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Chemogenetic activation of hypophysiotropic TRH neurons increases TSH release. a–c Colocalization of Trh mRNA (a, magenta) and hM3D-mCherry (b, cyan) in the PVN 2 weeks after bilateral injection of AAV-TRH-hM3D-mCherry (PVN 3D ). Cells expressing Trh mRNA were positive for hM3D-mCherry (yellow arrowheads; c and d). Red arrowheads label hM3D-mCherry-positive cells without Trh mRNA expression; scale bar, 50 µm. e Plasma TSH concentrations 45 min after CNO administration to Trhr1 +/+ (Bl6) and littermate Trhr1 −/− mice without (PVN Con , gray) and with injection of AAV-TRHhM3D-mCherry into the PVN (PVN 3D , red). TSH plasma concentrations are shown as percentage of Bl6 for normalization, because of a slight but nonsignificant increase of TSH in Trhr1 −/− compared to Bl6 mice. Two-way ANOVA for genotype: F(1/20) = 5.3, p = 0.032; *p < 0.05 (Bonferroni post test); mean ± S.E.M.; n as indicated. f Relative change in Fos mRNA expression (2 −ΔΔCT ) in the pituitary 45 min after CNO administration to Bl6 and Trhr1 −/− mice without (PVN Con , gray) and with injection of AAV-TRH-hM3D-mCherry into the PVN (PVN 3D , red). Two-way ANOVA for genotype: F(1/19) = 4.4, p = 0.049; *p < 0.05 (Bonferroni post test); mean ± S.E.M.; n as indicated. g and h Two weeks after bilateral injection of AAV-TRH-hM3D-mCherry (PVN 3D )
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The hypothalamic–pituitary–thyroid (HPT) axis maintains circulating thyroid hormone levels in a narrow physiological range. As axons containing thyrotropin-releasing hormone (TRH) terminate on hypothalamic tanycytes, these specialized glial cells have been suggested to influence the activity of the HPT axis, but their exact role remained enigmatic....
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... The presence of caveolin in the terminal pole of β1and β2-tanycytes [112] suggests the endocytosis/transport of molecules derived from the blood by a non-clathrin mechanism [113], as with that of other receptor-mediated processes. Thus, an intriguing possibility is brain entry of TRH through transport mediated by TRH receptors in β1or β2-tanycytes since tanycytes might express Trhr [114], but see [115], a mechanism analogous to that suggested for leptin [116] and ghrelin [117] transport in tanycytes. Peripherally injected TRH effects may therefore be due, in part, to a central site of action. ...
Thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH2) is an intercellular signal produced mainly by neurons. Among the multiple pharmacological effects of TRH, that on food intake is not well understood. We review studies demonstrating that peripheral injection of TRH generally produces a transient anorexic effect, discuss the pathways that might initiate this effect, and explain its short half-life. In addition, central administration of TRH can produce anorexic or orexigenic effects, depending on the site of injection, that are likely due to interaction with TRH receptor 1. Anorexic effects are most notable when TRH is injected into the hypothalamus and the nucleus accumbens, while the orexigenic effect has only been detected by injection into the brain stem. Functional evidence points to TRH neurons that are prime candidate vectors for TRH action on food intake. These include the caudal raphe nuclei projecting to the dorsal motor nucleus of the vagus, and possibly TRH neurons from the tuberal lateral hypothalamus projecting to the tuberomammillary nuclei. For other TRH neurons, the anatomical or physiological context and impact of TRH in each synaptic domain are still poorly understood. The manipulation of TRH expression in well-defined neuron types will facilitate the discovery of its role in food intake control in each anatomical scene.
... The presence of caveolin in the terminal pole of β1-and β2-tanycytes [112] suggests the endocytosis/transport of molecules derived from the blood by a non-clathrin mechanism [113], as that of other receptor-mediated processes. Thus, an intriguing possibility is brain entry of TRH through transport mediated by TRH receptors in β1-or β2-tanycytes, since tanycytes might express Trhr [114], but see [115], a mechanism analogous to that suggested for leptin [116] and ghrelin [117] transport in tanycytes. Peripherally injected TRH effects may therefore be due, in part, to a central site of action. ...
Thyrotropin releasing hormone (TRH; pGlu-His-Pro-NH2) is an intercellular signal produced mainly by neurons. Among the multiple pharmacological effects of TRH, that on food-intake is not well understood. We review data that show that peripheral injection of TRH generally produces a transient anorexic effect, discuss the pathways that might initiate this effect, and explain its short half-life. In addition, central administration of TRH can produce anorexic or orexigenic effects, depending on the site of injection, that are likely due to interaction with TRH receptor 1. Anorexic effects are most notable when TRH is injected into the hypothalamus and the nucleus accumbens, while the orexigenic effect has only been detected by injection into the brain stem. Functional evidence suggests that TRH neurons that are prime candidate vectors for TRH action on food-intake include the caudal raphe nuclei projecting to the dorsal motor nucleus of the vagus, and possibly TRH neurons from the tuberal lateral hypothalamus projecting to the tuberomammillary nuclei. For other TRH neurons, the anatomical or physiological context and impact of TRH in each synaptic domain are still poorly understood. The manipulation of TRH expression in well-defined neuron types will facilitate the discovery of its role in food-intake control in each anatomical scene.
... Article are polarized, with their soma being in direct contact with the cerebrospinal fluid (CSF) and their single basal process extending far into the hypothalamic parenchyma and terminating around blood vessels and/or neurons 5 . Thus, tanycytes are poised to facilitate the bidirectional exchange of metabolites, hormones and signalling molecules between the central nervous system and the periphery 2,3,5,6,[15][16][17][18][19] . Even so, it remains unresolved whether tanycytes are regulated indirectly or by direct innervation to release any specific molecules to exert systemic commands 3,7,8,15,[19][20][21] . ...
... Thus, tanycytes are poised to facilitate the bidirectional exchange of metabolites, hormones and signalling molecules between the central nervous system and the periphery 2,3,5,6,[15][16][17][18][19] . Even so, it remains unresolved whether tanycytes are regulated indirectly or by direct innervation to release any specific molecules to exert systemic commands 3,7,8,15,[19][20][21] . The innervation of tanycytes is supported by ultrastructural studies that identify 'synaptoid contacts' 22,23 , presynapse-like elements enriched in synaptic vesicles, along the basal processes of tanycytes [22][23][24][25] . ...
Empirical evidence suggests that heat exposure reduces food intake. However, the neurocircuit architecture and the signalling mechanisms that form an associative interface between sensory and metabolic modalities remain unknown, despite primary thermoceptive neurons in the pontine parabrachial nucleus becoming well characterized¹. Tanycytes are a specialized cell type along the wall of the third ventricle² that bidirectionally transport hormones and signalling molecules between the brain’s parenchyma and ventricular system3–8. Here we show that tanycytes are activated upon acute thermal challenge and are necessary to reduce food intake afterwards. Virus-mediated gene manipulation and circuit mapping showed that thermosensing glutamatergic neurons of the parabrachial nucleus innervate tanycytes either directly or through second-order hypothalamic neurons. Heat-dependent Fos expression in tanycytes suggested their ability to produce signalling molecules, including vascular endothelial growth factor A (VEGFA). Instead of discharging VEGFA into the cerebrospinal fluid for a systemic effect, VEGFA was released along the parenchymal processes of tanycytes in the arcuate nucleus. VEGFA then increased the spike threshold of Flt1-expressing dopamine and agouti-related peptide (Agrp)-containing neurons, thus priming net anorexigenic output. Indeed, both acute heat and the chemogenetic activation of glutamatergic parabrachial neurons at thermoneutrality reduced food intake for hours, in a manner that is sensitive to both Vegfa loss-of-function and blockage of vesicle-associated membrane protein 2 (VAMP2)-dependent exocytosis from tanycytes. Overall, we define a multimodal neurocircuit in which tanycytes link parabrachial sensory relay to the long-term enforcement of a metabolic code.
... However, different metabolic-associated conditions, such as hypoglycemia, chronic HFD-induced obesity, insulin intolerance, and hyperglycemia, can induce contrasting signaling events and outcomes. For instance, leptin activates the ERK signaling pathway, and insulin and insulin-like growth factor 1 (IGF-1) initiate a conventional intracellular signaling pathway that forms an interconnected link between metabolic modulation and cognition [20,105]. ...
Diabetes is a chronic metabolic condition associated with high levels of blood glucose which leads to serious damage to the heart, kidney, eyes, and nerves. Elevated blood glucose levels damage brain function and cognitive abilities. They also lead to various neurological and neuropsychiatric disorders, including chronic neurodegeneration and cognitive decline. High neuronal glucose levels can cause drastic neuronal damage due to glucose neurotoxicity. Astrocytes, a type of glial cell, play a vital role in maintaining brain glucose levels through neuron–astrocyte coupling. Hyperglycemia leads to progressive decline in neuronal networks and cognitive impairment, contributing to neuronal dysfunction and fostering a neurodegenerative environment. In this review, we summarize the various connections, functions, and impairments of glial cells due to metabolic dysfunction in the diabetic brain. We also summarize the effects of hyperglycemia on various neuronal functions in the diabetic brain.
Keywords: astrocytes; diabetes; metabolic complications; glial dysfunction; neurodegeneration
... In addition, T3 released from tanycytes may directly act on the ARC, regulating energy homeostasis [369]. Food deprivation results in increased DIO2 expression in ME tanycytes and in a global increase in the levels of T3 in the hypothalamus [375,[379][380][381][382]. In vivo, activation of TRH receptors type-1 (TRHR1s) results in the selective increase in the levels of intracellular Ca ++ in ME tanycytes, enhancing the outgrowth of tanycytic processes that ensheathe TRH terminals, and increasing the activity of PPII [383]. Given the above, ME tanycyte-TRH neuron interactions may control the HPT axis [19,369]. ...
Neural progenitor cells (NPCs) are multipotent neural stem cells (NSCs) capable of self-renewing and differentiating into neurons, astrocytes and oligodendrocytes. In the postnatal/adult brain, NPCs are primarily located in the subventricular zone (SVZ) of the lateral ventricles (LVs) and subgranular zone (SGZ) of the hippocampal dentate gyrus (DG). There is evidence that NPCs are also present in the postnatal/adult hypothalamus, a highly conserved brain region involved in the regulation of core homeostatic processes, such as feeding, metabolism, reproduction, neuroendocrine integration and autonomic output. In the rodent postnatal/adult hypothalamus, NPCs mainly comprise different subtypes of tanycytes lining the wall of the 3rd ventricle. In the postnatal/adult human hypothalamus, the neurogenic niche is constituted by tanycytes at the floor of the 3rd ventricle, ependymal cells and ribbon cells (showing a gap-and-ribbon organization similar to that in the SVZ), as well as suprachiasmatic cells. We speculate that in the postnatal/adult human hypothalamus, neurogenesis occurs in a highly complex, exquisitely sophisticated neurogenic niche consisting of at least four subniches; this structure has a key role in the regulation of extrahypothalamic neurogenesis, and hypothalamic and extrahypothalamic neural circuits, partly through the release of neurotransmitters, neuropeptides, extracellular vesicles (EVs) and non-coding RNAs (ncRNAs).
... Several POPs were significantly associated with thyroid hormones. It is noteworthy that T4 was negatively associated with PBDE and positively with 1,234,678-HpCDF; T3 was positively associated with 2378-TeCDF and 12,378-PeCDF; and rT3 was positively associated with PCB 81, 12,378-PeCDF, and 234,678-HxCDF, and negatively with tributyltin, OTC, and methoxychlor (Müller-Fielitz et al. 2017). These findings imply that prenatal exposure to POPs, with the effects possibly mediated by thyroid hormones levels in placenta, may negatively impact childhood growth and development. ...
... We found that the M5 tanycytes have a close connection to the fenestrated capillaries and cover the latter with their endfeet. As the functional plasticity of endfeet is a Gqdependent process 42 , the M5 channel might underlie opening of voltage-gated channels increasing the intracellular calcium concentration to initiate endfoot plasticity. An absence of M5 tanycytes may thus impair hypothalamic barrier functioning and feedback integration. ...
The median eminence (ME) is a circumventricular organ at the base of the brain that controls body homeostasis. Tanycytes are its specialized glial cells that constitute the ventricular walls and regulate different physiological states, however individual signaling pathways in these cells are incompletely understood. Here, we identify a functional tanycyte subpopulation that expresses key taste transduction genes including bitter taste receptors, the G protein gustducin and the gustatory ion channel TRPM5 (M5). M5 tanycytes have access to blood-borne cues via processes extended towards diaphragmed endothelial fenestrations in the ME and mediate bidirectional communication between the cerebrospinal fluid and blood. This subpopulation responds to metabolic signals including leptin and other hormonal cues and is transcriptionally reprogrammed upon fasting. Acute M5 tanycyte activation induces insulin secretion and acute diphtheria toxin-mediated M5 tanycyte depletion results in impaired glucose tolerance in diet-induced obese mice. We provide a cellular and molecular framework that defines how bitter taste cells in the ME integrate chemosensation with metabolism.
... Dairy goat are seasonal breeding livestock within which the hypothalamic-pituitary-thyroid (HPT) axis plays a Frontiers in Genetics frontiersin.org crucial role in sexual maturation and reproduction (Müller-Fielitz et al., 2017). TSHB is an important component of thyroid stimulating hormone (TSH), deciding the biological specificity and synthesis rate of TSH, and is closely related to the photoperiod of seasonal reproduction in mammals (Huang et al., 2013). ...
The dairy goat is one of the earliest dairy livestock species, which plays an important role in the economic development, especially for developing countries. With the development of agricultural civilization, dairy goats have been widely distributed across the world. However, few studies have been conducted on the specific characteristics of dairy goat. In this study, we collected the whole-genome data of 89 goat individuals by sequencing 48 goats and employing 41 publicly available goats, including five dairy goat breeds (Saanen, Nubian, Alpine, Toggenburg, and Guanzhong dairy goat; n = 24, 15, 11, 6, 6), and three goat breeds (Guishan goat, Longlin goat, Yunshang Black goat; n = 6, 15, 6). Through compared the genomes of dairy goat and non-dairy goat to analyze genetic diversity and selection characteristics of dairy goat. The results show that the eight goats could be divided into three subgroups of European, African, and Chinese indigenous goat populations, and we also found that Australian Nubian, Toggenburg, and Australian Alpine had the highest linkage disequilibrium, the lowest level of nucleotide diversity, and a higher inbreeding coefficient, indicating that they were strongly artificially selected. In addition, we identified several candidate genes related to the specificity of dairy goat, particularly genes associated with milk production traits (GHR, DGAT2, ELF5, GLYCAM1, ACSBG2, ACSS2), reproduction traits (TSHR, TSHB, PTGS2, ESR2), immunity traits (JAK1, POU2F2, LRRC66). Our results provide not only insights into the evolutionary history and breed characteristics of dairy goat, but also valuable information for the implementation and improvement of dairy goat cross breeding program.
... Therefore, more studies are needed to clarify the greater concentrations of TSH caused by exposure to MCs. Also, changes in tanycytes arrangement in the median eminence of hypothalamus observed by histopathology might result in failure of TRH neurons to receive negative feedback regulation from T3 (Fekete and Lechan, 2014;Müller-Fielitz et al., 2017), and thus concentrations of TRH were unchanged after MCs exposure, which requires further investigation. ...
Microcystins (MCs) produced by some cyanobacteria can cause toxicity in animals and humans. In recent years, growing evidence suggests that MCs can act as endocrine disruptors. This research systematically investigated effects of microcystin-LR (MC-LR) on endocrine organs, biosynthesis of hormones and positive/negative feedback of the endocrine system in rats. Male, Sprague-Dawley rats were acutely administrated MC-LR by a single intraperitoneal injection at doses of 45, 67.5 or 90 μg MC-LR/kg body mass (bm), and then euthanized 24 h after exposure. In exposed rats, histological damage of hypothalamus, pituitary, adrenal, testis and thyroid were observed. Serum concentrations of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and corticosterone (CORT), expressions of genes and proteins for biosynthesis of hormones were lesser, which indicated an overall suppression of the hypothalamus-pituitary-adrenal (HPA) axis. Along the hypothalamus-pituitary-gonadal (HPG) axis, lesser concentrations of gonadotropin-releasing hormone (GnRH) and testosterone (T), but greater concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol (E2) were observed. Except for greater transcription of cyp19a1 in testes, transcriptions of genes and proteins for T and E2 biosynthesis along the HPG axis were lesser. As for the hypothalamus-pituitary-thyroid (HPT) axis, after MCs treatment, greater concentrations of thyroid-stimulating hormone (TSH), but lesser concentrations of free tri-iodothyronine (fT3) were observed in serum. Concentrations of free tetra-iodothyronine (fT4) were greater in rats dosed with 45 μg MCs/kg, bm, but lesser in rats dosed with 67.5 or 90 μg MCs/kg, bm. Transcripts of genes for biosynthesis of hormones and receptors along the HPT axis and expressions of proteins for biosynthesis of tetra-iodothyronine (T4) and tri-iodothyronine (T3) in thyroid were significantly altered. Cross-talk among the HPA, HPG and HPT axes probably occurred. It was concluded that MCs caused an imbalance of positive and negative feedback of hormonal regulatory axes, blocked biosynthesis of key hormones and exhibited endocrine-disrupting effects.
... Therefore, more studies are needed to clarify the greater concentrations of TSH caused by exposure to MCs. Also, changes in tanycytes arrangement in the median eminence of hypothalamus observed by histopathology might result in failure of TRH neurons to receive negative feedback regulation from T3 (Fekete and Lechan, 2014;Müller-Fielitz et al., 2017), and thus concentrations of TRH were unchanged after MCs exposure, which requires further investigation. ...
Microcystins (MCs) produced by some cyanobacteria can cause toxicity in animals and humans. In recent years, growing evidence suggests that MCs can act as endocrine disruptors. This research systematically investigated effects of microcystin-LR (MC-LR) on endocrine organs, biosynthesis of hormones and positive/negative feedback on the endocrine system in rats. Male, Sprague-Dawley rats were acutely administrated MC-LR by a single intraperitoneal injection at doses of 45, 67.5 or 90 μg MC-LR/kg body mass (bm), and then euthanized 24 h after exposure. In exposed rats, histological damage of hypothalamus, pituitary, adrenal, testis and thyroid were observed. Serum concentrations of corticotropin-releasing hormone, adrenocorticotropic hormone and corticosterone, expressions of genes and proteins for biosynthesis of hormones were less, which indicated an overall suppression of the hypothalamus-pituitary-adrenal (HPA) axis. Along the hypothalamus-pituitary-gonadal (HPG) axis, lesser concentrations of gonadotropin-releasing hormone and testosterone (T), but greater concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol (E2) were observed. Except for greater transcription of cyp19a1 in testes, transcriptions of genes and proteins for T and E2 biosynthesis along the HPG axis were lesser. As for the hypothalamus-pituitary-thyroid (HPT) axis, after MCs treatment, greater concentrations of thyroid-stimulating hormone, but lesser concentrations of free tri-iodothyronine (fT3) were observed in serum. Concentrations of free tetra-iodothyronine (fT4) were greater in rats dosed with 45 μg MCs/kg, bm, but lesser in rats dosed with 67.5 or 90 μg MCs/kg, bm. Transcripts of genes for biosynthesis of hormones and receptors along the HPT axis and expressions of proteins for biosynthesis of T4 and T3 in thyroid were significantly altered. Cross-talk among the HPA, HPG and HPT axes probably occurred. It was concluded that MCs caused an imbalance of positive and negative feedback of hormonal regulatory axes, blocked biosynthesis of key hormones and exhibited endocrine-disrupting effects.
