3. Structure of Hypothalamus

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Paper : 06 Animal Physiology Module : 18 Hypothalamic hormones

Development Team

Paper Coordinator: Prof. Rakesh Kumar Seth Department of Zoology, University of Delhi Principal Investigator: Prof. Neeta Sehgal

Department of Zoology, University of Delhi

Content Writer: Dr. Anju Jain¹, Dr. Varsha Baweja², Dr. Anna Senrung¹, 1Daulat Ram college, University of Delhi

2 Desh Bandhu College, University of Delhi

Content Reviewer: Prof. Neeta Sehgal

Department of Zoology, University of Delhi Co-Principal Investigator: Prof. D.K. Singh

Department of Zoology, University of Delhi

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Description of Module

Subject Name ZOOLOGY

Paper Name Zool 006 Animal Physiology Module Name/Title Neuro-endocrine Physiology Module Id M18 Hypothalamic Hormones

Keywords Hypothalamus, nuclei, neurosecretory cells, hormones

1. Learning Outcomes

After studying this module, you shall be able to:

 Know the structure of the hypothalamus

 Define hypothalamic hormones and their functions

 Understand the role of hypothalamus in the regulation of endocrine signaling system

2. Introduction

All vertebrate animals have many body systems (circulatory, respiratory, digestive, immune, excretory, endocrine, nervous, etc) working in coordination to maintain and sustain the individual organism. This coordination is regulated by the nervous and endocrine system through the release of neurotransmitters and hormones respectively. Further, these two systems are integrated by an eminent part of the brain called the Hypothalamus (Greek,

“under the thalamus") lying below the thalamus and above the pituitary gland forming the floor and ventrolateral wall of the third cerebral ventricle (Fig: 1). The hypothalamus stimulates endocrine signaling in response to the information received through neurons from all parts of the body via the production and release of neurohormones called the hypothalamic hormones. These neurohormones cascade to either the release or inhibition of pituitary hormones (a class of hormones pivotal to endocrine signaling in the body). This concept of neurohumoral relation between the hypothalamus and the pituitary gland is majorly attributed to the work of Geoffrey W Harris.

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Figure: 1. Hypothalamus-Pituitary Complex

Source: https://en.wikipedia.org/wiki/File:1806_The_Hypothalamus-Pituitary_Complex.jpg

3. Structure of Hypothalamus

3.1 Subdivisions and nuclei

The hypothalamus has faint regions with distinct nuclei regulating homeostatic functions of the body. Some of the major hypothalamic nuclei are – preoptic, anterior hypothalamic, paraventricular, dorsomedial, posterior, mammillary, ventromedial, arcuate, supraoptic, and suprachiasmatic (Fig: 2).

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Figure: 2. Nuclei of the Hypothalamus

Source: https://endocrinecourt2011b2c.wikispaces.com/Hypothalamus+Researcher+2

The hypothalamus though small in size (about the size of an almond) plays a crucial physiological role in mediating the endocrine, autonomic and behavioral functions. Its dorsal border is demarcated by the hypothalamic sulcus whereas, the ventral side is exposed extending from the optic chiasma to the mammillary bodies (Fig: 2 & 3). Three regions are differentiated on the ventral surface of the hypothalamus starting from the anterior limit of the optic chiasma to the posterior limit of the mammillary gland: (i) Supraoptic or anterior region corresponding to the optic level, (ii) tuberal or middle region corresponding to the region of the median eminence (= tuber cinereum), (iii) mammillary or posterior region corresponding to the level of the mammillary bodies (Fig: 4).

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Figure: 3. Diagram of hypothalamus showing hypothalamic sulcus Source: Authors

Figure: 4. Divisions of the hypothalamic ventral surface with some major nuclei.

Source: Authors

The supraoptic region is the most important division lying above the optic chiasma and holding three important nuclei – Supraoptic nucleus, paraventricular nucleus and

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suprachiasmatic nucleus. The supraoptic nucleus contains nervous cells (neurons) that produce an antidiuretic hormone (ADH). The paraventricular nucleus contains nervous cells (neurons) that produce oxytocin (predominantly) and corticotropin-releasing hormone (CRH). Suprachiasmatic nucleus is located above the optic chiasma and regulates circadian rhythms.

Tuberal region is divided into the medial and lateral part (lateral hypothalamic area, LHA) by a plane passing through the fornix. The median part holds two nuclei –ventromedial and arcuate nucleus. The ventromedial nucleus controls eating and is referred to as satiety center (bilateral lesions of the ventromedial nucleus leads to overeating). In contrast, bilateral lesions in the lateral hypothalamic area lead to anorexia and are referred to as feeding center.

The arcuate nucleus is also known as infundibular or periventricular nucleus seemingly holds neurons that regulate the endocrine functions of the anterior pituitary gland (adenohypophysis). Neurons with endocrine functions are also found in the nuclei of the preoptic region and other tuberal nuclei.

The mammillary region contains posterior hypothalamic and mammillary nuclei. The cells of the posterior hypothalamic nucleus seemingly appear to have an influence on thermoregulation. The mammillary nuclei though anatomically forms part of the hypothalamus, no correlation with autonomic and endocrine functions have been observed and are rather believe to influence memory.

3.2 Neurosecretory cells of hypothalamus

Neurosecretory cells of the hypothalamus are neuroendocrine cells (neurons) that receive neuronal input (neurotransmitters) from nerve cells from all parts of the CNS and transduce it into hormonal secretions which are released into the blood stream, whereby, bringing about neuroendocrine integration. More precisely, they produce prohormones in their cell bodies which are translated into active forms during axonal transport and stored at the axon terminals in vesicular granules until exocytosis occurs by depolarization of plasma membrane.

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Structurally they are like that of the typical neurons with dendrites, axons, and terminals but unlike that of the typical neuron, they lie adjacent to blood capillaries and release their products into the circulation (Fig: 5).

Figure: 5. Neurosecretory cell structure.

Source: Authors

Two well known neurosecretory cells (neurons) of the hypothalamus are magnocellular and parvocellular (Fig: 6). Magnocellular neurosecretory cells are large neuroendocrine cells with long axons that terminate into the posterior lobe of the pituitary gland (neurohypophysis). They are of two types: Oxytocin-producing and vasopressin-producing neurosecretory cells though some can produce both hormones. Parvocellular neurosecretory cells are much smaller neuroendocrine cells with shorter axons terminating at median eminence. They release their products, corticotropin-releasing hormone (CRH) and other hormones into the capillary network in the median eminence from where they are conveyed to the anteriorr lobe of the pituitary via the hypophyseal portal system (Fig: 7).

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Figure: 6. Neurosecretory cells in the hypothalamus. Source: Authors

Figure: 7. Schematic view of communication between the hypothalamus and adenohypophysis.

Source: Authors

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4. Hormones of Hypothalamus

The hormones produced from the hypothalamus (hypothalamic hormones) are:

 Thyrotropin-releasing hormone/factor (TRH/TRF)

 Corticotropin-releasing hormone/factor (CRH/CRF)

 Dopamine (DA)

 Growth-hormone-releasing hormone (GHRH)

 Gonadotropin-releasing hormone (GnRH)

 Gonadotropin-inhibitory hormone (GnIH)

 Somatostatin (SS)

 Oxytocin (OXY/OXT)

 Vasopressin (Antidiuretic hormone – ADH)

These hypothalamic hormones are produced by the cell bodies of the neurosecretory cells (neurons) which are unevenly distributed and aggregated to form the many nuclei of the hypothalamus (Fig: 2 & 8). The hormones once secreted are transported through the axon of the neurosecretory cells (neurons) to either the posterior lobe of the pituitary gland (neurohypophysis) which includes the hormones, oxytocin and vasopressin or to the median eminence which comprises the rest of the hypothalamic hormones. Oxytocin and vasopressin hormones are stored as neurosecretory granules in the posterior lobe of pituitary gland and extruded into the circulation when needed. The rest of the hypothalamic hormones are transported from the median eminence to the anterior lobe of the pituitary gland (adenohypophysis) where they regulate the release or inhibition of pituitary hormones.

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Figure: 8. Hypothalamus-Pituitary Complex. Source: Authors 4.1 Thyrotropin-releasing hormone or factor (TRH/TRF)

Figure: 9. Structural formula of thyrotropin-releasing hormone (TRH)

Source: https://en.wikipedia.org/wiki/Thyrotropin-releasing_hormone#/media/File:Thyrotropin- releasing_hormone.svg

TRH is also known as prolactin-releasing hormone (PRH) (Fig. 9). The hormone is produced by parvocellular neurosecretory cells of the paraventricular nucleus. It was first

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sequenced and synthesized by Roger Guillemin and Andrew V. Schally in 1969 and were awarded Nobel Prize in Medicine in 1977 for the same. The polypeptide precursor synthesized is a 242-amino acid which undergoes a series of enzymatic reactions leading to the production of the mature tripeptide TRH which probably regulates body temperature. The secreted TRH through the hypophyseal portal system reaches the anterior pituitary gland where it stimulates thyrotroph and lactotroph endocrine cells to unleash thyroid-stimulating hormone (TSH) and prolactin. TSH targets the thyroid gland to release thyroid hormone which controls metabolism, growth and development. Prolactin targets mammary glands for milk production.

4.2 Corticotropin-releasing hormone or factor (CRH/CRF)

Figure: 10. Corticotropin-releasing hormone, PDB rendering based on 1go9 Source: https://en.wikipedia.org/wiki/Corticotropin-

releasing_hormone#/media/File:PBB_Protein_CRH_image.jpg

CRH is a 41-amino acid polypeptide (Fig. 10) produced during stress by the parvocellular neurosecretory cells of the hypothalamic paraventricular nucleus. It was discovered first by Vale et al. (1981) in sheep. It is procure from 196-amino acid preprohormone. Reaches the anterior lobe of pituitary via the portal system and stimulates the corticotroph endocrine cells to secrete adrenocorticotropic hormone (ACTH). ACTH stimulates adrenal glands to release corticosteroids which helps to regulate metabolism and probably play a role in immune response. CRH production in the hypothalamus is stimulated when there is a decrease in the secretion of glucocorticoids from the adrenal cortex (Fig: 11).

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Figure: 11. Regulation of hypothalamic CRH production.

Source: Authors

4.3 Dopamine (Prolactin-inhibiting hormone)

Figure: 12. Dopamine structure

Source: https://en.wikipedia.org/wiki/Dopamine#/media/File:Dopamine.svg

Dopamine is an amine synthesized from 3,4-dihydroxyphenethylamine (L-DOPA) by the removal of carboxyl group. It was George Barger and James Ewens who first synthesized the hormone in 1910 (Fig. 12). It acts as a precursor for norepinephrine (noradrenaline) and epinephrine (adrenaline). It is produced by the neurosecretory cells of the hypothalamic arcuate nucleus. It inhibits the secretion of hormone prolactin and hence referred to sometimes as prolactin-inhibiting factor/hormone or prolactostatin. Disruption of dopamine secreting cells causes Parkinson's disease.

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4.4 Growth-hormone-releasing hormone (GHRH)

GHRH has two active forms: 44- and 40-amino acids. It is produced by the cells of the hypothalamic arcuate nucleus and release into the anterior lobe of pituitary gland via the hypophyseal portal system. In the anterior lobe of pituitary, it stimulates somatotroph endocrine cells to produce growth hormone (GH). GH regulates the metabolism of proteins, lipids, carbohydrates and indirectly promotes growth. The major target organs of GH are the liver and the adipose tissue.

4.5 Gonadotropin-releasing hormone (GnRH)

Figure: 13. The structure of GNRH1 (from PDB 1YY1) Source: https://en.wikipedia.org/wiki/Gonadotropin- releasing_hormone#/media/File:GNRH1_structure.png

GnRH is synonymous with follicle-stimulating and luteinizing hormone-releasing hormone (FSH-RH, LH-RH). It is a peptide of 10 amino acids secreted from the preoptic nucleus of the hypothalamus (Fig. 13). It stimulates the secretion of luteinizing (LH) and follicle-stimulating hormone (FSH) from gonadotroph endocrine cells of the anterior lobe of the pituitary gland. These hormones stimulate the production of estrogen and progesterone in females and testosterone in males. GnRH is necessary for normal sexual physiology in both

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males and females and are released in periodic pulses after every 1-2 hours. High level of male and female hormones – testosterone, estrogen and progesterone – inhibits the production of GnRH by the hypothalamus (Fig: 14).

Figure: 14. Inhibition mechanism of GnRH secretion. Source: Authors

4.6 Gonadotropin-inhibitory Hormone (GnIH)

The gonadotropin-inhibitory hormone is a hypothalamic dodecapeptide discovered in the Japanese quail in 2000. It was named so due to its gonadotropin inhibitory property in the cultured quail anterior pituitary gland. It is primarily produced by the neurosecretory cells of the paraventricular nucleus (PVN) in birds and from the dorsomedial hypothalamic area (DMH) in mammals. GnIH directly inhibits gonadotropin release (Fig: 15) unlike that of sex steroids and inhibin that do so via gonadal feedback (Fig: 14).

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Figure: 15. Diagrammatic representation of the GnIH action on the GnRH neuron and the pituitary gland. GnIH = Gonadotropin-inhibitory hormone. Source: Authors

4.7 Somatostatin

Figure: 16 Chemical structure of Somatostatin

Source: https://en.wikipedia.org/wiki/Somatostatin#/media/File:Somatostatin.svg

Somatostatin is synonymous with growth hormone-inhibiting hormone (GHIH). It has two active forms – one of 14 amino acids and the other of 28 amino acids (Fig.16). It is produced by neurosecretory cells of the hypothalamic ventromedial nucleus and then released to the anterior pituitary gland via the hypophyseal portal system. It inhibits the production of growth hormone from somatotroph endocrine cells in the anterior lobe of pituitary gland. It also inhibits the secretion or release of thyroid-stimulating hormone (TSH). Somatostatin is

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also secreted by the pancreas and the intestine inhibiting the production of insulin, glucagon and varied other hormones.

4.8 Oxytocin (OXY)

Figure: 17. Structure of oxytocin

Source: https://en.wikipedia.org/wiki/Oxytocin#/media/File:Oxytocin_with_labels.png

Oxytocin (Greek, “quick birth”) is a neuropeptide hormone composed of nine amino acids produced by magnocellular neurosecretory cells of the paraventricular and supraoptic nucleus and store in the posterior pituitary gland. It is released into the bloodstream in response to stretching of the uterus and cervix during parturition and suckling of nipples by the baby during breastfeeding. It brings about the contraction of the uterus and ejection of milk (Fig:

18). These properties were discovered by Sir Henry Hallett Dale in 1906 and Ott and Scott in 1910 respectively. It was elucidated and sequenced by Du Vigneaud and was awarded the Nobel Prize in 1955.

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Figure: 18. Neurohormone pathway of oxytocin. Soure: Authors 4.9 Vasopressin

Figure: 19. Chemical structure of the argipressin

Source: https://en.wikipedia.org/wiki/Vasopressin#/media/File:Vasopressin_labeled.png

Vasopressin is also known as antidiuretic hormone (ADH) composed of nine amino acids.

It regulates reabsorption of water in the kidney and constriction of blood vessels thereby increasing blood pressure. It is found in most mammals and contains arginine in most species and hence referred to as arginine vasopressin (AVP) or argipressin (Fig. 19). It is produced by the magnocellular neurosecretory cells in the hypothalamic paraventricular and supraoptic

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nuclei. It travels down the axon and is stored in the posterior pituitary gland bound to a protein. It is released into the blood stream when the blood osmolarity increases (Fig: 20).

Figure: 20. Regulation of blood osmolarity by the hypothalamus. Source: Authors

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Figure: 21. Overview of major hormones produced by the hypothalamus and pituitary gland (in response to hypothalamic hormones). Thyroid-stimulating hormone (TSH); adrenocorticotropic hormone (ACTH);

melanocyte-stimulating hormone (MSH); prolactin (PRL); growth hormone (GH); follicle-stimulating hormone (FSH); Luteinizing hormone (LH); thyrotropin-releasing hormone (TRH); corticotropin-releasing hormone (CRH); dopamine (DA) or prolactin-inhibiting hormone (PIH) or prolactostatin; growth-hormone-releasing hormone (GHRH); Gonadotropin-releasing hormone (GnRH); somatostatin (SS) or growth hormone-inhibiting hormone (GHIH); Oxytocin (OXY); antidiuretic hormone (ADH); dark bar indicates inhibition property.

Source: Authors

5. Regulation of Hypothalamic hormone regulation

Secretion of the hypothalamic hormones are governed by various internal and external stimuli - age and sex of the individual, sleep-wake cycle, photoperiod, stress, feeding, etc.

A significant regulatory mechanism of hypothalamic hormone secretion or suppression is the negative or positive feedback (Fig: 21, 22) from the end products or hormones released from the target endocrine glands of specific tropic hormones of the pituitary gland or the tropic hormones of the pituitary themselves.

Majority of the hypothalamic hormones are governed by negative feedback (Fig: 11, 14 &

19). Oxytocin production is governed by positive feedback (Fig: 17).

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Figure: 22. A simple neuroendocrine pathway showing control of endocrine hormones by negative or positive feedback. Negative feedback is an inhibition response from the end products of a stimulus whereby the intensity of the stimulus decreases. Positive feedback is a stimulation response from the end products of a stimulus whereby the intensity of the stimulus increases leading to more product formation. Bars indicate inhibition response. Source: Authors

6. Summary

 Hypothalamic hormones are neuroendocrine hormones produced by the neurosecretory neurons of the hypothalamus. The hypothalamus acts as the integration center for the nervous and the endocrine system. There are about 8 hormones produced by the hypothalamus:

 Thyrotropin-releasing hormone (TRH): Stimulate thyrotroph cells in the anterior lobe of pituitary gland to secrete thyroid stimulating hormone (TSH).

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 Corticotropin-releasing hormone (CRH): Stimulate corticotroph cells in the anterior lobe of pituitary gland to secrete adrenocorticotropic hormone (ACTH) and melanocyte- stimulating hormone (MSH).

 Dopamine (DA): It inhibits the secretion of hormone prolactin (PRL).

 Growth-hormone-releasing hormone (GHRH): Stimulate somatotroph cells in the anterior lobe of pituitary gland to secrete growth hormone (GH).

 Gonadotropin-releasing hormone (GnRH): Stimulate gonadotroph cells in the anterior lobe of pituitary gland to secrete follicle-stimulating hormone (FSH) and Luteinizing hormone (LH).

 Gonadotropin-inhibitory hormone (GnIH): Inhibits the activity of GnRH neuron of the hypothalamus and the gonadotrophs of the anterior pituitary gland.

 Somatostatin (SS): It is also known as growth hormone-inhibiting hormone (GHIH). It inhibits the production of growth hormone and thyroid-stimulating hormone (TSH) in the anterior lobe of the pituitary gland.

 Oxytocin (OXY): It stimulates the contraction of the uterus and ejection of milk from the breast.

 Vasopressin (Antidiuretic hormone – ADH): It helps reabsorption of water in the kidney tubules and maintains blood volume.

 TRH, CRH, DA, GHRH, GnRH, SS are released into the anterior lobe of the pituitary gland via the hypophyseal portal system where they stimulate or inhibit the endocrine cells to release respective hormones according to the internal and external environmental needs of the body.

 OXY and ADH are stored as vesicular granules in the posterior lobe of the pituitary gland and released into the general circulation according to the need of the body.

3. Structure of Hypothalamus

Development Team

Contents:

1. Learning Outcomes

2. Introduction

3. Structure of Hypothalamus

4. Hormones of Hypothalamus

5. Regulation of Hypothalamic hormone regulation

6. Summary