The Neuroendocrine System

The Scharrers (1940) first hypothesized that the peptides of the neurohypophysis were in fact synthe-tized by specialized hypothalamic neurons and transported within their axons to the neural lobe to be released into peripheral blood. In the late 1940s, Harris and collaborators proposed the hypophysial portal chemotransmitter hypothesis of anterior pituitary

Figure 5 The anterior lobe of the pituitary gland. The anterior lobe synthetizes several hormones. Their release is induced by chemical signals, called releasing factors, that are secreted by hypothalamic neurons. These factors enter the hypothalamo-pituitary portal system, comprising first a capillary bed in the hypothalamus and then a venous drainage channel and, in the anterior lobe, a second capillary bed. OC, optic chiasm.

Figure 5 The anterior lobe of the pituitary gland. The anterior lobe synthetizes several hormones. Their release is induced by chemical signals, called releasing factors, that are secreted by hypothalamic neurons. These factors enter the hypothalamo-pituitary portal system, comprising first a capillary bed in the hypothalamus and then a venous drainage channel and, in the anterior lobe, a second capillary bed. OC, optic chiasm.

control, which stated that the factors regulating the anterior lobe are formed by hypothalamic neurons (later termed hypophysiotropic neurons) and transported to be released into the hypophysial portal circulation and carried to the anterior pituitary (Fig. 5), where they control the synthesis and release of anterior pituitary hormones into the general circulation. Both of these hypotheses have been confirmed and rationalized into a unified theory of neurosecretion in which the nervous system controls endocrine function. Neurosecretion is the phenomenon of synthesis and release of specific substances by neurons. Some neurosecretions are exported into the peripheral or hypophysial blood and act as true hormones; others, released in close apposition to other neurons, act as neurotransmitters or neuromodulators. Trans lation of neuronal signals into chemical ones has been termed neuroendocrine transduction and the cells have been called neuroendocrine transductors by R. J. Wurtman and F. Anton-Tay (1969). Two types of neurotransducer cells regulate visceral function: (i) neurosecretomotor cells, in which the neurosecretion acts directly through synapses on gland cells, and (ii) neuroendocrine cells, in which the neurosecretion passes into the blood and acts on distant targets.

Neurosecretory cells possess in common with other neurons the usual aspects of neuron functions. Most of the insight into the physiology of neurosecretory systems has been gained from studies of the hypotha-lamo-hypophyseal system. This system brings nervous and endocrine cells together in one anatomical entity in which the nervous system and the glandular cells of the anterior hypophysis communicate. These two structures share common properties. They both secrete peptidergic hormones (releasing and inhibiting hypo-thalamic factors and the hypophyseal stimulins), and both exhibit electrical properties such as excitability, with production of action potentials. Thus, electro-physiological techniques, which were previously reserved for studies of nerve and muscle cells, can be applied to the hypothalamo-hypophyseal system in both its nervous and endocrine structures. The elec-trophysiological properties of these cells reveal the existence of (i) stimulus-secretion coupling, particularly at the level of neurosecretory terminals in the posterior hypophysis, the median eminance, and the endocrine cells of the anterior hypophysis, and (ii) modifications in membrane electrical properties exerted by the binding of different regulatory factors to their receptors. These observations are used to explain the modulatory mechanism of membrane properties brought into play by each factor in order to enhance or inhibit hormonal release. Thus, the electrical properties play a central role in the regulation of endocrine secretion in the anterior hypophysis. These electrical properties, common to nervous and endocrine cells, are linked to changes in membrane permeability to different ions (i.e., Ca2 + , Na + , K + , and Cl").

The pituitary gland is divided into two main functional units—the neural (or posterior) lobe and the adenohypophysis (or anterior) lobe (Figs. 3 and 5). In many mammalian species an intermediate lobe (derived embryologically from the same tissue as the anterior lobe) is present, but in humans these lobe cells are dispersed throughout the entire pituitary gland.

In the neurohypophyseal system, hypothalamic neurons transmit action potentials along their axons in a similar manner to that used by unmyelinated neurons, and each action potential triggers the release of secretory granules from nerve endings by calcium-dependent exocytosis into the general circulation. The neural lobe is an anatomical part of the neurohypo-physis that is commonly viewed as consisting of three portions—the neural lobe (infundibular process or posterior pituitary), the stalk, and the infundibulum. This latter portion forms the base of the third ventricle (Figs. 3 and 5). In fact, there is a fourth intrahypotha-lamic component of the neurohypophysial system that consists of the cells of origin of the two principal nerve tracts that terminate in the neural lobe—supraopti-cohypophysial and paraventriculohypophysial.

The neurohypophysial hormones secreted by the magnocellular neurons are vasopressin (antidiuretic hormone) and oxytocin, which are synthesized within the cell bodies in association with specific proteins, the neurophysins. Like most peptidergic hormones, vaso-pressin and oxytocin are cleaved from a larger prohormone. These prohormones are synthesized in the cell bodies of the magnocellular neurons and are cleaved within vesicles during their transport down the axons. Vasopressin, oxytocin, and at least two forms of neurophysins are secreted into the blood circulation; they are responsive to appropriate physiological stimuli and can be altered by stressful conditions.

Although the anterior lobe does not receive any direct nerve supply, its secretions are under control exerted by the hypothalamus. This control is mediated by chemical factors (hypophysiotropic hormones) secreted by the parvocellular neuroendocrine neurons located in several hypothalamic regions: the medial basal and periventricular regions and the arcuate, tuberal, preoptic, and paraventricular nuclei. Parvo-cellular neurons secrete peptides in the interstitial space of the base of the third ventricle and then diffuse into the capillary plexus of the median eminence that is interposed between the peripheral arterial system and the pituitary sinusoidal circulation (Fig. 3). By this anatomical arrangement, neurohormonal mediators synthesized and released by the hypothalamus are brought into direct contact with the adenohypophysis. The hormones released by the anterior lobe of the pituitary gland are called tropic (literally "switch-on") hormones. Each is the second and final messenger in a sequence of chemical signals leading from the brain to a particular endocrine gland. All the tropic hormones of the anterior lobe are simultaneously trophic hormones, in whose absence their target glands atrophy.

A different functional link leads from the neurons of the hypothalamus to the posterior lobe of the pituitary complex. This link is more direct since it does not include part of the circulatory system. It begins in two circumscribed magnocellular nucleus. They are the first hypothalamic nuclei whose function has been identified with some precision. All, or nearly all, of the axons originating in the supraoptic nucleus, along with approximately 30% of the axons originating in the paraventricular nucleus, pass through the pituitary stalk and reach the posterior lobe of the pituitary. The remaining 70% have several destinations, of which one is especially notable: The paraventricular nucleus is a substantial contributor to the pathway descending from the hypothalamus direct to the lateral horn of the spinal cord, which contains the spinal cord's pregan-glionic sympathetic motor neurons.

Unlike the anterior one, the posterior lobe is a part of the brain. Nevertheless, it contains no neurons; the terminations of the supraoptic and paraventricular axons make no synaptic contacts. Instead, they lie embedded in a tissue composed of modifed glial cells called the pituicytes and a dense plexus of capillaries. The glandular products of the supraoptic and paraventricular nuclei are synthesized in the cell body and packaged in neurosecretory vesicles in which some hormonal maturation may occur. These neurosecre-tory vesicles are transported down the axon to the neural terminal, where hormones are stored and released by secretion when the neuron is stimulated.

Recently, it has been demonstrated that a type of ependymal glial cell called tanycyte, which ensheaths the terminals of hypothalamic neurons, regulates the release of luteinizing hormone-releasing hormone (LHRH) from the hypothalamus and may therefore play a key role in the onset of puberty. LHRH axons that travel with the processes of tanycytes can be covered by slips of glioplasm. At the perivascular space level, the nerve terminals may be partially covered or exposed, potentially impeding or enhancing the secretion of LHRH into capillaries. Such observation, realized at a cellular level, illustrates the tremendous plasticity of the hypothalamus. Interestingly, it was found that these glial cells in the median eminence possess estrogen and epidermal growth factor receptors, whereas LHRH neurons apparently do not. Taken together, these observations provide strong evidence that, at puberty, glia is a crucial target for estrogenic action that may induce morphological changes accompanied by release of chemical signals that modulate hypothalamic neurons.

somatic responses. In line with this view, vasopressin, oxytocin, and other regulating hormones are not the only peptides of neurobiological interest that can be found in the hypothalamus. The opioid peptides, bendorphin, and the enkephalins can also be detected in this structure, as can angiotensin II, substance P, neurotensin, cholecystokinin, and a host of other peptides known to be involved in multiple behavioral responses. Interestingly, almost every type of pepti-dergic neuron previously studied, including both parvocellular and magnocellular hypothalamic neurons, has been found to contain more than one type of peptide that could act synergistically. Furthermore, peptides released by the hypothalamic magnocellular and parvocellular neurons are not unique to these cells; they have also been found in other regions of the nervous system. Such peptidergic projections are well suited for coordinating neuroendocrine and auto-nomic responses. For example, regulatory peptides released at brain sites other than the median eminence may modulate behavior by actions independent of the release of pituitary hormones. The behavioral effects of regulatory peptides are thematically related to the type of endocrine effects produced by the same peptide acting on the pituitary. Corticotropin-releasing hormone (CRH) is an example of such a regulatory peptide. On the one hand, it acts on the pituitary to stimulate the release of adrenocorticotropic hormone in response to stress. On the other hand, when injected intracerebroventricularly, CRH evokes many of the behavioral and autonomic reactions normally seen in response to stress.

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