Hypothalamus

The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Different nuclei within the hypothalamus play roles in hormone regulation and secretion, autonomic regulation, thermoregulation, food and water intake, sleep and circadian rhythms, memory, and emotional behavior. The hypothalamus has both neural and circulatory connections with the pituitary gland. Abnormalities in the hypothalamus can lead to a wide range of clinical conditions.

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Development

The hypothalamus is a collection of various nuclei within the center of the brain that develops early during embryologic life.

Neural tube

The 1st step is development of the neural tube.

  • Develops from ectoderm 
  • Trilaminar embryo invaginates to form the neural fold → neural tube (closed by 6 weeks)
  • Neural tube becomes the CNS.
Early embryonic development of the nervous system

Early embryonic development of the nervous system

Image: “The neuroectoderm begins to fold inward to form the neural groove. As the two sides of the neural groove converge, they form the neural tube, which lies beneath the ectoderm.” by OpenStax College. License: CC BY 4.0

Primary and secondary neural vesicles

The neural tube develops 3 “bulges” known as the primary vesicles:

  • Prosencephalon (forebrain) → splits into 2 secondary vesicles:
    • Telencephalon → cerebrum
    • Diencephalon goes on to form:
      • Thalamus
      • Hypothalamus
      • Epithalamus (includes the pineal gland)
      • Subthalamus
  • Mesencephalon (midbrain, no secondary vesicles) → midbrain
  • Rhombencephalon (hindbrain) → splits into 2 secondary vesicles:
    • Metencephalon:
      • Pons
      • Cerebellum
    • Myelencephalon → medulla oblongata
Neural tube development

Neural tube development:
Primary and secondary vesicle formation

Image: “The embryonic brain develops complexity through enlargements of the neural tube called vesicles” by OpenStax College. License: CC BY 4.0

Gross Anatomy

Location

  • Located in the center of the brain
  • Just superior to the brain stem
  • Forms part of the walls and floor of the 3rd ventricle
  • Symmetrical; has right and left halves
hypothalamus within the brain

Location of the hypothalamus within the brain

Image: “The cerebrum is a large component of the CNS in humans, and the most obvious aspect of it is the folded surface called the cerebral cortex” by OpenStax College. License: CC BY 4.0

Boundaries

Table: Boundaries of the hypothalamus
BoundaryStructures
Superior
  • Thalamus
  • Floor of the 3rd ventricle
Anterior
  • Anterior commissure
  • Lamina terminalis
LateralCerebral hemispheres
MedialMedial 3rd ventricle
Posterior
  • Posterior commissure
  • Aqueduct of Sylvius
Inferior
  • Optic chiasm
  • Pituitary (hypophysial) stalk and gland
  • Brain stem

Parasagittal zones

Each ½ of the hypothalamus contain 3 primary zones or areas (from lateral to medial):

  • Lateral hypothalamic area: diffuse fiber systems
  • Medial hypothalamic area: contains the defined nuclei
  • Periventricular gray zone: immediately adjacent to the 3rd ventricle

Rostrocaudal levels

The hypothalamus can also be divided into 4 primary levels, moving from anterior (rostral) to posterior (caudal). These levels describe the locations of different functional nuclei within the hypothalamus (all of which are in the medial hypothalamic area). The levels include:

  1. Preoptic: found between the optic chiasm and the anterior commissure:
    • Lateral preoptic area
    • Medial preoptic area
  2. Supraoptic: anteriormost level behind the preoptic area:
    • Paraventricular nucleus
    • Anterior nucleus
    • Supraoptic nucleus
    • Suprachiasmatic nucleus
  3. Tuberal: between the supraoptic and mammillary levels:
    • Lateral hypothalamus
    • Dorsomedial nucleus
    • Ventromedial nucleus
    • Arcuate nucleus
  4. Mammillary: posteriormost (caudal) level:
    • Posterior nucleus
    • Mammillary bodies
Sagittal cut of diencephalon with hypothalamic nuclei and areas highlighted

Sagittal diagram of the hypothalamus and pituitary gland

Image by Lecturio.

Neurovasculature

The hypothalamus is a major coordinating center within the body. It receives information and can exert its effects via nerves, blood, and CSF.

Afferent nerve connections of the hypothalamus

The hypothalamus gets afferent input from:

  • Somatic nerves
  • Visceral nerves 
  • Visual/optic nerves 
  • Olfactory nerves
  • Cerebral cortex
  • Hippocampus (via the fornix)
  • Amygdala (via the stria terminalis)
  • Thalamus
  • Other nuclei within the hypothalamus

Efferent nerve connections of the hypothalamus

The hypothalamus sends efferent signals to:

  • Descending fibers in the brain stem and spinal cord → affect peripheral autonomic nervous system:
    • Vagus nerve
    • Sympathetic preganglionic neurons
  • Mammillothalamic tract: mammillary body → thalamus
  • Mammillotegmental tract: mammillary body → tegmentum of the midbrain (brain stem)
  • Limbic system

Connections with the pituitary gland

The hypothalamus is the primary regulator of the pituitary. The hypothalamus is therefore key in converting and integrating nerve signals with endocrine signals. The hypothalamus is connected to the pituitary in 2 ways: via nerve fibers and via the circulation.

Nerve fiber connections: the hypothalamohypophysial tract

  • Neurons in the paraventricular and supraoptic nuclei have direct projections that end in the posterior pituitary.
  • Secretions include:
    • Paraventricular nuclei: primarily produce oxytocin (stimulate uterine contractions in labor and milk release during lactation)
    • Supraoptic nuclei: primarily produce antidiuretic hormone (ADH; a vasoconstrictor that stimulates ↑ absorption of water from the renal tubules)
Diagram of the nervous connections

Diagram of the nervous connections between the hypothalamus and the posterior pituitary gland:

ADH: antidiuretic hormone
OT: oxytocin
Image: “Neurosecretory cells in the hypothalamus release oxytocin (OT) or ADH into the posterior lobe of the pituitary gland” by OpenStax College. License: CC BY 4.0, edited by Lecturio.

Bloodstream connections: the hypothalamohypophysial portal system

  • Formed from branches off the internal carotid arteries
  • Arteries travel through the median eminence (the pituitary “stalk”) → capillaries
  • Capillaries surround cells within the anterior lobe of the pituitary.
  • Neurosecretory cells in the medial zone of the hypothalamus have projections to the median eminence and secrete hormones into the portal system:
    • Releasing hormones:
      • Corticotropin-releasing hormone (CRH)
      • Thyrotropin-releasing hormone (TRH)
      • Gonadotropin-releasing hormone (GnRH)
      • Growth hormone–releasing hormone (GHRH)
    • Release-inhibiting hormones:
      • Somatostatin
      • Dopamine
Diagram of the hypothalamohypophysial portal system

Diagram of the hypothalamohypophysial portal system connecting the hypothalamus and the anterior pituitary

Image: “The hypothalamus produces separate hormones that stimulate or inhibit hormone production in the anterior pituitary” by OpenStax College. License: CC BY 4.0, edited by Lecturio.

Vasculature

Arterial supply:

The hypothalamus is supplied by the circle of Willis:

  • Anterior cerebral artery → anteromedial branches
  • Posterior communicating artery → posteromedial branches
  • Posterior cerebral artery → thalamoperforating branches
Circle_of_Willis

The circle of Willis: The anterior cerebral artery, posterior communicating artery, and posterior cerebral artery supply blood to the hypothalamus.

Image: “Circle of Willis” by OpenStax. License: CC BY 4.0

Venous drainage:

  • Circle of intercavernous sinuses
  • Hypothalamohypophysial portal system

Functions

Overview

The hypothalamus is a sensory and motor integration center and is a primary regulator of the endocrine and autonomic nervous systems. The hypothalamus plays a major role in:

  • Hormone regulation and secretion
  • Autonomic effects (e.g., HR, blood pressure, GI secretions and motility, etc.)
  • Thermoregulation
  • Food and water intake
  • Sleep and circadian rhythms
  • Memory
  • Emotional behavior

Preoptic level

The preoptic area contains:

  • Lateral preoptic area: a continuation of the lateral hypothalamic nuclei
  • Medial preoptic area:
    • Associated with sexual arousal and sexual dimorphism
    • Produces/secretes GnRH → released into the hypothalamohypophysial portal system
    • Involved in thermoregulation
    • Lesions in this region are associated with: 
      • Loss of control of sexual behavior
      • Amenorrhea
      • Impotence

Supraoptic level

The supraoptic level contains several important nuclei including (from superior to inferior):

  • Paraventricular nucleus: 
    • Medial division: synthesizes and secretes a number of hormones that regulate the pituitary gland
      • CRH 
      • TRH
      • GHRH
      • Somatostatin (inhibits growth hormone and thyroid-stimulating hormone (TSH) release)
      • Dopamine (inhibits prolactin secretion)
    • Intermediate division: synthesizes hormones that are released from the posterior pituitary gland
      • Oxytocin (primary secretion)
      • ADH produced in small amounts
    • Lateral division: has some direct projections into the vagus nerve
  • Anterior nucleus: 
    • A caudal continuation of the medial preoptic area
    • Involved in thermoregulation (cooling) and sleep
    • Lesions in this region may lead to hyperthermia.
  • Supraoptic nucleus:
    • Has direct projections to the posterior pituitary
    • Produces:
      • ADH (primarily)
      • Oxytocin (smaller amounts)
  • Suprachiasmatic nucleus: 
    • Located just above the optic chiasm
    • Gets direct input from the retina
    • A “master biologic clock”

Tuberal level

The tuberal level contains:

  • Lateral hypothalamic nuclei:
    • Involved in:
      • Regulating appetite and satiety
      • Digestive function
      • Sleep
      • Pain perception
      • Blood pressure
    • Lesions here may lead to: 
      • Narcolepsy
      • Motility or functional GI disorders
      • Eating disorders (due to ↓↓ desire to eat)
  • Dorsomedial nucleus:
    • Involved in:
      • Physiologic circadian rhythms (e.g., eating and drinking, energy consumption)
      • Ingestive behavior
      • Cardiovascular response to stress
    • Lesions here may lead to: overeating (hyperphagia), obesity
  • Ventromedial nucleus:
    • Involved in:
      • Appetite, satiety, and energy regulation
      • Fear response via afferent input from the amygdala
    • Lesions here may lead to: hyperphagia, obesity
  • Arcuate nucleus: 
    • A primary regulator of the anterior pituitary gland via the hypothalamohypophysial portal system
    • Secretes:
      • GnRH
      • Dopamine → regulates prolactin secretion
      • Neuropeptide Y → regulates appetite and body weight
    • Lesions here may lead to: galactorrhea, hyperphagia

Mammillary level

The mammillary level includes:

  • Posterior nucleus: 
    • Involved in thermoregulation (heating the body)
    • Lesion here may lead to: hypothermia
  • Mammillary bodies: 
    • Involved in regulating emotions and recollective memory
    • Lesion here may lead to:
      • Memory deficits
      • Pathogenesis of Wernicke encephalopathy

Clinical Relevance

  • Central diabetes insipidus (DI): condition in which the kidneys are unable to concentrate urine because of a lack of circulating ADH. These low levels of ADH are due to either decreased production within the hypothalamus or decreased release from the posterior pituitary gland. Presentation is with polyuria, nocturia, and polydipsia. Central and nephrogenic DI are differentiated based on measured ADH levels and response to the water deprivation test. Central DI is treated with desmopressin.
  • Functional hypothalamic amenorrhea: primary cause of secondary amenorrhea (cessation of menses). Functional hypothalamic amenorrhea results from the decreased pulsation of GnRH from the hypothalamus that occurs during times of severe physical or psychologic stress. The condition is most commonly seen in association with eating disorders or overexercise (common in female athletes). Management usually requires nutritional support and counseling.
  • Hyperthermia: may occur if there is a lesion (stroke or CNS damage) in the anterior nucleus of the hypothalamus, which is involved in thermoregulation, specifically, cooling the body down. Damage to this region prevents the body from being able to cool itself. 
  • Narcolepsy: occurs when the lateral hypothalamus is unable to secrete orexin, a substance that promotes wakefulness in many areas of the brain, allowing inappropriate sudden transitions to sleep, cataplexy, sleep paralysis, and hypnagogic hallucinations.
  • Hyperprolactinemia: elevated levels of prolactin in the blood. Although the most common cause of hyperprolactinemia is a prolactin-secreting pituitary adenoma, loss of inhibitory dopamine secretion by the hypothalamus can also be a cause. This condition can occur when dopaminergic neurons from the hypothalamus are damaged or if the infundibulum is transected during suprasellar surgery. Presentations can include galactorrhea (milky discharge), oligomenorrhea, and erectile dysfunction.

References

  1. Castro, A., Merchut, M., Neafsey, E., Wurster R. (2002). Neuroscience: An Outline Approach. St. Louis: Mosby, pp. 369–375.
  2. Saladin, K.S., Miller, L. (2004). Anatomy and Physiology, 3rd ed., pp. 530–531. 
  3. Bear, M. (2021). Neuroanatomy, hypothalamus. StatPearls. Retrieved August 10, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/901/ 
  4. Kibble, J.D., Halsey, C.R. (2015). Neurophysiology. Chapter 2 of Medical Physiology: The Big Picture. New York: McGraw-Hill Education. https://accessmedicine.mhmedical.com/content.aspx?bookid=1291&sectionid=75575843 
  5. Barrett, K.E., Barman, S.M., Brooks, H.L., Yuan, J.X. (2019). Hypothalamic regulation of hormonal functions. Chapter 17 of Ganong’s Review of Medical Physiology, 26th ed. New York: McGraw-Hill Education. Retrieved August 10, 2021, from https://accessmedicine.mhmedical.com/content.aspx?bookid=2525&sectionid=204292033

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