The Hypothalamus And Neuroendocrine Regulation

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Neural regulation of pituitary secretion is one of the most important, well-characterized, and diverse functions of the hypothalamus. In fact, the demonstration that the hypothalamus exerts regulatory control over the pituitary is one of the landmark discoveries that tied the fields of neurobiology and endocrinology together. Recognition that hypothalamic control over the pituitary was humoral in nature resulted from structural studies that demonstrated a vascular link, or portal plexus, connecting these structures. Thus, the organizational features of the hypothalamic-pituitary axis are introduced below as a prelude to examining specific examples of hypothalamic control over pituitary secretion.

As noted earlier, the ventral diencephalon is connected to the subjacent pituitary via the infundibular stalk. Large-caliber magnocellular axons whose parent neurons reside in rostral hypothalamus traverse this stalk to terminate directly in the posterior lobe of the pituitary gland. This is the only direct neural connection between the hypothalamus and pituitary and represents only a small portion of the regulatory capacity of the hypothalamus over pituitary function. Control of the secretory activity of the anterior pituitary is achieved through a portal vascular plexus that arises in the median eminence and then pursues a directed course along the stalk to end in the anterior lobe of this gland. An important feature of this portal system is the absence of the BBB in the capillaries of the median eminence. Fenestrations in the median eminence vessels allow peptides and neurotransmitters released from axons in their vicinity to gain access to the portal plexus, whereupon they are transported to the anterior pituitary to influence the secretory activity of cells in that portion of the gland. This architecture forms the basis for the neurohumoral regulation of pituitary function that is the foundation of neuroen-docrinology (Fig. 2).

The absence of the BBB is a defining feature of a group of structures known as circumventricular organs (CVOs). These regions, which include the median eminence, are found on the midline of the brain

Neurohumoral Regulation

Figure 2 The basic organization of the hypothalamic-pituitary axis is illustrated in the schematic diagram. The anterior lobe of the pituitary is regulated by hypothalamic peptides and neurotransmitters that are released from parvocellular hypothalamic neurons into a vascular (portal) plexus and then travel to the anterior lobe to either stimulate or inhibit the release of hormones from cells in this portion of the gland. This is possible because the vessels at the neurohemal contact zone in the median eminence are fenestrated and large numbers of axon terminals terminate on the perivascular space adjacent to these vessels (bottom, right). Large magnocellular neurons project through the infundibular stalk (IS) to terminate in the posterior, or neural, lobe of the pituitary. ac, anterior commissure; f, fornix; OC, optic chiasm; ot, optic tract; III, third ventricle.

Figure 2 The basic organization of the hypothalamic-pituitary axis is illustrated in the schematic diagram. The anterior lobe of the pituitary is regulated by hypothalamic peptides and neurotransmitters that are released from parvocellular hypothalamic neurons into a vascular (portal) plexus and then travel to the anterior lobe to either stimulate or inhibit the release of hormones from cells in this portion of the gland. This is possible because the vessels at the neurohemal contact zone in the median eminence are fenestrated and large numbers of axon terminals terminate on the perivascular space adjacent to these vessels (bottom, right). Large magnocellular neurons project through the infundibular stalk (IS) to terminate in the posterior, or neural, lobe of the pituitary. ac, anterior commissure; f, fornix; OC, optic chiasm; ot, optic tract; III, third ventricle.

surrounding the third and fourth ventricles. Only two of the CVOs (the median eminence and OVLT) are found within the hypothalamus, but all are intimately associated with hypothalamic function by virtue of the connections that they maintain with various hypothalamic nuclei. For example, the absence of the BBB in the subfornical organ and area postrema allows neurons in these regions to respond to circulating cues and then modulate the activity of the hypothalamic-pituitary axis through classical synaptic connections with hypothalamic neurons. Thus, the absence of the BBB is essential not only for the ability of the hypothalamus to control the secretory activity of the pituitary but also for the feedback regulation of the hypothalamic-pituitary axis that imparts precision on endocrine regulation of peripheral systems.

The neurons that contribute to regulation of anterior pituitary secretion exhibit common features that are reflective of their function. First, they are confined to the hypothalamus and give rise to axons that terminate in the median eminence. Two hypothalamic nuclei, the paraventricular and arcuate, are particularly devoted to anterior pituitary regulation. Substantial numbers of parvocellular neurons in these nuclei give rise to dedicated projections to the external zone of the median eminence where their terminals abut on the perivascular space (contact zone) surrounding the fenestrated capillaries of the portal plexus. Neurons exhibiting the same organization are also dispersed in other areas of hypothalamus. For example, neurons involved in the regulation of growth hormone secretion are concentrated in the rostral periventricular and arcuate nuclei, whereas those that are important for regulation of ovulation in females are dispersed throughout the preoptic area. All these neurons project exclusively to the portal plexus in the median eminence and thereby exert their function in a neuroendocrine fashion.

A second feature of these neurons is their neuro-chemical diversity. Although they all have common structural features, the differing functions of these neurons are defined by their neurochemical pheno-type. Many of the neurons manufacture and release small peptides that either stimulate or inhibit the secretory activity of cells in the anterior pituitary. Others utilize small molecule neurotransmitters such as dopamine toward the same end. These "releasing" or "inhibiting" factors impart another level of regulatory control over the hypothalamic-pituitary axis that is best illustrated by considering a specific example, such as growth hormone (GH) secretion. Peripheral metabolism is heavily influenced by release of GH from the anterior pituitary gland and this release, in turn, is regulated by two populations of hypothalamic neurons that produce opposite effects in the pituitary. Stimulation of GH release is under the control of neurons in the arcuate nucleus that produce growth hormone-releasing hormone, whereas inhibition of GH release results from the activity of somatostatinergic neurons in the rostral periventricu-lar nucleus. Differential activation of these opposing systems permits precise regulation of GH secretion and emphasizes the importance of feedback regulation in activating the appropriate regulatory circuitry.

A role for hypothalamic timing mechanisms in neuroendocrine regulation is predicted by the rhythmic profiles of hormone release by the anterior pituitary and its target organs. This is clearly exemplified by the temporal profile of cortisol secretion by the adrenal gland. Release of plasma corticosteroids is under control of the hypothalamic-pituitary-adrenal (HPA) axis and exhibits a circadian profile, with peak levels occurring at the end of the dark phase in humans and the end of the light phase in rat. Although the temporal relations of these peaks differ between the two species, the temporal association of the peaks to activity is the same. Release of corticosteroids from the adrenal is under the control of corticotropin-releasing factor (CRF) neurons in the paraventricular hypotha-lamic nucleus. Release of CRF into the portal plexus at the median eminence elicits the synthesis and release of adrenocorticotropin hormone from the anterior pituitary, which subsequently stimulates corticosteroid release from the adrenal. Evidence suggests that the SCN modulates the activity of the HPA axis through a disynaptic pathway in which SCN neurons synapse on neurons in the dorsomedial hypothalamic nucleus that are presynaptic to CRF neurons in the paraventricular nucleus. Control of the HPA axis is also exquisitely sensitive to other sensory cues, such as feeding and stress. Thus, control of the HPA axis is a dynamic process in which the hypothalamus plays an important integrative role that defines the magnitude and temporal profile of corticosteriod release. It is probable that similar organizational principles account for the rhythmic release of other hormones.

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