the lifetime of the individual. In contrast, handling of newborn rat pups (a much briefer form of separation of the pup from the mother) produces a lifelong reduction in activity of the stress hormone axis. Actions of glucocorticoid and thyroid hormones play a role in these effects. There is growing evidence that for rodents elevated stress hormone activity over a lifetime increases the rate of brain aging, whereas a lifetime of reduced stress hormone activity reduces the rate of brain aging (see below).

Whereas the developmental actions of hormones on the brain are confined to windows of early development during fetal and neonatal life and the peripubertal period, these same hormones produce reversible effects on brain structure and function throughout the life of the mature nervous system. Sex hormones activate reproductive behaviors, including defense of territory, courtship, and mating, and they regulate neuroendocrine function to ensure successful reproduction; however, reflecting sexual differentiation of the brain and secondary sex characteristics of the body, the activational effects of sex hormones in adult life are often gender-specific.

Thyroid hormone actions maintain normal neuronal excitability and promote a normal range of nerve cell structure and function; excesses or insufficiencies of thyroid hormone have adverse effects on brain function and cognition, which are largely reversible. Among these effects are exacerbation of depressive illness.

There are two types of adrenal steroids -- mineralocorticoids and glucocorticoids -- which regulate salt intake and food intake, respectively, and also modulate metabolic and cognitive function during the diurnal cycle of activity and rest. Adrenal steroids act to maintain homeostasis and glucocorticoids do so in part by opposing, or containing, the actions of other neural systems that are activated by stress and also by promoting adaptation of the brain to repeatedly stressful experiences. Containment effects of glucocorticoids oppose stress-induced activity of the noradrenergic arousal system and the hypothalamic system that releases ACTH from the pituitary. Adaptational effects of stress hormones during prolonged or repeated stress increase or decrease neurochemicals related to brain excitability and neurotransmission and produce changes in neuronal structure. Adrenal steroids biphasically modulate LONG-TERM POTENTIATION (LTP) in the hippocampus, with high levels of stress hormones also promoting long-term depression (LTD). LTP and LTD may be involved in learning and memory mechanisms.

Primary targets of stress hormones are the hippocampal formation and also the AMYGDALA. Repeated stress causes atrophy of hippocampal pyramidal neurons and inhibits the replacement of neurons of the dentate gyrus by cognitive function, enhancing episodic and declarative memory at low to moderate levels but inhibiting these same functions at high levels or after acute stress. Along with adrenal steroids, the sympathetic nervous system participates in creating the powerful memories associated with traumatic events, in which the amygdala plays an important role. Glucocorticoid hormones act in both the amygdala and hippocampus to promote consolidation.

Steroid hormones and thyroid hormone act on cells throughout the body via intracellular receptors that regulate gene expression. Such intracellular receptors are found heterogeneously distributed in the brain, with each hormone having a unique regional pattern of localization across brain regions. The hypothalamus and amygdala have receptors for sex hormones, with both sexes expressing receptors for androgens, estrogens, and progestins, although, because of sexual differentiation, there are somewhat different amounts of these receptors expressed in male and female brains. The hippocampus and amygdala have receptors for adrenal steroids, whereas thyroid hormone receptors are widely distributed throughout the nervous system, particularly in the forebrain and CEREBELLUM.

Effects mediated by intracellular receptors are generally slow in onset over minutes to hours and long-lasting because alterations in gene expression produce effects on cells that can last for hours and days, or longer. Steroid hormones also produce rapid effects on the membranes of many brain cells via cell surface receptors that are like the receptors for neurotransmitters. These actions are rapid in onset and short in duration. However, the precise nature of the receptors for these rapid effects is in most cases largely unknown.

Hormones participate in many disease processes, in some cases as protectors and in other cases as promoters of abnormal function. Adrenal steroids exacerbate neural damage from strokes and seizures and mediate damaging effects of severe and prolonged stress. Estrogens enhance normal declarative and episodic memory in estrogen-deficient women, and estrogen replacement therapy appears to reduce the risk of Alzheimer's disease in postmenopausal women. Estrogens also have antidepressant effects; they modulate pain mechanisms; and they regulate the neural pathways involved in movement, with the result that estrogens enhance performance of fine motor skills and enhance reaction times in a driving simulation test in women. Androgen effects are less well studied in these regards.

Age-related decline of gonadal function reduces the beneficial and protective actions of these hormones on brain function. At the same time, age-related increases in adrenal steroid activity promote age-related changes in brain cells that can culminate in neuronal damage or cell death. Lifelong patterns of adrenocortical function, determined by early experience (see above), contribute to rates of brain aging, at least in experimental animals.

Hormones are mediators of change, acting in large part by modulating expression of the genetic code, and they provide an interface between experiences of the individual and the structure and function of the brain, as well as other organs of the body. Hormone action during development and in adult life participates in the processes that determine individual differences in physiology, behavior, and cognitive function.

Neuroendocrinology

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Further Readings