The parvocellular neuroendocrine system

Parvocellular neurons of the hypophysiotropic area give rise to the tuberoinfundibular tract, which reaches the infundibular capillary bed. Action potentials traveling along these neurons result in calcium-dependent exocytosis of releasing hormones from some and inhibiting hormones from others, for transport to the adenohypophysis in the portal vessels. The cell types of the adenohypophysis are stimulated/inhibited in accordance with Table 26.2. In the left-hand column, the only non-peptide parvocellular hormone is the prolactin-inhibiting hormone, which is dopamine, secreted from the arcuate (infundibular) nucleus.

Table 26.2 Hypothalamic parvocellular releasing/inhibiting hormones (RH/IH)

The releasing/inhibiting hormones are not wholly specific: they have major effects on a single cell type, and minor effects on one or two others.

Multiple controls exist for parvocellular neurons of the hypophysiotropic area. The controls include: depolarization by afferents entering from the limbic system and from the reticular formation; hyperpolarization by local-circuit GABA neurons, some of which are sensitive to circulating hormones; and inhibition of transmitter release by opiate-releasing internuncials, which are numerous in the intermediate region of the hypothalamus. The picture is further complicated by the fact that opiates and other modulatory peptides may be released into the portal vessels and activate receptors on the endocrine cells of the adenohypophysis. Stress causes increased secretion of ACTH, which in turn stimulates the adrenal cortex to raise the plasma concentration of glucocorticoids, including cortisol. Normally, cortisol exerts a negative feedback effect by exciting inhibitory hypothalamic neurons having glucocorticoid receptors. In patients suffering from major depression, this feedback system fails (Clinical Panel 26.1).

The magnocellular neuroendocrine system

Magnocellular neurons in the supraoptic and paraventricular nuclei give rise to the hypothalamohypophyseal tract, which descends to the neurohypophysis (posterior lobe) (Figure 26.3). Minor contributions to the tract are received from opiatergic and other peptidergic neurons in the periventricular region of the hypothalamus, and from aminergic neurons of the brainstem.

Two hormones are secreted by separate neurons located in both the supraoptic and paraventricular nuclei: antidiuretic hormone (vasopressin) and oxytocin. Axonal swellings containing the secretory granules for these hormones make up nearly half the volume of the neurohypophysis. The largest swellings, called Herring bodies, may be as large as erythrocytes. The Herring bodies provide a local depot of granules for release by smaller, terminal swellings into the capillary bed.

Antidiuretic hormone

Antidiuretic hormone (ADH) continuously stimulates water uptake by the distal convoluted tubules and collecting ducts of the kidneys. The chief regulator of electrical activity in the ADH-secreting neurons is the osmotic pressure of the blood. A rise of as little as 1% in the osmotic pressure causes the plasma to be diluted to normal levels by means of increased water uptake. The neurons are themselves sensitive to osmolar changes, but they are facilitated by inputs from osmolar and volume detectors elsewhere, notably from the vascular and subfornical circumventricular organs (Box 26.1).

Box 26.1 Circumventricular organs

Six patches of brain tissue close to the ventricular system contain neurons and specialized glial cells abutting fenestrated capillaries. These are the circumventricular organs (CVOs) (Figure Box 26.1.1). The median eminence and neurohypophysis are described in the main text. The vascular organ of the lamina terminalis and the subfornical organ close to the interventricular foramen send axons into the supraoptic and paraventricular nuclei of the hypothalamus and facilitate depolarization of neurons secreting ADH. In conditions of lowered blood volume, the kidney secretes renin, which, on conversion to angiotensin II, stimulates these two CVOs to complete a positive feedback loop.

The pineal gland synthesizes melatonin, an amine hormone implicated in the sleep–wake cycle. Melatonin is synthesized from serotonin, the requisite enzymes being unique to this gland. Melatonin is liberated into the pineal capillary bed at night and has a sleep-inducing effect; it may have other benefits, including clearance of harmful free radicals liberated from tissues during the aging process. Daytime secretion is suppressed by activity in sympathetic fibers reaching it from the superior cervical ganglia by way of the walls of the straight venous sinus. The relevant central pathway is from the paired suprachiasmatic nuclei via the posterior longitudinal fasciculus.

From the third decade onward, calcareous deposits (‘pineal sand’) accumulate within astrocytes in the pineal. Calcification is often detectable in plain radiographs of the head. A shift of the gland may denote a space-occupying lesion within the skull. However, a normal pineal may lie slightly to the left, because the right cerebral hemisphere is usually a little wider than the left at this level.

The area postrema is embedded in the roof of the fourth ventricle at the level of the obex. It is the chemoreceptor trigger zone, or emetic (vomiting) center. The emetic center contains neurons sensitive to a wide range of toxic substances, and it serves a protective function by reflexly eliciting emesis via connections with hypothalamus and reticular formation.

Figure Box 26.1.1 Circumventricular organs.

Some ADH neurons also synthesize corticotropin-releasing hormone (CRH), the two hormones being released together from collateral branches into the capillary pool of the infundibulum. It is of interest that ADH neuronal activity is increased when the body is stressed, and that the output of ACTH is boosted by the presence of ADH in the adenohypophysis.

Withdrawal of ADH secretion results in diabetes insipidus (Clinical Panel 26.2).

Clinical Panel 26.2 Hypothalamic disorders

The most dramatic disorder of hypothalamic function is diabetes insipidus, which is brought about by interruption of the hypothalamohypophyseal pathway – sometimes by tumors in the region, sometimes by head injury. The patient drinks upwards of 10 liters of water per day, and excretes a similar amount of urine. Historically, the term insipidus refers to the absence of taste sensation from the urine, in contrast to diabetes mellitus, in which the urine is sweet-tasting (mellitus) owing to its sugar content.

Hypophysectomy (surgical removal of the pituitary gland) can be performed in the treatment of other diseases, without causing more than temporary diabetes insipidus, provided the pituitary stalk is sectioned at a low level. Within a short period, sufficient ADH is secreted into the capillary bed of the median eminence to ensure adequate water conservation.

A wide variety of hypothalamic dysfunctions have been reported in the clinical literature. Causes are also varied, and include tumors, congenital malformations, and head injury. Clinical manifestations include gross obesity, disturbances of autonomic control, excessive sleepiness, and memory loss.

Autonomic centers

In animals, stimulation of the anterior hypothalamic area produces parasympathetic effects: slowing of the heart, constriction of the pupil, salivary secretion, and intestinal peristalsis. On the other hand, stimulation of the posterior hypothalamic area produces sympathetic effects: increase in heart rate and blood pressure, pupillary dilation, and intestinal stasis. Axons from both areas project to autonomic nuclei in the brainstem and spinal cord. In the midbrain and pons, this projection occupies the posterior longitudinal fasciculus as seen in Chapter 17.

Temperature regulation

The preoptic nucleus in the anterior hypothalamus contains thermosensitive neurons which initiate appropriate responses to changes in the core temperature of the body. Activity of these neurons is reinforced by information received (via the spinoreticular tract) from thermosensitive neurons supplying the skin (Ch. 11).

Elevation of the core temperature can be corrected by the posterior hypothalamic nucleus, which sends axons to synapse on the preganglionic thoracolumbar lateral horn neurons of the spinal cord, directing blood flow into the skin and activating sweat glands.

Hypothalamic control of the sympathetic system diminishes with age. For this reason, the elderly are particularly prone to develop hypothermia in cold weather.

Hyperthermia is characteristic of fevers. Infectious agents (bacteria, viruses, parasites) cause tissue macrophages to liberate endogenous pyrogen, a protein that causes the hypothalamic ‘thermostat’ to be reset to a higher value. The chief mechanisms used to raise the body temperature to the new set point are cutaneous vasoconstriction and shivering.

Drinking

The chief center controlling the intake of water appears to be a ribbon of cells alongside the lateral nucleus known as the zona incerta (Figure 26.2). Stimulation of this region may produce excessive drinking; lesions may result in refusal to drink, with consequent severe dehydration.

Eating

Eating habits have obvious social and cultural components, causing dietary practice to vary widely among individuals and among communities. The hypothalamus provides a baseline for caloric and nutrient intake, in the form of interplay between the lateral and ventromedial nuclei. Together, they constitute the appestat (appetite set point). Stimulation of a lateral hypothalamic feeding center causes a cat or rat to eat excessively, whereas destruction of this center results in refusal to eat. Conversely, stimulation of a ventromedial satiety center inhibits the urge to eat, and bilateral ventromedial lesions result in persistent overeating and gross obesity. The satiety center is normally very sensitive to glucose levels in the blood. Of interest here is that serotonin is capable of altering the appetite set point, by inhibiting the lateral nucleus. Anorexics tend to have a raised level of serotonin production, and bulimics a reduced level.

Hypothalamic response to psychological stress: gender matters

It has long been known that the characteristic male response to psychological stress is fight-or-flight. Corticotropin RH released by the paraventricular nucleus (and fortified by vasopressin co-release) leads to adrenocorticotropic hormone (ACTH) release by the adenohypophysis. ACTH activates release of cortisol from the adrenal cortex. Cortisol in turn activates energy stores throughout the body.

Historically, it transpires that in laboratory analyses of the stress response, the great majority of human subjects tested have been men. Stress tests carried out on women by Taylor et al. (2000) demonstrated that their response to stressful situations was characterized by ‘tend-and-befriend’. ‘Tend’ translates as protecting offspring. ‘Befriend’ translates as affiliating with social groups with a view to protecting the future of the family group. A significant calming effect in stressed females is achieved by oxytocin released into the capillary bed of the neurohypophysis, in combination with estrogen. Together, they counteract sympathetic overactivity in stressful situations.

Recent fMRI studies in both genders reveals male activation of the lateral prefrontal cortex (a significant decision center in the context of approach or withdrawal, cf. Ch. 29); the predominant female activation was in the cingulate gyrus, the predominant cortical emotional control center (cf. Ch. 34).

Rage and fear

The lateral and ventromedial nuclei are concerned with mood as well as food. Cats that are overweight in consequence of ventromedial lesions tend to be highly aggressive. Conversely, animals rendered underweight by ventromedial stimulation tend to be unduly docile (see also the amygdala in Ch. 34).

Sleeping and waking

The tiny (0.26 mm³) suprachiasmatic nucleus embedded in the upper surface of the optic chiasm receives a direct input from the retina. It participates in setting the normal sleep–wake cycle, through connections with the pineal gland. For reasons unknown, this nucleus contains peptidergic (vasopressin) neurons which are twice as numerous in homosexual men than in heterosexuals of either sex.

Lesions of the posterior hypothalamic area may cause hypersomnolence or even coma. This area contains the tuberomammillary nucleus (Figure 26.1), housing hundreds of histaminergic neurons, which project widely to the gray matter of the brain and spinal cord. Some of the fibers run rostrally within the medial forebrain bundle, in company with aminergic fibers of brainstem origin. Histaminergic fibers destined for the cerebral cortex fan out below the genu of the corpus callosum. They branch within the superficial layers of the frontal cortex, and run back to supply the cortex of the parietal, occipital, and temporal lobes.

In animals, there is abundant physiological evidence in support of an arousal function for the histaminergic system. The tuberomammillary nucleus is normally activated during the awake state by the peptide orexin liberated by a small group of neurons in the lateral hypothalamus. Failure of orexin production appears to underly the disabling sleep attacks characteristic of narcolepsy (Ch. 30).

Sexual arousal

A subset of neurons (known as INAH₃) within the medial part of the preoptic nucleus is more than twice as large in males than females. It is also rich in androgen receptors and activated by circulating testosterone. In females, estrogen-rich neurons are contained within the ventromedial nucleus. In laboratory animals, electrical stimulation of these nuclei elicits appropriate sexual responses.

Memory

The mammillary bodies belong to a limbic, Papez circuit involving the fornix, which sends fibers to it, and the mammillothalamic tract which projects to the anterior nucleus of the thalamus. This circuit has a function in relation to memory (Ch. 34).