Neuroendocrinology

Neuroendocrinology is the study of the interactions between the nervous system and the endocrine system. The concept arose from the recognition that the secretion of hormones from the pituitary gland was closely controlled by the brain, and especially by the hypothalamus.

Pioneers of neuroendocrinology

In the 1920s, several groups in France and the USA noted that hypophysectomy in laboratory animals arrests body growth and inhibits many endocrine functions). The group around Herbert McLean Evans (1882–1971) led the way in the early purification, then isolation and molecular structure of hormones from the anterior lobe that control peripheral endocrine glands and regulate growth. In 1952, Vincent du Vigneaud and his group isolated and synthesized oxytocin and vasopressin from extracts of the posterior lobe of the pituitary.

In 1939, one of the most important events in the history of neuroendocrinology took place: a meeting in New York of the Association for Research in Nervous and Mental Diseases on the theme, "The Hypothalamus and Central Levels of Autonomic Function"; at this meeting, Ernst and Berta Scharrer proposed the concept of neurosecretion by presenting histological images of neurons of the hypothalamus of that appeared to secrete substances, probably of proteinic–peptidic nature. The word “Neuro-Endocrinologie” (in French, with the hyphen) appearedsoon after, in 1946, as the title of a treatise by Roussy and Mosinger.

Geoffrey Harris] (1913-1971) has been called the "father" of neuroendocrinology. Working in Oxford, he showed that the anterior pituitary gland of mammals is regulated by factors that are secreted by hypothalamic neurons into the hypothalamo-hypophysial portal circulation. By contrast, the hormones of the posterior pituitary gland (oxytocin and vasopressin)are secreted into the systemic circulation directly from the nerve endings of hypothalamic neurons.

The first of the hypothalamic factors to be fully identified were thyrotropin-releasing hormone (TRH) and gonadotropin releasing hormone (GnRH). TRH is a small peptide that stimulates the secretion of thyroid stimulating hormone (TSH); GnRH (also called luteinising hormone releasing hormone, LHRH) stimulates the secretion of luteinizing hormone and follicle stimulating hormone (FSH). Roger Guillemin and Andrew W. Schally isolated these factors from the hypothalamus of sheep and pigs, and then identified their structures; they were awarded the Nobel Prize in Physiology and Medicine in 1977 for their contributions to understanding "the peptide hormone production of the brain."

Neuroendocrine systems of the hypothalamus

Oxytocin and vasopressin, the two peptide hormones of the posterior pituitary gland (the "neurohypophysis"), are secreted into the systemic circulation from the neurosecretory nerve endings of magnocellular neuroendocrine neurons. The cell bodies of these neurons are in the supraoptic nucleus and the paraventricular nucleus, and their electrical activity is regulated by afferent synaptic inputs from other brain regions. By contrast, 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 (ACTH), luteinizing hormone (LH), follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), prolactin and growth hormone) remains under the control of the brain. The brain controls the anterior pituitary gland by “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. These vessels, the hypothalamo-hypophysial portal vessels, carry the hypothalamic factors to the adenohypophysis where they bind to specific receptors on the surface of the hormone-producing cells.

For example, growth hormone secretion is controlled by two neuroendocrine systems: the growth hormone releasing hormone (GHRH) neurons and the somatostatin neurons, which stimulate and inhibit GH secretion respectively. The GHRH neurones are located in the arcuate nucleus of the hypothalamus, while 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 the portal blood vessels. Growth hormone is secreted in pulses, which arise from alternating episodes of GHRH release and somatostatin release; this alternation reflects neuronal interactions between the GHRH and somatostatin cells, and negative feedback from growth hormone and from insulin-like growth factor I (IGF-I), the production of which by the liver is stimulated by grwoth hormone.

So why are these systems of interest to physiologists and neuroscientists? Firstly, neuroendocrine systems regulate things that matter to most of us. They control reproduction in all its aspects, from bonding to sexual behavior, they control spermatogenesis and the ovarian cycle, puberty parturition, lactation and maternal behaviour . They control the way we respond to stress and infection. They regulate our metabolism – they influence our eating and drinking behaviour, and influence how energy intake is used – i.e. how fat we get . They influence our mood. They regulate body fluid and electrolyte homeostasis, and blood pressure. In other words, these are systems of importance to many major health concerns, as well of sometimes of intimate personal interest.

Secondly, these neurons are large; they are mini “ factories” for producing secretory products; their nerve terminal 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. For these reasons and more, neuroendocrine neurons are good "model systems" for studying general questions, like “how does a neurone regulate the synthesis, packaging and secretion of its product?” and “how is information encoded in electrical activity?”

The scope of neuroendocrinology

Today, neuroendocrinology embraces many different topics that arose directly or indirectly from the core concept of neuroendocrine neurons. Neuroendocrine neurones control the gonads – and gonadal steroids in turn influence the brain]; and so do corticosteroids secreted from the adrenal gland under the influence of ACTH. The study of these feedbacks became naturally the province of neuroendocrinologists. The peptides secreted by hypothalamic neuroendocrine neurons into the blood proved to be released also into the brain, and their central actions often seem to complement their peripheral actions. Thus, understanding these central actions also became the province of neuroendocrinologists, sometimes even when these peptides cropped up in quite different parts of the brain apparently serving 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.

Recently, several new hormonal systems have been discovered - leptin released by adipocytes (fat cells) and ghrelin released from the stomach both act back on the hypothalamus to regulate appetite and metabolism. These systems too have become embraced by the field of neuroendocrinology, because of the commonality of concepts.

Neuroendocrine systems have been important to our understanding of many basic principles in neuroscience and physiology – for instance our understanding of stimulus-secretion coupling - how the electrical activity of a neuron results in release of a chemical signal, and we have learned from neuroendocrine systems that the pattern of the electrical signals can be as important as the number of them in determining how much is released. The origins and significance of patterning in neuroendocrine secretion are still dominant themes in neuroendocrinology today.