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During brain development, radial glial (RG) cells and the different progenitor subtypes are characterized by their bipolar morphology that includes an ovoid cell body and one or two radial processes that span across the developing cerebral wall. Different cells transport the reduced form of vitamin C, ascorbic acid (AA), using sodium-dependent ascorbic acid cotransporters (SVCT1 or SVCT2). SVCT2 is mainly expressed in the nervous system (CNS); however, its localization in the central nervous system during embryonic development along with the mechanism by which RG take up vitamin C and its intracellular effects is unknown. Thus, we sought to determine the expression and localization of SVCT2 during CNS development. SVCT2 is preferentially localized in the RG body at the ventricular edge of the cortex during the neurogenic stage (E12 to E17). The localization of SVCT2 overexpressed by in utero electroporation of E14 embryos is consistent with ventricular polarization. A similar distribution pattern was observed in human brain tissue sections at 9 weeks of gestation; however, SVCT2 immunoreaction was also detected in the inner and outer subventricular zone (SVZ). Finally, we used C17.2 neural stem cell line, J1ES cells and primary cell cultures derived from the brain cortex to analyze functional SVCT2 activity, AA effects in progenitor cells bipolar morphology, and SVCT2 expression levels in different culture conditions. Our results indicate that basal RG cells and apical intermediate and subapical progenitors are the main cell types expressing SVCT2 in the lissencephalic brain. SVCT2 was mainly detected in the apical region of the ventricular zone cells, contacting the cerebrospinal fluid. In gyrencephalic brains, SVCT2 was also detected in progenitor cells located in the inner and outer SVZ. Finally, we defined that AA has a strong radializing (bipolar morphology) effect in progenitor cells in culture and the differentiation condition modulates SVCT2 expression.

Endozepines are endogenous ligands for the benzodiazepine receptors and also target a still unidentified GPCR. The endozepine octadecaneuropeptide (ODN), an endoproteolytic processing product of the diazepam-binding inhibitor (DBI) was recently shown to be involved in food intake control as an anorexigenic factor through ODN-GPCR signaling and mobilization of the melanocortinergic signaling pathway. Within the hypothalamus, the DBI gene is mainly expressed by non-neuronal cells such as ependymocytes, tanycytes, and protoplasmic astrocytes, at levels depending on the nutritional status. Administration of ODN C-terminal octapeptide (OP) in the arcuate nucleus strongly reduces food intake. Up to now, the relevance of extrahypothalamic targets for endozepine signaling-mediated anorexia has been largely ignored. We focused our study on the dorsal vagal complex located in the caudal brainstem. This structure is strongly involved in the homeostatic control of food intake and comprises structural similarities with the hypothalamus. In particular, a circumventricular organ, the area postrema (AP) and a tanycyte-like cells forming barrier between the AP and the adjacent nucleus tractus solitarius (NTS) are present. We show here that DBI is highly expressed by ependymocytes lining the fourth ventricle, tanycytes-like cells, as well as by proteoplasmic astrocytes located in the vicinity of AP/NTS interface. ODN staining observed at the electron microscopic level reveals that ODN-expressing tanycyte-like cells and protoplasmic astrocytes are sometimes found in close apposition to neuronal elements such as dendritic profiles or axon terminals. Intracerebroventricular injection of ODN or OP in the fourth ventricle triggers c-Fos activation in the dorsal vagal complex and strongly reduces food intake. We also show that, similarly to leptin, ODN inhibits the swallowing reflex when microinjected into the swallowing pattern generator located in the NTS. In conclusion, we hypothesized that ODN expressing cells located at the AP/NTS interface could release ODN and modify excitability of NTS neurocircuitries involved in food intake control.

Tanycytes are emerging as key players in the neuroendocrine control of gonadotrophin-releasing hormone (GnRH) release. Rodent studies have demonstrated that the structural relationship between tanycytes and GnRH terminals in the median eminence is highly dynamic, regulated by gonadal steroids and undergoes age-related changes. The present study aimed to determine whether the number and organisation of tanycytes changes throughout life in the female infundibular nucleus/median eminence (INF/ME) region. Post-mortem hypothalamic tissues were collected at the Netherlands Brain Bank and were stained for vimentin by immunohistochemistry. Hypothalami of 22 control female subjects were categorised into three periods: infant/prepubertal, adult and elderly. We measured the fractional area covered by vimentin immunoreactivity in the INF. Qualitative analysis demonstrated a remarkable parallel organisation of vimentin-immunoreactive processes during the infant/prepubertal and adult periods. During the elderly period, this organisation was largely lost. Semi-quantitatively, the fractional area covered in vimentin immunoreactivity was significantly higher at the infant/prepubertal compared to the adult period and almost reached statistical significance compared to the elderly period. By contrast, the number of tanycyte cell bodies did not appear to change throughout life. The results of the present study thus demonstrate that the number and structure of tanycytic processes are altered during ageing, suggesting that tanycytes might be involved in the age-related changes observed in GnRH release., (© 2017 British Society for Neuroendocrinology.)

Lactate transporters play an important role in the glutamate recycling. Here their kinetics and tissue distribution with emphasis on the brain are addressed. Recent evidence shows their participation in important brain functions that involve intercellular communication, such as hypothalamic glucose sensing. Furthermore, we describe the regulation of their expression and some animal models that have allowed clarification of their functions.

In the adult hypothalamus and ependymal lining of the third ventricle, tanycytes function as multipotential progenitor cells that enable continuous neurogenesis, suggesting that tanycytes may be able to mediate the restoration of homeostatic function after stroke. Voluntary wheel running has been shown to alter neurochemistry and neuronal function and to increase neurogenesis in rodents. In the present study, we found that voluntary exercise improved the survival rate and energy balance of stroke-prone spontaneously hypertensive rats (SHRSP/Kpo). We also investigated the effect of exercise on the proliferation and differentiation of hypothalamic cells using immunoreactivity for tanycytes and neural markers. The proliferation of elongated cells, which may be the tanycytes, was enhanced in exercising SHRSP compared to sedentary rats before and after stroke. In addition, the proliferation of cells was correlated with the induction of fibroblast growth factor-2 in the subependymal cells of the third ventricle and in the cerebrospinal fluid. Some of the newborn cells of exercising SHRSP showed differentiation into mature neurons after stroke. Our results suggest that voluntary exercise correlates with hypothalamic neurogenesis, leading to recovery of homeostatic functions in the adult brain after stroke.

The discovery of thyrotropin releasing hormone (TRH) in 1969 was the definitive step in decoding the hypothalamic-pituitary thyroid (HPT) axis, thereby opening up the era of neuroendocrinology, while it also revolutionized the diagnostic and therapeutic approach to patients with thyroid diseases. TRH, produced in the hypothalamus, is the central regulator of the HPT. It functions via neurons originating in the paraventricular nucleus (PVN), which integrates multiple neuronal and humoral signals and resets the HPT axis according to variations of external and internal environmental conditions. The TRH activates TSH in the pituitary that stimulates the secretion of thyroxine from thyroid which, in turn, exerts a negative feedback on TSH and TRH secretion. However, various factors are involved in the regulation of the HPT axis. Leptin has both indirect and direct effects on TRH regulation, the former by regulating agouti-related peptide (AGRP) in the arcuate nucleus (ARN) that antagonizes the α-MSH stimulatory activity on pro-TRH gene expression in the PVN, and the latter by stimulating hypothalamic TRH expression, TRH transcription via stimulation of pro-convertase 1 and 2 expression, which lead to enhanced processing of pro-TRH into TRH. The interplay of TRH with leptin and the recently reported influence of ghrelin on the HPT axis can alter the setpoint of the axis. The polyphenol resveratrol, as recently observed, exerts an anxiolytic and antidepressant activity in subclinical hypothyroid (SCH) rats. Resveratrol, by decreasing both TSH and TRH mRNA expression, regulates the HPT axis, while in parallel it regulates the Wnt/β-catenin pathway in the hippocampus. These findings open up possibilities for the therapeutic use of resveratrol as coadjuvant, especially in overt and SCH states marked by anxiety and depression. The clinician should be aware of clinical changes that can invalidate the normal regulation of the HPT axis, the most commonly observed being medications and comorbidities., Competing Interests: The author declares that he has no conflict of interest concerning this article.

Summary: It is becoming increasingly apparent that non-neuronal cells play a critical role in generating and regulating the flow of information within the brain. Among these non-neuronal cells, astroglial cells have been shown to play important roles in the control of both synaptic transmission and neurosecretion. In addition to modulating neuronal activity, astroglial cells interact with endothelial cells throughout the central nervous system to define specific functional domains. In the hypothalamus, neurons that release gonadotropin-releasing hormone (GnRH), the neurohormone that controls both sexual development and adult reproductive function, offer an attractive model system in which to study glial–neuronal–endothelial interactions. Within the median eminence of the hypothalamus, alterations of the anatomical relationship that exists between GnRH axon terminals and ependymoglial cell processes belonging to tanycytes regulate the direct access of GnRH neurosecretory axons to the vascular wall. This cell plasticity presumably modulates the release of GnRH into the portal vasculature during the reproductive cycle. Both structural changes and GnRH secretory activity appear to be modulated, at least in part, by specific cell–cell signalling molecules secreted by astrocytes, tanycytes and endothelial cells. It is becoming increasingly clear that among the different factors that may be involved, glial cells use growth factor members of the epidermal growth factor (EGF) family, acting via receptors endowed with tyrosine kinase activity, to produce morphological changes and release neuroactive substances that directly excite nearby neurons, whereas endothelial cells of the median eminence employ nitric oxide to induce neuroglial plasticity and facilitate GnRH release. [Copyright &y& Elsevier]

Objective: Excess nutrient supply and rapid weight gain during early life are risk factors for the development of obesity during adulthood. This metabolic malprogramming may be mediated by endocrine disturbances during critical periods of development. Ghrelin is a metabolic hormone secreted from the stomach that acts centrally to promote feeding behavior by binding to growth hormone secretagogue receptors in the arcuate nucleus of the hypothalamus. Here, we examined whether neonatal overnutrition causes changes in the ghrelin system., Methods: We used a well-described mouse model of divergent litter sizes to study the effects of postnatal overfeeding on the central and peripheral ghrelin systems during postnatal development., Results: Mice raised in small litters became overweight during lactation and remained overweight with increased adiposity as adults. Neonatally overnourished mice showed attenuated levels of total and acyl ghrelin in serum and decreased levels of Ghrelin mRNA expression in the stomach during the third week of postnatal life. Normalization of hypoghrelinemia in overnourished pups was relatively ineffective at ameliorating metabolic outcomes, suggesting that small litter pups may present ghrelin resistance. Consistent with this idea, neonatally overnourished pups displayed an impaired central response to peripheral ghrelin. The mechanisms underlying this ghrelin resistance appear to include diminished ghrelin transport into the hypothalamus., Conclusions: Early postnatal overnutrition results in central resistance to peripheral ghrelin during important periods of hypothalamic development. Because ghrelin signaling has recently been implicated in the neonatal programming of metabolism, these alterations in the ghrelin system may contribute to the metabolic defects observed in postnatally overnourished mice.

The medial hypothalamus is composed of nuclei of the tuberal hypothalamus, the paraventricular nucleus of the anterior hypothalamus, and the neurohypophysis. Its arrangement, around the third ventricle of the brain, above the adenohypophysis, and in direct contact with the vasculature, means that it serves as an interface with circulating systems, providing a key conduit through which the brain can sample, and control, peripheral body systems. Through these interfaces, and interactions with other parts of the brain, the medial hypothalamus centrally governs diverse homeostatic processes, including energy and fluid balance, stress responses, growth, and reproductive behaviors. Here, we summarize recent studies that reveal how the diverse cell types within the medial hypothalamus are assembled in an integrated manner to enable its later function. In particular, we discuss how the temporally protracted operation of signaling pathways and transcription factors governs the appearance and regionalization of the hypothalamic primordium from the prosencephalic territory, the specification and differentiation of progenitors into neurons in organized nuclei, and the establishment of interfaces. Through analyses of mouse, chick, and zebrafish, a picture emerges of an evolutionarily conserved and highly coordinated developmental program. Early indications suggest that deregulation of this program may underlie complex human pathological conditions and dysfunctional behaviors, including stress and eating disorders., (© 2013 Elsevier Inc. All rights reserved.)