A review of central 5-HT receptors and their function

The brain is the key organ of the response to stress because it determines what is threatening and, therefore, potentially stressful, as well as the physiological and behavioral responses which can be either adaptive or damaging. Stress involves two-way communication between the brain and the cardiovascular, immune, and other systems via neural and endocrine mechanisms. Beyond the "flight-or-fight" response to acute stress, there are events in daily life that produce a type of chronic stress and lead over time to wear and tear on the body ("allostatic load"). Yet, hormones associated with stress protect the body in the short-run and promote adaptation ("allostasis"). The brain is a target of stress, and the hippocampus was the first brain region, besides the hypothalamus, to be recognized as a target of glucocorticoids. Stress and stress hormones produce both adaptive and maladaptive effects on this brain region throughout the life course. Early life events influence life-long patterns of emotionality and stress responsiveness and alter the rate of brain and body aging. The hippocampus, amygdala, and prefrontal cortex undergo stress-induced structural remodeling, which alters behavioral and physiological responses. As an adjunct to pharmaceutical therapy, social and behavioral interventions such as regular physical activity and social support reduce the chronic stress burden and benefit brain and body health and resilience.

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Physiology and Neurobiology of Stress and Adaptation: Central Role of the Brain

中枢神経系疾患の治療は正常細胞（ニューロン）の機能維持を目的とするが，脳血管障害のように機能障害の原因が細胞の死滅に基づくことは多い．一方，脳腫瘍の治療においては薬物療法や放射線療法といった腫瘍細胞の死滅を目標とするものが大きな位置を占める．いずれの場合にも，細胞死の機序を理解することは各種病態や治療法の理解のうえで重要である．現在のところ最も研究の進んでいる細胞死の型はアポトーシスである．そのなかで重要な位置を占めるミトコンドリアにおける反応および抗アポトーシス因子について概要を紹介する．

Neuroscience 細胞死：最近の知見

I Introduction UNTIL 35 yr ago, most scientists did not take research on the pineal gland seriously The decade beginning in 1956, however, provided several discoveries that laid the foundation for what has become a very active area of investigation These important early observations included the findings that, 1), the physiological activity of the pineal is influenced by the photoperiodic environment (1–5); 2), the gland contains a substance, N-acetyl-5-methoxytryptamine or melatonin, which has obvious endocrine capabilities (6, 7); 3), the function of the reproductive system in photoperiodically dependent rodents is inextricably linked to the physiology of the pineal gland (5, 8, 9); 4), the sympathetic innervation to the pineal is required for the gland to maintain its biosynthetic and endocrine activities (10, 11); and 5), the pineal gland can be rapidly removed from rodents with minimal damage to adjacent neural structures using a specially designed trephine (12) Since the mid 1960s, research on t

Pineal Melatonin: Cell Biology of Its Synthesis and of Its Physiological Interactions*

Extracellular stimuli elicit changes in gene expression in target cells by activating intracellular protein kinase cascades that phosphorylate transcription factors within the nucleus. One of the best characterized stimulus-induced transcription factors, cyclic AMP response element (CRE)-binding protein (CREB), activates transcription of target genes in response to a diverse array of stimuli, including peptide hormones, growth factors, and neuronal activity, that activate a variety of protein kinases including protein kinase A (PKA), pp90 ribosomal S6 kinase (pp90RSK), and Ca2+/calmodulin-dependent protein kinases (CaMKs)[corrected]. These kinases all phosphorylate CREB at a particular residue, serine 133 (Ser133), and phosphorylation of Ser133 is required for CREB-mediated transcription. Despite this common feature, the mechanism by which CREB activates transcription varies depending on the stimulus. In some cases, signaling pathways target additional sites on CREB or proteins associated with CREB, permitting CREB to regulate distinct programs of gene expression under different conditions of stimulation. This review discusses the molecular mechanisms by which Ser133-phosphorylated CREB activates transcription, intracellular signaling pathways that lead to phosphorylation of CREB at Ser133, and features of each signaling pathway that impart specificity at the level of CREB activation.

CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals.

Transcription factor CREM appears to play a key physiological and developmental role within the hypothalamic-pituitary-gonadal axis This axis is modulated by the pineal hormone melatonin, whose production is in turn driven by the endogenous clock There is striking circadian fluctuation of a novel CREM isoform, ICER, which is expressed at high levels during the night ICER is generated from an alternative, intronic promoter and functions as a powerful repressor of cyclic AMP-induced transcription Rhythmic adrenergic signals originated by the clock direct ICER expression by stimulation of the cAMP signal transduction pathway

Adrenergic signals direct rhythmic expression of transcriptional repressor CREM in the pineal gland

Daily rhythms in physiological and behavioral processes are controlled by a network of circadian clocks, reset by inputs and delivering circadian signals to the brain and peripheral organs. In mammals, at the top of the network is a master clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus, mainly reset by ambient light. The nocturnal synthesis and release of melatonin by the pineal gland are tightly controlled by the SCN clock and inhibited by light exposure. Several roles of melatonin in the circadian system have been identified. As a major hormonal output, melatonin distributes temporal cues generated by the SCN to the multitude of tissue targets expressing melatonin receptors. In some target structures, like the Pars tuberalis of the adenohypophysis, these melatonin signals can drive daily rhythmicity that would otherwise be lacking. In other target structures, melatonin signals are used for the synchronization (i.e., adjustment of the timing of existing oscillations) of peripheral oscillators, such as the fetal adrenal gland. Due to the expression of melatonin receptors in the SCN, endogenous melatonin is also able to feedback onto the master clock, although its physiological significance needs further characterization. Of note, pharmacological treatment with exogenous melatonin can synchronize the SCN clock. From a clinical point of view, provided that the subject is not exposed to light at night, the daily profile of circulating melatonin provides a reliable estimate of the timing of the human SCN. During the past decade, a number of melatonin agonists have been developed for treating circadian, psychiatric and sleep disorders. These drugs may target the SCN for improving circadian timing or act indirectly at some downstream level of the circadian network to restore proper internal synchronization.

Melatonin: Both master clock output and internal time-giver in the circadian clocks network

https://www.cell.com/current-biology/pdf/S0960-9822(06)01857-4.pdf

Kisspeptin Mediates the Photoperiodic Control of Reproduction in Hamsters

THE CREM (cyclic AMP-responsive element modulator) gene encodes multiple regulators of the cAMP-transcriptional response by alternative splicing1. A developmental switch in CREM expression occurs during spermatogenesis, whereby CREM function is converted from an antagonist to an activator (CREMτ; ref. 2) which accumulates to extremely high levels from the premeiotic spermatocyte stage onwards. To define the physiological mechanisms controlling the CREM developmental switch, we have hypophysectomized rats and observed the extinction of CREMτ expression in testis, thereby demonstrating a central role of the pituitary-hypothalamic axis. We then used the seasonal-dependent modulation of spermatogenesis in hamsters to dissect the hormonal programme controlling this developmental process. By this approach, combined with direct administration of pituitary-derived hormones, we have established that follicle-stimulating hormone (FSH) is responsible for the CREM switch. FSH appears to regulate CREM expression by alternative polyadenylation, which results in a dramatic enhancement of transcript stability.

Pituitary hormone FSH directs the CREM functional switch during spermatogenesis

The efferent projections of the suprachiasmatic nucleus (SCN) in the golden hamster have been examined by using the anterograde tracer Phaseolus vulgaris leucoagglutinin (Pha-L). SCN projections were further localized through a combination of restricted SCN-lesions and immunocytochemistry for three well-known peptidergic transmitters contained in SCN neurons, viz. vasopressin (VP), vasoactive intestinal peptide (VIP), and gastrin-releasing peptide (GRP). Thus, major terminal fields of SCN-derived VP were detected in the medial preoptic nucleus, the anterior part of the paraventricular nucleus of the thalamus (PVA), the medial parvicellular part of the paraventricular nucleus of the hypothalamus (PVN), and the medial part of the dorsomedial nucleus of the hypothalamus (DMH). VIP-containing projections from the SCN were discovered in the PVA, anterior and dorsal parvicellular divisions of the PVN, subparaventricular area, and medial DMH. Efferent fibers from the SCN containing GRP were restricted to the subparaventricular area, medial DMH, and supraoptic nucleus. In addition, Pha-L tracing indicated the existence of SCN projections which could not be ascribed to one of the presently investigated peptides. Furthermore, a pronounced innervation of the contralateral SCN was observed, of which the neurotransmitter remains to be established. The results of the present study indicate that the different neuronal populations in the SCN, as characterized by their transmitter content, also show a clear diversity in their preferential target areas.

Paul Pévet

Papers

Adrenergic signals direct rhythmic expression of transcriptional repressor CREM in the pineal gland

Melatonin: Both master clock output and internal time-giver in the circadian clocks network

Kisspeptin Mediates the Photoperiodic Control of Reproduction in Hamsters

Pituitary hormone FSH directs the CREM functional switch during spermatogenesis

Efferent projections of the suprachiasmatic nucleus in the golden hamster (Mesocricetus auratus)