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Chapter 1: Hypothalamus: Structural Organization

Patrick Dougherty, Ph.D., Department of Anesthesiology and Pain Medicine, MD Anderson Cancer Center

Last Review 20 Oct 2020

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Figure 1.1 The homeostasis system

1.1 Anatomy of the Hypothalamus

The role of the hypothalamus in regulation of homeostasis is essential for survival and reproduction of the species. The importance of this function is underscored by the structural organization and connectivity of the hypothalamus as almost every major subdivision of the neuraxis communicates with the hypothalamus and is subject to its influence.

Landmarks that are visible on the ventral and medial (ventricular) surfaces of the brain define the boundaries of the hypothalamus. The rostral boundary visible on the ventral surface of the brain is formed by the optic chiasm while the mammillary bodies define the posterior boundary. Between these structures the oval prominence from the floor of the third ventricle is the tuber cinereum and evaginating from this is the median eminence which then tapers into the infundibular stalk which together form the inferior boundary of the hypothalamus. On the medial (ventricular) surface of the brain other structures contributing to the rostral boundary that are visible include the lamina terminalis and the anterior commisure. Also visible on the medial surface of the brain is the hypothalamic sulcus, which is the rostral continuation of the sulcus limitans that defines the superior boundary of the hypothalamus. Finally, the internal capsule that is only visible on coronal or horizontal sections of the brain forms the lateral boundary.

The hypothalamus is composed of three longitudinally oriented cell columns, or zones, that run the entire rostrocaudal length of the hypothalamus (Figure 1.2). These zones can be further subdivided into four nuclear groups, or regions, based on rostrocaudal position.

Figure 1.2 Boundaries of the hypothalamus

Zones. Immediately bordering the third ventricle, just inside of the ependymal cell lining, is a thin layer of cells that comprise the periventricular zone. This zone contains few distinct nuclei, but two that are very prominent are the arcuate nucleus and the paraventricular nucleus, which are involved in neuroendocrine and autonomic regulation. Immediately adjacent to the periventricular zone is the medial zone, which is comprised of several cytoarchitectonically distinct nuclei that are listed below. Nuclei in the medial zone are especially involved in the regulation of the autonomic nervous system as well as involved in regulation of the neuroendocrine system. Finally, the lateral zone, has few nuclei or clear landmarks, but contains important fiber pathways such as the median forebrain bundle. Demarcated by the fornix, the lateral zone is involved in regulation of the autonomic nervous system.

Figure 1.3 Hypothalamic zones

Regions. Each of the zones described above are further subdivided into regions based on rostrocaudal landmarks (Figure 1.4). The anterior region runs from the lamina terminalis to the caudal aspect of the optic chiasm. The portion of the anterior region that is rostral to the optic chiasm is often also referred to as the preoptic region, however this distinction is now less emphasized. The next region that is identified when proceeding caudally is the tuberal region. The margins of this region include the areas that are above and including the tuber cinereum. Finally, the posterior region is defined by the area above and including the mammillary bodies.

Figure 1.4 Regions of the hypothalamus

Nuclei. There are eleven major nuclei in the hypothalamus (Figure 1.5). The functions of many of these will be covered in further detail in later sections. However, a brief note on the organization of these can be useful. The nuclei can be grouped based on their locations in the hypothalamic zones and regions. Starting medially, the paraventricular nucleus is located in the periventricular zone and runs rostrocaudally through the anterior into the tuberal region. The arcuate nucleus also has a portion located in the periventricular zone though it also extends laterally into the medial zone. This nucleus sits in the floor of the tuberal region of the hypothalamus. Both of these nuclei, along with the supraoptic nucleus, located just above the optic chiasm in the anterior region of the medial zone extending laterally into the lateral zone, have key roles in neuroendocrine regulation. The paraventricular nucleus also has an important role in regulation of the autonomic nervous system. Additional nuclei found in the anterior region of the medial zone include the suprachiasmatic nucleus involved in circadian timing, the anterior nucleus involved in control of the autonomic nervous system, and the preoptic nucleus which also extends into the lateral zone and involved in control of the autonomic nervous system. Additional nuclei in the tuberal region of the medial zone include the dorsomedial and ventromedial nuclei, which are involved in control of behavior and of appetite, body weight and insulin secretion, respectively. Nuclei of the posterior region of the medial zone include the posterior nucleus, which is another autonomic nervous system control center, and the mammillary nuclei, which are involved in control of emotional expression and memory. Finally, the lateral tuberal complex in the tuberal region of the lateral zone is involved in control of appetite.

Figure 1.5 Nuclei of the hypothalamus

1.2 Circuitry of the Hypothalamus

The hypothalamus has the most complex circuitry of any brain region. Like other brain areas there are neural interconnections. But unlike other brain areas, there are also extensive non-neural communication pathways between the hypothalamus and other brain regions and the periphery.

Neural Connections. The most noteworthy (and complex) feature of the neural connections of the hypothalamus is that except for a few exceptions, they are extensively bi-directional.

Limbic Circuits. These pathways are essential for the normal expression and control of emotions, learning and reproductive behavior. The bi-directional (afferent and efferent) pathways include the medial forebrain bundle, the fornix, the stria terminalis and the ventral amygdalofugal pathway. The medial forebrain bundle interconnects basal forebrain structures including the septal nuclei and ventral striatum with hypothalamus and structures in the brainstem tegmentum including the locus ceruleus, the parabrachial nucleus, dorsal motor nucleus of the vagus. The fornix interconnects the hippocampal formation to the septal, preoptic and medial mammillary nuclei. The stria terminalis interconnects the amygdala to the septal region and the hypothalamus especially, the preoptic and ventromedial regions. Finally, the ventral amygdalofugal pathway interconnects the amygdala, especially the central amygdaloid nucleus with the septal region and the preoptic areas of the hypothalamus. In addition to these bi-directional pathways, there are also two unidirectional efferent limbic pathways from the hypothalamus. The mammillothalamic tract projects from the mammillary nuclei to the anterior nucleus of the thalamus. The anterior nucleus of the thalamus in turn projects to the cingulate cortex, which completes the circuit of Papez by projecting back onto the subiculum of the hippocampus. The circuit of Papez was the first circuit proposed to mediate emotions and still is considered one of the chief circuits of the limbic system. The mammillotegmental tract projects from the mammillary nuclei to the brainstem tegmentum and as far caudal as the lateral gray of the spinal cord.

Figure 1.6

Sensory and Autonomic Circuits. These pathways provide visceral and somatosensory input to the hypothalamus and output of the hypothalamus to control the autonomic nervous system. These pathways are especially important for the control of feeding, insulin release and reproduction. The bi-directional pathways in this circuitry include the medial forebrain bundle noted as part of limbic circuitry above, as well as the dorsal longitudinal fasciculus. Whereas the medial forebrain bundle runs laterally through the brainstem and hypothalamus, the dorsal longitudinal fasciculus runs medially through the periventricular and periaqueductal gray matter. Both pathways bring visceral and somatic input to the hypothalamus from the nucleus of the solitary tract, the parabrachial nuclei, the reticular formation and the periaqueductal gray. The medial forebrain bundle also brings monoaminergic fibers containing noradrenaline and serotonin into the hypothalamus from various brainstem nuclei including the raphe nuclei that have key roles in modulating neuroendocrine functions. More rostral projections of these monoaminergic fibers as well as peptide-containing efferent fibers that originate in the hypothalamus and join the medial forebrain bundle as it ascends into the orbital cortex, insula and frontal cortex are involved in the control of motivation. Descending efferent projections of the hypothalamus through these pathways terminate on parasympathetic nuclei of the brainstem such as the dorsal motor nucleus of the vagus. Unidirectional afferent input to the hypothalamus is derived from the spinohypothalamic tract and the retino-hypothalamic tract. The spinohypothalamic tract is a component of the anterolateral system of somatosensory fibers that also includes the spinothalamic tract and provides input concerning pain as well as input necessary for orgasm. The retino-hypothalamic tract provides input to the suprachiasmatic nucleus that is used to entrain circadian rhythms to the light-dark cycle. Finally, unidirectional efferent pathways from the hypothalamus include the hypothalamo-spinal tract, which projects onto brainstem and finally spinal preganglionic sympathetic and parasympathetic neurons in the spinal intermediolateral cell column, and a histamine projection to thalamus and cortex from the inferior lateral tuberal region that regulates the sleep-wake cycle.

Neuro-Humoral Connections. Unlike any other brain structure the hypothalamus both sends and receives information by way of the blood stream. There are two pathways that comprise the neuro-humoral connections of the hypothalamus.

The Pituitary. These pathways include the hypophyseal-portal system of blood vessels that surround the median eminence, the infundibulum and pituitary gland. The details of this system in neuroendocrine function will comprise the third chapter of this section.

Figure 1.7

Circumventricular Organs. There are several sites at which the blood brain barrier is highly permeable and at which specific transporters are present that allow passage of chemosensory stimuli from the blood into the brain. For example, the organum vasculosum of the lamina terminalis is the site at which pyrogens such as interleukin-1 and tumor necrosis factor bind to receptors that transport these molecules into the CNS and initiate the central synthesis of prostaglandins. These in turn act on the anterior nucleus to initiate a change in body temperature set-point resulting in fever. Passage of hormones through both the organum vasculosum and the median eminence is essential for normal feedback on the hypothalamus for neuroendocrine control. The area postrema is the location of the chemotoxic trigger zone at which emesis is induced by various toxins in the blood stream and that affect the hypothalamus to induce taste aversion. Passage of peptides through the subfornical organ are thought to participate in mechanisms of learning, while passage of signals through the pineal body affects circadian and circannual timing patterns.

1.3 Functions of the Hypothalamus

It has been highlighted several times in this section that the overarching function of the hypothalamus is the integration of body functions for the maintenance of homeostasis. The multiplicity of functions that are entailed in this level of integration should be intuitively obvious. The table below lists many of these functions and the nuclear groups that are most closely associated their execution.

Nucleus	Zone(s)	Region(s)	Functions
Paraventricular	Periventricular, Medial	Anterior,Tuberal	Fluid balance, milk let-down, parturition, autonomic & anterior pituitary control
Preoptic	Medial, Lateral	Anterior	Lateral anterior thermoregulation, sexual behavior
Anterior	Medial	Anterior	Lateral anterior thermoregulation, sexual behavior
Suprachiasmatic	Medial	Anterior	Biological rhythms
Supraoptic	Medial, Lateral	Anterior	Fluid balance, milk let-down, parturition
Dorsomedial	Medial	Tuberal	Emotion (rage)
Ventromedial	Medial	Tuberal	Appetite, body weight, insulin regulation
Arcuate	Periventricular, Medial	Tuberal	Control of anterior pituitary, feeding
Posterior	Medial	Posterior	Thermoregulation
Mammillary	Medial	Posterior	Emotion and short-term memory
Lateral Complex	Lateral	Tuberal	Appetite and body weight control

Thermoregulation, Neuroendocrine control, Feeding and Satiety. The details concerning thermoregulation, neuroendocrine function, and control of feeding will be the subject of later chapters.

Biological Timing and Rhythms. Circadian timing refers to the daily fluctuations that occur in hormone levels, body temperature, sleep-wake cycle, etc.; while circannual timing refers to fluctuations in function that occur on a yearly cycle. The chief hypothalamic nucleus involved in this process is the suprachiasmatic nucleus (SCN), which can be considered as the body’s master clock. The neurons in the SCN have an intrinsic rhythm of discharge activity that will re-cycle in the absence of light at 25 hour intervals. This activity is an intrinsic property of SCN neurons that can be maintained for days while the cells are maintained in culture. Input to the SCN from the retinohypothalamic tract resets and entrains the activity of SCN neurons to the daily 24 hour light-dark cycle by regulating the transcription of the light-sensitive clock, bmal, period (per) and cryptochrome (cry) genes. The retino-hypothalamic tract is a non-rod, non-cone dependent input to the SCN from a subset of retinal ganglion cells that are directly activated by light interacting with the pigment melanopsin. The SCN has projections into multiple hypothalamic nuclei that control the specific functions that show daily or annual rhythms. Thus, the SCN is considered as a master pacemaker that regulates the functions of multiple intra- and extra-hypothalamic slave oscillators. One extraordinary example of an extra-hypothalamic slave oscillator is the induction of fetal circadian timing from the mother. A specific, and perhaps more concrete example of this circuitry is illustrated by the regulation of melatonin secretion. Activation of the SCN by light results in increased input to the paraventricular nucleus, which in turn activates sympathetic pre-ganglionic neurons in the T1-T2 spinal intermediolateral cell column. These neurons inhibit the superior cervical ganglion which sends noradrenergic innervation into the pineal gland that inhibits the release of melatonin. With the onset of darkness, this inhibition is removed, and so melatonin secretion increases through a disinhibition process (Figure 1.8).

Figure 1.8

There are two major classes of disorders in circadian timing, phase shifting and entrainment failure, both of which manifest themselves as sleep disorders. The most common phase shift disorder is the rapid time-zone change syndrome, or jet lag, characterized by daytime sleepiness and nighttime insomnia. The molecular biology of this disorder is becoming well-defined. Circadian disruption is more sensitive to advances in local time than to delays. Circadian expression of mPer in SCN reacts rapidly to an advance in light onset whereas expression of mCry advances slowly, at a maximum rate of 3hours/cycle. It is only when the expression of both genes resume their baseline parallel expression that the behavioral and light:dark cycles become re-aligned. In contrast, mPer and mCry expression cycles react rapidly and in parallel with a delay in light cycle, such that a complete reset is achieved within one cycle. A second type of phase shift disorder is delayed sleep phase syndrome commonly seen in adolescents and possibly linked to an endocrine-mediated desensitization of SCN pacemakers to phase-advancing stimuli. Finally, advanced sleep phase syndrome, characterized by onset of sleep in the early evening followed by very early pre-dawn awakening is commonly observed in the elderly and is associated with a missense mutation in mPer2. Entrainment failure is often, though not always, observed in the blind. It is important to remember that the retino-hypothalamic tract has nothing to do with vision and so can be preserved in the blind, and may also be absent in those with vision.

It has become increasingly evident that circadian timing can have tremendous impact on the susceptibility to disease as well as conversely, to the optimal timing of curative therapy (Figure 1.9). Chronomorbidity refers to the observation that certain disorders characteristically show peak prevalence at particular times of the day, whereas Chronotherapeutics is the application of therapies at the time of day when their effects can be expected to have the greatest impact. The best current example of effective chronotherapeutics is that treatment of seasonal affective disorder (a form of entrainment failure) is successfully treated with bright light therapy only when applied during the morning hours.

Figure 1.9

1.4 Summary

The hypothalamus is the key brain site for integration of multiple biologic systems to maintain homeostasis. Neurons in the hypothalamus discharge in relation to multiple physiologic indices and change discharge rate with changes in these indices, thus establishing set points. The three major systems controlled by the hypothalamus for maintenance of homeostasis are the autonomic nervous system, the neuroendocrine system, and the limbic system.

The hypothalamus has well defined anatomical boundaries. Different regions of the hypothalamus are especially associated with the control of specific physiological subsystems.

The broad scope of brain regions affected by the hypothalamus is reflected by a very widespread extent of connectivity of the hypothalamus to other brain areas and by unique neuro-humoral communication pathways.

One key function of the hypothalamus is regulation of body functions in concert with the daily light:dark cycle. Intrinsic timing mechanisms of neurons in the suprachiasmatic nucleus controlled by the expression of the light sensitive clock, bmal, per, and cry genes establish the master pacemaker of the body. The activity of these cells is set in phase to light by inputs from a special subset of non-rod, non-cone dependent melanopsin-containing retinal ganglion cells via the retino-hypothalamic tract.

 

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