Neuroendocrinology

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Neuroendocrinology is the branch of biology (specifically of physiology) which studies the interaction between the nervous system and the endocrine system; i.e. how the brain regulates the hormonal activity in the body. [1] The nervous and endocrine systems often act together in a process called neuroendocrine integration, to regulate the physiological processes of the human body. Neuroendocrinology arose from the recognition that the brain, especially the hypothalamus, controls secretion of pituitary gland hormones, and has subsequently expanded to investigate numerous interconnections of the endocrine and nervous systems.

Contents

The endocrine system consists of numerous glands throughout the body that produce and secrete hormones of diverse chemical structure, including peptides, steroids, and neuroamines. Collectively, hormones regulate many physiological processes. The neuroendocrine system is the mechanism by which the hypothalamus maintains homeostasis, regulating reproduction, metabolism, eating and drinking behaviour, energy utilization, osmolarity and blood pressure.

Neuroendocrine system

Hypothalamus

Hypothalamic interaction with the posterior and anterior pituitary glands. The hypothalamus produces the hormones oxytocin and vasopressin in its endocrine cells (left). These are released at nerve endings in the posterior pituitary gland and then secreted into the systemic circulation. The hypothalamus releases tropic hormones into the hypophyseal portal system to the anterior pituitary (right). The anterior pituitary then secretes trophic hormones into the circulation which elicit different responses from various target tissues. These responses then signal back to the hypothalamus and anterior pituitary to either stop producing or continue to produce their precursor signals. Neuroendocrinology Figure (2).jpg
Hypothalamic interaction with the posterior and anterior pituitary glands. The hypothalamus produces the hormones oxytocin and vasopressin in its endocrine cells (left). These are released at nerve endings in the posterior pituitary gland and then secreted into the systemic circulation. The hypothalamus releases tropic hormones into the hypophyseal portal system to the anterior pituitary (right). The anterior pituitary then secretes trophic hormones into the circulation which elicit different responses from various target tissues. These responses then signal back to the hypothalamus and anterior pituitary to either stop producing or continue to produce their precursor signals.

The hypothalamus is commonly known as the relay center of the brain because of its role in integrating inputs from all areas of the brain and producing a specific response. In the neuroendocrine system, the hypothalamus receives electrical signals from different parts of the brain and translates those electrical signals into chemical signals in the form of hormones or releasing factors. These chemicals are then transported to the pituitary gland and from there to the systemic circulation. [2]

Pituitary gland

The pituitary gland is divided into three lobes: the anterior pituitary, the intermediate pituitary lobe, and the posterior pituitary. The hypothalamus controls the anterior pituitary's hormone secretion by sending releasing factors, called tropic hormones, down the hypothalamo-hypophysial portal system. [3] For example, thyrotropin-releasing hormone released by the hypothalamus in to the portal system stimulates the secretion of thyroid-stimulating hormone by the anterior pituitary.[ citation needed ]

The posterior pituitary is directly innervated by the hypothalamus; the hormones oxytocin and vasopressin are synthesized by neuroendocrine cells in the hypothalamus and stored at the nerve endings in the posterior pituitary. They are secreted directly into systemic circulation by the hypothalamic neurons. [3]

Major neuroendocrine axes

Oxytocin and vasopressin (also called anti-diuretic hormone), the two neurohypophysial hormones of the posterior pituitary gland (the neurohypophysis), are secreted from the nerve endings of magnocellular neurosecretory cells into the systemic circulation. The cell bodies of the oxytocin and vasopressin neurons are in the paraventricular nucleus and supraoptic nucleus of the hypothalamus, respectively, [2] and the electrical activity of these neurons is regulated by afferent synaptic inputs from other brain regions. [4]

By contrast, the hormones of the anterior pituitary gland (the adenohypophysis) are secreted from endocrine cells that, in mammals, are not directly innervated, yet the secretion of these hormones (adrenocorticotrophic hormone, luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, prolactin, and growth hormone) remains under the control of the hypothalamus. The hypothalamus controls the anterior pituitary gland via releasing factors and release-inhibiting factors; these are substances released by hypothalamic neurons into blood vessels at the base of the brain, at the median eminence. [5] These vessels, the hypothalamo-hypophysial portal vessels, carry the hypothalamic factors to the anterior pituitary, where they bind to specific receptors on the surface of the hormone-producing cells. [3]

For example, the secretion of growth hormone is controlled by two neuroendocrine systems: the growth hormone-releasing hormone (GHRH) neurons and the somatostatin neurons, which stimulate and inhibit GH secretion, respectively. [6] The GHRH neurons are located in the arcuate nucleus of the hypothalamus, whereas the somatostatin cells involved in growth hormone regulation are in the periventricular nucleus. These two neuronal systems project axons to the median eminence, where they release their peptides into portal blood vessels for transport to the anterior pituitary. Growth hormone is secreted in pulses, which arise from alternating episodes of GHRH release and somatostatin release, which may reflect neuronal interactions between the GHRH and somatostatin cells, and negative feedback from growth hormone. [6]

Functions

The neuroendocrine systems control reproduction [7] in all its aspects, from bonding to sexual behaviour. They control spermatogenesis and the ovarian cycle, parturition, lactation, and maternal behaviour. They control the body's response to stress [8] and infection. [9] They regulate the body's metabolism, influencing eating and drinking behaviour, and influence how energy intake is utilised, that is, how fat is metabolised. [10] They influence and regulate mood, [11] body fluid and electrolyte homeostasis, [12] and blood pressure. [13]

The neurons of the neuroendocrine system are large; they are mini factories for producing secretory products; their nerve terminals are large and organised in coherent terminal fields; their output can often be measured easily in the blood; and what these neurons do and what stimuli they respond to are readily open to hypothesis and experiment. Hence, neuroendocrine neurons are good "model systems" for studying general questions, like "how does a neuron regulate the synthesis, packaging, and secretion of its product?" and "how is information encoded in electrical activity?"[ citation needed ][It appears that this is a primary source observation.]

History

Pioneers

Walter Lee Gaines noted the activity of the pituitary in the lactation of cows in 1915. [14] He also noted that anaesthesia could block lactation and response to the suckling reflex. [15]

Ernst and Berta Scharrer, [16] of the University of Munich the Albert Einstein College of Medicine are credited as co-founders the field of neuroendocrinology with their initial observations and proposals in 1945 concerning neuropeptides.

Geoffrey Harris [17] is considered by many to be the "father" of neuroendocrinology. Harris, the Dr. Lee's Professor of Anatomy at Oxford University, is credited with showing that the anterior pituitary gland of mammals is regulated by hormones secreted by hypothalamic neurons into the hypothalamohypophysial portal circulation. By contrast, the hormones of the posterior pituitary gland are secreted into the systemic circulation directly from the nerve endings of hypothalamic neurons. This seminal work was done in collaboration with Dora Jacobsohn of Lund University. [18]

The first of these factors to be identified are thyrotropin-releasing hormone (TRH) and gonadotropin-releasing hormone (GnRH). TRH is a small peptide that stimulates the secretion of thyroid-stimulating hormone; GnRH (also called luteinizing hormone-releasing hormone) stimulates the secretion of luteinizing hormone and follicle-stimulating hormone.

Roger Guillemin, [19] a medical student of Faculté de Médecine of Lyon, and Andrew W. Schally of Tulane University isolated these factors from the hypothalamus of sheep and pigs, and then identified their structures. Guillemin and Schally were awarded the Nobel Prize in Physiology and Medicine in 1977 for their contributions to understanding "the peptide hormone production of the brain".[ citation needed ]

In 1952, Andor Szentivanyi, of the University of South Florida, and Geza Filipp wrote the world's first research paper showing how neural control of immunity takes place through the hypothalamus. [20]

Modern scope

Today, neuroendocrinology embraces a wide range of topics that arose directly or indirectly from the core concept of neuroendocrine neurons. Neuroendocrine neurons control the gonads, whose steroids, in turn, influence the brain, as do corticosteroids secreted from the adrenal gland under the influence of adrenocorticotrophic hormone. The study of these feedbacks became the province of neuroendocrinologists. The peptides secreted by hypothalamic neuroendocrine neurons into the blood proved to be released also into the brain, and the central actions often appeared to complement the peripheral actions. So understanding these central actions also became the province of neuroendocrinologists, sometimes even when these peptides cropped up in quite different parts of the brain that appeared to serve functions unrelated to endocrine regulation. Neuroendocrine neurons were discovered in the peripheral nervous system, regulating, for instance, digestion. The cells in the adrenal medulla that release adrenaline and noradrenaline proved to have properties between endocrine cells and neurons, and proved to be outstanding model systems for instance for the study of the molecular mechanisms of exocytosis. And these, too, have become, by extension, neuroendocrine systems.

Neuroendocrine systems have been important to our understanding of many basic principles in neuroscience and physiology, for instance, our understanding of stimulus-secretion coupling. [21] The origins and significance of patterning in neuroendocrine secretion are still dominant themes in neuroendocrinology today.

Neuroendocrinology is also used as an integral part of understanding and treating neurobiological brain disorders. One example is the augmentation of the treatment of mood symptoms with thyroid hormone. [22] Another is the finding of a transthyretin (thyroxine transport) problem in the cerebrospinal fluid of some patients diagnosed with schizophrenia. [23]

Experimental techniques

Since the original experiments by Geoffrey Harris investigating the communication of the hypothalamus with the pituitary gland, much has been learned about the mechanistic details of this interaction. Various experimental techniques have been employed. Early experiments relied heavily on the electrophysiology techniques used by Hodgkin and Huxley. Recent approaches have incorporated various mathematical models to understand previously identified mechanisms and predict systemic response and adaptation under various circumstances.[ citation needed ]

Electrophysiology

Electrophysiology experiments were used in the early days of neuroendocrinology to identify the physiological happenings in the hypothalamus and the posterior pituitary especially. In 1950, Geoffrey Harris and Barry Cross outlined the oxytocin pathway by studying oxytocin release in response to electrical stimulation. [24] In 1974, Walters and Hatton investigated the effect of water dehydration by electrically stimulating the supraoptic nucleus—the hypothalamic center responsible for the release of vasopressin. [24] Glenn Hatton dedicated his career to studying the physiology of the Neurohypophyseal system, which involved studying the electrical properties of hypothalamic neurons. [24] Doing so enabled investigation into the behavior of these neurons and the resulting physiological effects. Studying the electrical activity of neuroendocrine cells enabled the eventual distinction between central nervous neurons, neuroendocrine neurons, and endocrine cells. [25]

Mathematical Models

Hodgkin-Huxley Model

The Hodgkin–Huxley model translates data about the current of a system at a specific voltage into time-dependent data describing the membrane potential. Experiments using this model typically rely on the same format and assumptions, but vary the differential equations to answer their particular questions. Much has been learned about vasopressin, GnRH, somatotrophs, corticotrophs, and lactotrophic hormones by employing this method. [8]

Integrate-and-Fire Model

The integrate-and-fire model aims for mathematic simplicity in describing biological systems by focusing on, and only on the threshold activity of a neuron. By doing so, the model successfully reduces the complexity of a complicated system; however it ignores the actual mechanisms of action and replaces them with functions that define how the output of a system depends on its input. [8] This model has been used to describe the release of hormones to the posterior pituitary gland, specifically oxytocin and vasopressin. [9]

Functional or Mean Fields Model

The functional or mean fields model relies on the premise "simpler is better". [8] It strives to reduce the complexity of modelling multi-faceted systems by using a single variable to describe an entire population of cells. The alternative would be to use a different set of variables for each population. When attempting to model a system where multiple populations of cells interact, using several sets quickly becomes overcomplicated. This model has been used to describe several systems, especially involving the reproductive cycle (menstrual cycles, luteinizing hormone, prolactin surges). [9] Functional models also exist to represent cortisol secretion, and growth hormone secretion. [9]

See also

Related Research Articles

<span class="mw-page-title-main">Endocrine system</span> Hormone-producing glands of a body

The endocrine system is a messenger system in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant organs. In vertebrates, the hypothalamus is the neural control center for all endocrine systems.

<span class="mw-page-title-main">Pituitary gland</span> Endocrine gland at the base of the brain

The pituitary gland is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the brain, protruding off the bottom of the hypothalamus. The human pituitary gland is oval shaped, about the size of a chickpea, and weighs 0.5 grams (0.018 oz) on average.

<span class="mw-page-title-main">Hypothalamus</span> Area of the brain below the thalamus

The hypothalamus is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus is located below the thalamus and is part of the limbic system. In the terminology of neuroanatomy, it forms the ventral part of the diencephalon. All vertebrate brains contain a hypothalamus. In humans, it is the size of an almond.

<span class="mw-page-title-main">Hypothalamic–pituitary–adrenal axis</span> Set of physiological feedback interactions

The hypothalamic–pituitary–adrenal axis is a complex set of direct influences and feedback interactions among three components: the hypothalamus, the pituitary gland, and the adrenal glands. These organs and their interactions constitute the HPA axis.

<span class="mw-page-title-main">Vasopressin</span> Mammalian hormone released from the pituitary gland

Human vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the AVP gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It then travels down the axon terminating in the posterior pituitary, and is released from vesicles into the circulation in response to extracellular fluid hypertonicity (hyperosmolality). AVP has two primary functions. First, it increases the amount of solute-free water reabsorbed back into the circulation from the filtrate in the kidney tubules of the nephrons. Second, AVP constricts arterioles, which increases peripheral vascular resistance and raises arterial blood pressure.

<span class="mw-page-title-main">Anterior pituitary</span> Anterior lobe of the pituitary gland

A major organ of the endocrine system, the anterior pituitary is the glandular, anterior lobe that together with the posterior lobe makes up the pituitary gland (hypophysis). The anterior pituitary regulates several physiological processes, including stress, growth, reproduction, and lactation. Proper functioning of the anterior pituitary and of the organs it regulates can often be ascertained via blood tests that measure hormone levels.

<span class="mw-page-title-main">Posterior pituitary</span> Posterior lobe of the pituitary gland

The posterior pituitary is the posterior lobe of the pituitary gland which is part of the endocrine system. The posterior pituitary is not glandular as is the anterior pituitary. Instead, it is largely a collection of axonal projections from the hypothalamus that terminate behind the anterior pituitary, and serve as a site for the secretion of neurohypophysial hormones directly into the blood. The hypothalamic–neurohypophyseal system is composed of the hypothalamus, posterior pituitary, and these axonal projections.

<span class="mw-page-title-main">Supraoptic nucleus</span> ADH secreting nucleus of the hypothalamus.

The supraoptic nucleus (SON) is a nucleus of magnocellular neurosecretory cells in the hypothalamus of the mammalian brain. The nucleus is situated at the base of the brain, adjacent to the optic chiasm. In humans, the SON contains about 3,000 neurons.

<span class="mw-page-title-main">Paraventricular nucleus of hypothalamus</span>

The paraventricular nucleus is a nucleus in the hypothalamus. Anatomically, it is adjacent to the third ventricle and many of its neurons project to the posterior pituitary. These projecting neurons secrete oxytocin and a smaller amount of vasopressin, otherwise the nucleus also secretes corticotropin-releasing hormone (CRH) and thyrotropin-releasing hormone (TRH). CRH and TRH are secreted into the hypophyseal portal system and act on different targets neurons in the anterior pituitary. PVN is thought to mediate many diverse functions through these different hormones, including osmoregulation, appetite, and the response of the body to stress.

Magnocellular neurosecretory cells are large neuroendocrine cells within the supraoptic nucleus and paraventricular nucleus of the hypothalamus. They are also found in smaller numbers in accessory cell groups between these two nuclei, the largest one being the circular nucleus. There are two types of magnocellular neurosecretory cells, oxytocin-producing cells and vasopressin-producing cells, but a small number can produce both hormones. These cells are neuroendocrine neurons, are electrically excitable, and generate action potentials in response to afferent stimulation. Vasopressin is produced from the vasopressin-producing cells via the AVP gene, a molecular output of circadian pathways.

<span class="mw-page-title-main">Arcuate nucleus</span>

The arcuate nucleus of the hypothalamus is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes several important and diverse populations of neurons that help mediate different neuroendocrine and physiological functions, including neuroendocrine neurons, centrally projecting neurons, and astrocytes. The populations of neurons found in the arcuate nucleus are based on the hormones they secrete or interact with and are responsible for hypothalamic function, such as regulating hormones released from the pituitary gland or secreting their own hormones. Neurons in this region are also responsible for integrating information and providing inputs to other nuclei in the hypothalamus or inputs to areas outside this region of the brain. These neurons, generated from the ventral part of the periventricular epithelium during embryonic development, locate dorsally in the hypothalamus, becoming part of the ventromedial hypothalamic region. The function of the arcuate nucleus relies on its diversity of neurons, but its central role is involved in homeostasis. The arcuate nucleus provides many physiological roles involved in feeding, metabolism, fertility, and cardiovascular regulation.

<span class="mw-page-title-main">Endocrine gland</span> Glands of the endocrine system that secrete hormones to blood

Endocrine glands are ductless glands of the endocrine system that secrete their products, hormones, directly into the blood. The major glands of the endocrine system include the pineal gland, pituitary gland, pancreas, ovaries, testes, thyroid gland, parathyroid gland, hypothalamus and adrenal glands. The hypothalamus and pituitary glands are neuroendocrine organs.

A neurohormone is any hormone produced and released by neuroendocrine cells into the blood. By definition of being hormones, they are secreted into the circulation for systemic effect, but they can also have a role of neurotransmitter or other roles such as autocrine (self) or paracrine (local) messenger.

Neuroendocrine cells are cells that receive neuronal input and, as a consequence of this input, release messenger molecules (hormones) into the blood. In this way they bring about an integration between the nervous system and the endocrine system, a process known as neuroendocrine integration. An example of a neuroendocrine cell is a cell of the adrenal medulla, which releases adrenaline to the blood. The adrenal medullary cells are controlled by the sympathetic division of the autonomic nervous system. These cells are modified postganglionic neurons. Autonomic nerve fibers lead directly to them from the central nervous system. The adrenal medullary hormones are kept in vesicles much in the same way neurotransmitters are kept in neuronal vesicles. Hormonal effects can last up to ten times longer than those of neurotransmitters. Sympathetic nerve fiber impulses stimulate the release of adrenal medullary hormones. In this way the sympathetic division of the autonomic nervous system and the medullary secretions function together.

<span class="mw-page-title-main">Hypothalamic–pituitary–gonadal axis</span> Concept of regarding the hypothalamus, pituitary gland and gonadal glands as a single entity

The hypothalamic–pituitary–gonadal axis refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single entity. Because these glands often act in concert, physiologists and endocrinologists find it convenient and descriptive to speak of them as a single system.

<span class="mw-page-title-main">Circumventricular organs</span> Interfaces between the brain and the circulatory system

Circumventricular organs (CVOs) are structures in the brain characterized by their extensive and highly permeable capillaries, unlike those in the rest of the brain where there exists a blood–brain barrier (BBB) at the capillary level. Although the term "circumventricular organs" was originally proposed in 1958 by Austrian anatomist Helmut O. Hofer concerning structures around the brain ventricular system, the penetration of blood-borne dyes into small specific CVO regions was discovered in the early 20th century. The permeable CVOs enabling rapid neurohumoral exchange include the subfornical organ (SFO), the area postrema (AP), the vascular organ of lamina terminalis, the median eminence, the pituitary neural lobe, and the pineal gland.

Hypothalamic–pituitary hormones are hormones that are produced by the hypothalamus and pituitary gland. Although the organs in which they are produced are relatively small, the effects of these hormones cascade throughout the body. They can be classified as a hypothalamic–pituitary axis of which the adrenal, gonadal, thyroid, somatotropic, and prolactin axes are branches.

Hypothalamic disease is a disorder presenting primarily in the hypothalamus, which may be caused by damage resulting from malnutrition, including anorexia and bulimia eating disorders, genetic disorders, radiation, surgery, head trauma, lesion, tumour or other physical injury to the hypothalamus. The hypothalamus is the control center for several endocrine functions. Endocrine systems controlled by the hypothalamus are regulated by antidiuretic hormone (ADH), corticotropin-releasing hormone, gonadotropin-releasing hormone, growth hormone-releasing hormone, oxytocin, all of which are secreted by the hypothalamus. Damage to the hypothalamus may impact any of these hormones and the related endocrine systems. Many of these hypothalamic hormones act on the pituitary gland. Hypothalamic disease therefore affects the functioning of the pituitary and the target organs controlled by the pituitary, including the adrenal glands, ovaries and testes, and the thyroid gland.

Parvocellular neurosecretory cells are small neurons that produce hypothalamic releasing and inhibiting hormones. The cell bodies of these neurons are located in various nuclei of the hypothalamus or in closely related areas of the basal brain, mainly in the medial zone of the hypothalamus. All or most of the axons of the parvocellular neurosecretory cells project to the median eminence, at the base of the brain, where their nerve terminals release the hypothalamic hormones. These hormones are then immediately absorbed into the blood vessels of the hypothalamo-pituitary portal system, which carry them to the anterior pituitary gland, where they regulate the secretion of hormones into the systemic circulation.

Behavioral endocrinology is a branch of endocrinology that studies the Neuroendocrine system and its effects on behavior. Behavioral endocrinology studies the biological mechanisms that produce behaviors, this gives insight into the evolutionary past. The field has roots in ethology, endocrinology and psychology.

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