Hypothalamus

Periventricular zone

The periventricular zone is a very thin region of the hypothalamus that lies next to the midline, medial to the medial zone and borders the third ventricle. It mainly contains the periventricular nucleus. The suprachiasmatic and arcuate nuclei are also sometimes classified as being part of this zone, however, these will be discussed as part of the medial zone. The majority of neurons in this area synthesize releasing hormones that modulate the release of several anterior pituitary hormones.

Medial zone

The medial zone of the hypothalamus contains several individual nuclei and is subdivided into four regions from anterior to posterior: the preoptic, the supraoptic (chiasmatic), tuberal, and the mammillary regions.

The preoptic area is located anterior to the optic chiasm and extends into the periventricular, medial, and lateral zones. It contains the periventricular nucleus within the periventricular zone, the medial preoptic nucleus in the medial zone and the lateral preoptic nucleus which lies in the lateral zone. The medial preoptic nucleus is the principal nucleus of this region. This nucleus is primarily involved in the regulation of gonadotropic hormones but has also been implicated in sexual behavior and the control of sleep-wake cycles.

The supraoptic region lies internal to the region of the optic chiasm and contains four nuclei: the supraoptic, paraventricular, suprachiasmatic, and anterior hypothalamic nuclei. The supraoptic and paraventricular nuclei contain neurons that synthesize oxytocin and antidiuretic hormone (ADH, vasopressin) which are transmitted via the supraopticohypophysial tract to the posterior pituitary and subsequently released into circulation to control water balance. The suprachiasmatic nucleus is often called the “master clock” of the body as it is responsible for the regulation of circadian rhythms through its connections with the retina, pineal gland and other hypothalamic nuclei. The anterior hypothalamic nucleus sits just posterior to the preoptic area and its primary role is in the maintenance of body temperature.

The tuberal region of the medial zone lies internal to the tuber cinereum and has three nuclei: the ventromedial, dorsomedial, and arcuate nuclei. The ventromedial nucleus is one of the largest nuclei of the hypothalamus. It is mainly involved in feeding behavior and is said to be a “satiety center”. The dorsomedial nucleus, which sits just posterior to the ventromedial nucleus, integrates feeding behavior with circadian activity and has been implicated in aggressive emotional behavior. The arcuate nucleus, on the other hand, contains neurons that produce releasing hormones which are transmitted to the anterior pituitary via the tuberoinfundibular tract and hypophyseal portal system. It plays a role in the regulation of appetite, cardiovascular system, sexual behavior, prolactin release and the monitoring of adipose tissue fat.

The mammillary region is the most posterior of the four medial zone regions. This region lies internal to the mammillary bodies and contains the medial, intermediate, and lateral mammillary nuclei, which collectively form the mammillary complex, the tuberomammillary nucleus and the posterior hypothalamic nucleus. The large medial mammillary nucleus is the main point of termination for axons of the postcommissural fornix, which arise from the hippocampal complex and relays input related to emotions. This nucleus also connects to the anterior nucleus of the dorsal thalamus via the mammillothalamic tract and forms an important part of the limbic system. The smaller intermediate and lateral mammillary nuclei have connections to the midbrain reticular formation. The mammillary nuclei play a role in the processing of immediate memory or short-term memory. The tuberomammillary nucleus contains histaminergic neurons and is involved in the promotion of wakefulness. The posterior hypothalamic nucleus is closely related to the midbrain periaqueductal gray and as such plays a similar role as this midbrain region in the modulation of emotion, cardiovascular function and pain modulation. The posterior hypothalamic nucleus also acts as a “thermostat” regulating body temperature.

Lateral zone

The lateral zone contains the lateral preoptic nucleus and lateral hypothalamic area. The lateral preoptic nucleus is said to play a role in promoting sleep via connections with the reticular activating system and the orexin neuronal system. The lateral hypothalamic area is formed by a diffuse group of neurons. Within the anterior aspect of this area are smaller condensations of neuronal cells which form the lateral hypothalamic nucleus and the lateral tuberal nuclei. The lateral hypothalamic nucleus serves as a “feeding center” and is involved in modulating feeding behavior. The neurons of the tuberal nuclei, on the other hand, either project to the tuberoinfundibular tract, and are thus involved in the transmission of releasing hormones to the hypophyseal portal system, or may play a role in the regulation of motor activity through connections with the cerebellum.

The lateral zone also contains a large bundle of longitudinally oriented fibers called the medial forebrain bundle. This neural pathway connects the hypothalamus with rostral regions such as the septal nuclei and with brainstem areas, such as the ventral tegmental area and reticular formation.

Afferent hypothalamic pathways

The hypothalamus receives the majority of its neural inputs (afferent tracts) mainly from various structures of the limbic system, as well as the brainstem and spinal cord. These afferent fibers mostly form reciprocal connections and arise from various sites including the orbitofrontal cortex, infralimbic and cingulate cortex, septal nuclei, thalamus, hippocampus, amygdala, brainstem tegmentum and spinal cord. Inputs from the limbic system carry information relating to the function of the hypothalamus in modulating autonomic and somatic aspects of emotional states. Afferent fibers from the brainstem and spinal cord on the other hand convey ascending visceral, gustatory and somatic sensory information. The principal afferent tracts of the hypothalamus are the fornix, medial forebrain bundle, stria terminalis (amygdalohypothalamic tract) and ventral amygdalofugal tracts.

• The fornix is the largest and most prominent single neural input to the hypothalamus. It is a myelinated tract originating from two regions of the hippocampal complex (subiculum and hippocampus) of the limbic system. Close to the anterior commissure, the fornix gives rise to a smaller precommissural bundle from the hippocampus and a larger postcommissural bundle from the subiculum. The precommissural bundle projects fibers to the septal and preoptic nuclei of the anterior regions of the hypothalamus, while fibers of the postcommissural bundle typically terminates in the medial mammillary nucleus posteriorly.
• The medial forebrain bundle consist of diffuse group of fibers that typically course longitudinally through the lateral hypothalamic zone. It contains ascending and descending fibers that connect autonomic and limbic structures of the forebrain with the hypothalamus and brainstem.
• The stria terminalis, also called the amygdalohypothalamic fibers, is a long, curved bundle of nerve fibers that follows the arch of caudate nucleus. It relays olfactory information thought to be related to reproductive behavior as well as autonomic and neuroendocrine information from the amygdaloid nuclear complex to the medial preoptic area and the anterior nucleus of the hypothalamus.
• The ventral amygdalofugal tracts arise from the basolateral portion of the amygdaloid nuclear complex and terminate mainly in the lateral hypothalamic zone and the septal and preoptic nuclei to influence the activities of the autonomic nervous system.

Additional afferent tracts of the hypothalamus include the mammillary peduncle, thalamohypothalamic tract, corticohypothalamic, retinohypothalamic and the spinohypothalamic fibers.

• The mammillary peduncle arises from the midbrain reticular formation and terminates in the lateral mammillary nucleus. This tract relays sensory input from sensory pathways.
• As its name suggests, the thalamohypothalamic tract conveys fibers from the thalamus (dorsomedial nucleus and paraventricular nuclei) to the lateral preoptic area of the hypothalamus.
• The corticohypothalamic tract arises from the prefrontal cortex as the only direct neocortical connection to the hypothalamus, and terminates in the lateral hypothalamic area.
• The retinohypothalamic tract originates from the retina and ends in the suprachiasmatic nucleus. This tract plays a role in the control of circadian rhythms.
• The spinohypothalamic fibers arise from the spinal cord and relay nociceptive information to the autonomic control centers of the hypothalamus. It is involved in neuroendocrine and cardiovascular responses to painful stimuli.

Efferent hypothalamic pathways

The hypothalamus projects efferent fibers from its subdivisions to various areas throughout the entire nervous system. The majority of these efferent pathways are reciprocal input to structures that project afferent fibers to the hypothalamus. Generally, the hypothalamus sends outputs to the limbic system, autonomic and somatic motor neurons, as well as the pituitary gland via neural and neurovascular connections. These outputs are largely transmitted by way of the same fiber bundles that conveyed inputs. For descriptive purposes, the hypothalamic efferent fibers are grouped into two: ascending and descending projections.

Ascending projections are those that terminate in forebrain structures and primarily include the mammillary fasciculus (mammillothalamic tract), hypothalamothalamic fibers, hypothalamoamygdaloid fibers and cerebellohypothalamic fibers.

• The mammillary fasciculus arises from the medial mammillary nucleus. This bundle bifurcates along its course into the mammillothalamic tract which terminates in the anterior nucleus of the thalamus and the mammillotegmental tract which projects to the tegmental nuclei of the midbrain reticular formation. The mammillotegmental tract reciprocates the mammillary peduncle.
• The hypothalamothalamic fibers originate primarily from the lateral preoptic area and terminate in the dorsomedial nucleus of the thalamus.
• The hypothalamoamygdaloid fibers arise from several hypothalamic nuclei and terminate mainly in the corticomedial nuclei of the amygdaloid complex.
• The cerebellohypothalamic fibers project from the cerebellar nuclei to various hypothalamic nuclei, integrating the somatomotor with the visceromotor centers.

Descending projections are those that project to brainstem and spinal cord targets. They consist of five main fiber tracts which are the hypothalamospinal tract, hypothalamomedullary fibers, posterior (dorsal) longitudinal fasciculus, mammillotegmental tract and hypothalamocerebellar fibers.

• The hypothalamospinal fibers originate primarily from the paraventricular nucleus of the hypothalamus. They course through the periaqueductal gray and adjacent reticular formation of the brainstem to terminate in the intermediolateral cell column of the spinal cord. Here, they synapse directly with preganglionic sympathetic and parasympathetic nuclei neurons.
• The hypothalamomedullary fibers also arise from the paraventricular nucleus and project to several nuclei including the solitary nucleus, dorsal vagal motor nucleus, nucleus ambiguus, and others within the anterolateral medulla. Together with the hypothalamospinal fibers, the hypothalamomedullary fibers form a direct connection between the hypothalamus and autonomic nuclei of the medulla and spinal cord.
• The posterior (dorsal) longitudinal fasciculus arises from nuclei within the medial hypothalamic zone and projects fibers to the brainstem (periaqueductal gray, reticular formation), and spinal cord autonomic nuclei. This tract is important in the control of chewing, swallowing, and shivering by the hypothalamus.
• The mammillotegmental tract originates from the medial mammillary nucleus and forms the descending branch of the mammillary fasciculus. It projects onto neurons of the posterior (dorsal) and anterior (ventral) tegmental nuclei within the periaqueductal gray.
• The hypothalamocerebellar fibers serve as a connection between the principal visceromotor center of the forebrain and the principal hindbrain center for the regulation and coordination of somatic motor activity.

Hypothalamic connections to the pituitary gland

The hypothalamus controls both lobes of the pituitary gland via a vascular link with the anterior pituitary (adenohypophysis) and a neural projection to the posterior pituitary (neurohypophysis). There are two main efferent tracts that connect the hypothalamus to the pituitary gland:

• The hypothalamohypophyseal tract (supraopticohypophyseal and paraventriculohypophyseal tracts) is a short tract composed of axons which carry the hormones antidiuretic hormone (ADH, or vasopressin) and oxytocin to the posterior pituitary. Each of these hormones are synthesized by a specific population of large (magnocellular) neurosecretory cells of the supraoptic and paraventricular nuclei. Stimulation of these neurosecretory cells causes release of these hormones at their teminals into the adjacent capillary plexus in the posterior pituitary and into general circulation.
• The tuberohypophyseal (tuberoinfundibular) tract is a collection of axons mainly from small neurons in the arcuate and periventricular nuclei that convey hypothalamic releasing and inhibiting hormones to the infundibular stalk and ultimately to the anterior pituitary. From the infundibular stalk, these hormones are carried to the adenohypophysis via a vascular connection called the hypophyseal portal system to modulate the production and release of anterior pituitary hormones. The releasing hormones of the hypothalamus include the thyrotropin-releasing hormone, corticotropin-releasing hormone, gonadotropin-releasing hormone, prolactin-releasing hormone, growth hormone-releasing hormone, and growth hormone-inhibiting hormone (somatostatin).

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Control of the pituitary gland

The hypothalamus modulates the release of pituitary hormones via two groups of neurons: the parvocellular (small) neurons and the magnocellular (large) neurons. The parvocellular neurons form the tuberoinfundibular tract which arises from the arcuate and periventricular nuclei and projects to the infundibular capillary bed, transporting hypothalamic releasing and inhibiting hormones to the adenohypophysis via the hypophyseal portal vessels. These hormones modulate the release of thyrothropin, growth hormone, prolactin, follicle stimulating hormone (FSH) or luteinizing hormone (LH), and adrenocorticotropic hormone (ACTH). The magnocellular neurons form the supraopticohypophyseal tract, which arises from the supraoptic and paraventricular nuclei and carries ADH and oxytocin to the posterior pituitary.

Regulation of body temperature

The preoptic region and anterior hypothalamic nuclei contain temperature-sensitive (thermo-sensitive) neurons that detect and respond to slight temperature changes in the core temperature of the body, with input from peripheral thermo-sensitive neurons located in the skin. Both nuclei are believed to initiate heat loss via mechanisms such as increasing blood flow into the skin, activating sweat glands and inhibiting heat-generating mechanisms by the posterior hypothalamus in order to maintain body temperature during temperature elevations.

The posterior hypothalamus on the other hand promotes heat conservation and heat production mechanisms such as piloerection (goose bumps) and the vasoconstriction of cutaneous vessels, thyroid hormone mediated increase in metabolism and shivering.

Control of food intake

The arcuate nucleus of the hypothalamus is involved in the integration of feeding related input from both the lateral and ventromedial nuclei, which together provide an appetite set point, a baseline for food intake. Animal experiments, involving either simulation or destruction of both nuclei in the past, led to the designation of the lateral hypothalamic nucleus as the ‘feeding center’ and the ventromedial nucleus as the ‘satiety center’. However, it is now known that the paraventricular nucleus is also involved in the control of food intake. The arcuate nucleus also senses changes in glucose levels as well as other secreted peptides such as ghrelin from gastric sections that stimulates food intake and leptin from adipose tissues that suppresses feeding. The precise mechanisms involved in the regulation of food intake are still under investigation.

Control of fluid intake

The medial preoptic nucleus is the main center responsible for controlling the intake of water. It does this by integrating input from peripheral receptors on parameters such as blood volume and pressure, and levels of angiotensin hormone. This information is then relayed to the cerebral cortex, which in turn initiates responses such as sensation of thirst to correct any deficits.

Control of the autonomic nervous system

The hypothalamus receives visceral sensory input from the ascending sensory system as well as information related to emotions from the limbic system. Stimulation of the anterior (preoptic and anterior nucleus) and medial hypothalamus produces parasympathetic effects such as slowing of the heart, constriction of the pupil and salivary secretion. On the other hand, stimulation of the posterior and lateral hypothalamus results in sympathetic effects such as increased in heart rate and blood pressure, pupillary dilation. Nerve fibers from both regions project to autonomic nuclei within the brainstem and spinal cord to maintain homeostasis.

Control of stress, emotional expression and aggression

The paraventricular nucleus of the hypothalamus receives inputs from various brainstem structures and from the limbic system in response to various forms of stress (psychological, physical, or physiologic) by initiating a restorative mechanism via the hypothalamus-pituitary-adrenal (HPA) axis. The paraventricular nucleus releases corticotropin-releasing hormone, which leads to the secretion of ACTH from the andenohypophysis and cortisol from the adrenal cortex, thus activating energy stores.

The limbic system receives, processes and relays emotional input to the hypothalamus. The hypothalamus through its connections with the autonomic nervous system initiates appropriate visceral responses such as changes in heart rate and blood pressure mediated by the sympathetic nervous system and associated changes in behavior. Aggressive behavior is associated with the stimulation of the lateral hypothalamus.

Control of sleep and waking

Another important function of the hypothalamus is the regulation of both arousal and sleep-wake cycles by the suprachiasmatic and tuberomammillary nuclei. The suprachiasmatic nucleus receives direct input from the retina and plays a role in establishing a normal sleep-wake cycle through its influence on endocrine, autonomic and behavioral functions, and connections with the pineal gland. The tuberomammillary nucleus, on the other hand, contains histaminergic neurons which project extensively to various gray matter regions of the brain and spinal cord and play an important role in arousal. A small group of neurons in the lateral hypothalamus release a peptide called orexin which activates the tuberomammillary nucleus in the wake state. Hypothalamic orexin production decreases at night and contributes to sleep promotion.

Control of sexual arousal

The anterior hypothalamus contains a group of neurons called the third interstitial nucleus. This nucleus lies within the medial part of the preoptic nucleus and has been implicated in sexual arousal. It exhibits sexual dimorphism and is about twice as large in males than in females. Neurons of this nucleus have abundant androgen receptors and are activated by testosterone in circulation. The ventromedial nucleus of the hypothalamus in females also contains estrogen-rich neurons and has been implicated in sexual responses.

Control of memory

The mammillary bodies, fornix, mammillothalamic tract and the anterior nucleus of the thalamus form a limbic (or Papez) circuit which is involved in memory. Additionally, input from the hippocampus, which is a region of learning and memory, plays a role in the influence of memories on emotion.

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