The intimate relationship of the hypothalamus with sexual development is exemplified by the appearance during puberty of hypertrophic neurons in the infundibular area that are rich in estrogen receptors; it has been proposed that some of the symptoms of menarche are timed and mediated by the specific pattern of genetic expression in these hypothalamic neurons (Karapanou). With aging, and more so in Alzheimer disease, the neuronal population in this region decreases markedly; the sleep disturbances of senescence and some aspects of the “sundowning” syndrome (confusion and delirium occurring in the evening) have also been attributed to this cell loss.
Regulation of Sympathetic and
Finally, the central role of the hypothalamus in the regulation of both sympathetic and parasympathetic activities must be emphasized. This key aspect of hypothalamic function is discussed in the preceding chapter.
The Pineal Gland and Melatonin
The pineal body is a small glandular structure (about 9 mm in diameter) that projects from the dorsal diencephalon and lies just posterior to the third ventricle. Given its central location in the brain, in the past the pineal body figured prominently in philosophic and religious writings; for Descartes, it was the seat of the soul. When this idea was discredited, the pineal gland was relegated to the status of a vestigial organ. The identification of melatonin, the pineal hormone—followed by recognition of its role in maintaining biologic, circadian rhythms—revived scientific interest in the structure.
It is the cyclic secretion of melatonin that appears to be the most important activity of the pineal gland. Melatonin secretion, however, is more accurately regarded as a linked manifestation of the circadian rhythm than as its controlling mechanism. The main cellular element of the gland, the pinealocyte, is thought to derive from neural photoreceptors in lower vertebrates. The latter cells, structurally analogous to retinal cones, transduce light directly into neural impulses and contribute to circadian entrainment of hormonal rhythms in these animals. In humans, the pineal no longer possesses the ability to transduce light directly. However, it retains its influence upon the circadian light–dark cycle, relying on inputs that originate in the retina, synapse in the suprachiasmatic nucleus, pass through descending sympathetic tracts to the intermediolateral cell columns and superior cervical ganglia, and then ascend to innervate noradrenergic terminals on the pinealocytes. Special retinal ganglion cells that contain melanopsin and are intrinsically photosensitive (called ipRGCs) have large receptive fields and physiologic response properties that make them well-suited to detect overall levels of ambient light (Berson). Darkness elicits a release of norepinephrine from these photoreceptors, ultimately stimulating the synthesis and release of melatonin. During daylight the retinal photoreceptor cells are hyperpolarized, norepinephrine release is inhibited, and melatonin secretion is suppressed. The serum concentration of the hormone peaks between 2 and 4 a.m. and gradually falls thereafter. An approximate circadian rhythmicity to melatonin release is preserved in continuous darkness. In humans, the clinical changes that occur with lesions of the suprachiasmatic nucleus cannot be separated from those that occur with lesions of the pineal gland.
Like other neuroendocrine cells, pinealocytes release peptides that are produced in the cell’s Golgi apparatus and packaged in secretory granules. Whether this is the main mechanism for melatonin release is unclear, as these cells can use an alternative ependymal type of vacuolar secretion. The entire gland is invested by a rich vasculature to receive and circulate the released peptide (in some mammals the blood flow per gram of pineal tissue is surpassed only by that of the kidney). The biochemistry and physiology of melatonin have been extensively reviewed by Brzezinski.