Robinson group ::

Most neuroendocrine systems form a cascade in both time and space, and we study both dimensions. The hypothalamus contains specialized groups of neuroendocrine neurons, so called because instead of forming synapses with other neurons, their major function is to release their products into blood. Neuroendocrinology is the study of this special interface between the nervous system and the pituitary endocrine system.

Some of the neurons project out from the hypothalamus, down the pituitary stalk to the posterior pituitary gland, where the peptide hormones, oxytocin and vasopressin are released directly from the neuron terminals into the circulation where they act on several peripheral tissues (e.g. uterus, mammary gland, kidney, blood vessels).

Other neuroendocrine neurons project to a region at the base of the hypothalamus (the median eminence) where their products are secreted into a specialised capillary circulation. This blood carries the secretory products into blood vessels (hypophysial portal vessels) that also travel down the pituitary stalk, but spread out again into capillaries in the anterior lobe of the pituitary gland where there are several different endocrine cell types producing at least 6 different hormones. These anterior pituitary endocrine cells express specific receptors for the individual secretory products of the hypothalamic neurons. In this way, the nervous system can control the release of all the pituitary hormones.

Moving down the cascade, the pituitary hormones travel in the peripheral circulation to all the organs of the body, regulating many different processes either directly, or via the production of other hormones, in yet another level of endocrine cascade. We are therefore interested in studying hormone patterns in the blood, since it is the signals that communicate the neuroendocrine output to the responding tissues. To this end we have developed specific methods for taking microsamples of blood from small rodents and also applied our technology to the problems of blood sampling in human infants. We can also send our own ‘signals” into the system by computer controlled systems for chronic infusions of hormones in different patterns, to examine the responses in different target tissues.

Finally, the neuroendocrine system relies on a variety of feed back signals from the tissues, or from the consequence of hormone action upon them, that are detected in the hypothalamus, so that hormone output can be adjusted appropriately. We are therefore very interested in how the groups of individual neurones or cells receive and integrate this information, to modify their output in response to physiological demands. Our recent work has revealed that there is a structural and functional network in both GH and GHRH systems, and understanding these network properties is only now beginning to be possible.

During development, the formation of both hypothalamic and pituitary structures is intimately linked, such that developmental failures in one can affect the other. We are interested in key genetic pathways that regulate the formation of a functional hypothalamo-pituitary axis, and how this may be disrupted both in animal models. This has important clinical implications and in many cases, can shed light on developmental pituitary deficits in children. Clinical links are important to our work, and much of our work in this area is carried out in close collaboration with clinical colleagues at Great Ormond Street Hospital, and we frequently have clinicians working on related projects in the laboratory. We also benefit from close interactions with other developmental biologists in other groups at NIMR.

Our interest in these pathways is not simply to learn about development. Both the hypothalamus and the pituitary are surprisingly plastic in their adaptive responses to changing needs of the organism, and there is good evidence for adult stem cells capable of generating different numbers of pituitary cells. Many of the mechanisms involved in development of the differentiated endocrine cell types may well play a role in post natal pituitary physiology and this is an expanding area of interest, being pursued by Paul Le Tissier.

We focus mostly on the growth hormone (GH) system. GH is the major hormone produced in the anterior pituitary gland and is important for regulating growth and metabolic responses in many different target tissues. It is secreted into the blood stream in response to positive and negative signals from two opposing hypothalamic neuronal systems, producing peptides called GH releasing hormone (GHRH) and somatostatin, GHRH stimulates GH release and somatostatin inhibits GH release, but it is the interplay between these factors that causes GH to be secreted from the pituitary in a pulsatile pattern. We have also shown that the pattern of GH secretion determines the effects that GH has on different tissues in the body, and we study this both in terms of growth of tissues and differentiation of cells, but also in terms of the gene pathways activated in response to GH, which vary enormously in different tissues.

Sometimes, such approaches generate unexpected observations, and one such example was the creation of a transgenic rat strain that developed a novel form of autosomal dominant, severe late-onset male specific visceral obesity without insulin resistance. This has important commercial potential and we have formed a separate group to study both the genetic and physiological mechanisms of visceral obesity in these “SLOB” rats. Such findings emphasise the value of careful physiological characterisation of neuroendocrine manipulations in transgenic rats and mice, because then we can see how these processes contribute to many disparate physiological functions in the intact normal animals. A valuable spin-off of our approach is that we can also produce and study novel animal models of clinical syndromes. By gaining a better understanding of the neuroendocrine system in both normal and pathological models, much of what we learn can be directly applied to a better understanding and treatment of human disease.

• Molecular Neuroendocrinology
• Carter group
• Hannah group
• Le Tissier group
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