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1.
Sci Rep ; 14(1): 10190, 2024 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-38702366

RESUMEN

Dysfunction of central serotonergic neurons is known to cause depressive disorders in humans, who often show reproductive and/or glucose metabolism disorders. This study examined whether dorsal raphe (DR) serotonergic neurons sense high glucose availability to upregulate reproductive function via activating hypothalamic arcuate (ARC) kisspeptin neurons (= KNDy neurons), a dominant stimulator of gonadotropin-releasing hormone (GnRH)/gonadotropin pulses, using female rats and goats. RNA-seq and histological analysis revealed that stimulatory serotonin-2C receptor (5HT2CR) was mainly expressed in the KNDy neurons in female rats. The serotonergic reuptake inhibitor administration into the mediobasal hypothalamus (MBH), including the ARC, significantly blocked glucoprivic suppression of luteinizing hormone (LH) pulses and hyperglycemia induced by intravenous 2-deoxy-D-glucose (2DG) administration in female rats. A local infusion of glucose into the DR significantly increased in vivo serotonin release in the MBH and partly restored LH pulses and hyperglycemia in the 2DG-treated female rats. Furthermore, central administration of serotonin or a 5HT2CR agonist immediately evoked GnRH pulse generator activity, and central 5HT2CR antagonism blocked the serotonin-induced facilitation of GnRH pulse generator activity in ovariectomized goats. These results suggest that DR serotonergic neurons sense high glucose availability to reduce gluconeogenesis and upregulate reproductive function by activating GnRH/LH pulse generator activity in mammals.


Asunto(s)
Glucosa , Cabras , Hormona Liberadora de Gonadotropina , Hormona Luteinizante , Receptor de Serotonina 5-HT2C , Neuronas Serotoninérgicas , Animales , Hormona Luteinizante/metabolismo , Femenino , Receptor de Serotonina 5-HT2C/metabolismo , Ratas , Neuronas Serotoninérgicas/metabolismo , Hormona Liberadora de Gonadotropina/metabolismo , Glucosa/metabolismo , Serotonina/metabolismo , Kisspeptinas/metabolismo , Núcleo Arqueado del Hipotálamo/metabolismo , Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Núcleo Dorsal del Rafe/metabolismo , Núcleo Dorsal del Rafe/efectos de los fármacos , Ratas Sprague-Dawley
2.
Mol Pain ; 20: 17448069241254201, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38670551

RESUMEN

It has been widely recognized that electroacupuncture (EA) inducing the release of ß-endorphin represents a crucial mechanism of EA analgesia. The arcuate nucleus (ARC) in the hypothalamus is a vital component of the endogenous opioid peptide system. Serving as an integration center, the periaqueductal gray (PAG) receives neural fiber projections from the frontal cortex, insular cortex, and ARC. However, the specific mechanisms how EA facilitates the release of ß-endorphin within the ARC, eliciting analgesic effects are yet to be elucidated. In this study, we conducted in vivo and in vitro experiments by transcriptomics, microdialysis, photogenetics, chemical genetics, and calcium imaging, combined with transgenic animals. Firstly, we detected 2 Hz EA at the Zusanli (ST36) increased the level of ß-endorphin and transcriptional level of proopiomelanocortin (POMC). Our transcriptomics profiling demonstrated that 2 Hz EA at the ST36 modulates the expression of c-Fos and Jun B in ARC brain nuclear cluster, and the transcriptional regulation of 2 Hz EA mainly occur in POMC neurons by Immunofluorescence staining verification. Meaning while, 2 Hz EA specifically activated the cAMP-PKA-CREB signaling pathway in ARC which mediating the c-Fos and Jun B transcription, and 2 Hz EA analgesia is dependent on the activation of cAMP-PKA-CREB signaling pathway in ARC. In order to investigate how the ß-endorphin produced in ARC transfer to integration center PAG, transneuronal tracing technology was used to observe the 2 Hz EA promoted the neural projection from ARC to PAG compared to 100 Hz EA and sham mice. Inhibited PAGGABA neurons, the transfer of ß-endorphin from the ARC nucleus to the PAG nucleus through the ARCPOMC-PAGGABA neural circuit. Furthermore, by manipulating the excitability of POMC neurons from ARCPOMC to PAGGABA using inhibitory chemogenetics and optogenetics, we found that this inhibition significantly reduced transfer of ß-endorphin from the ARC nucleus to the PAG nucleus and the effectiveness of 2 Hz EA analgesia in neurological POMC cyclization recombination enzyme (Cre) mice and C57BL/6J mice, which indicates that the transfer of ß-endorphin depends on the activation of POMC neurons prefect from ARCPOMC to PAGGABA. These findings contribute to our understanding of the neural circuitry underlying the EA pain-relieving effects and maybe provide valuable insights for optimizing EA stimulation parameters in clinical pain treatment using the in vivo dynamic visual investigating the central analgesic mechanism.


Asunto(s)
Núcleo Arqueado del Hipotálamo , Electroacupuntura , Sustancia Gris Periacueductal , Proopiomelanocortina , betaendorfina , Animales , Proopiomelanocortina/metabolismo , Proopiomelanocortina/genética , Sustancia Gris Periacueductal/metabolismo , Núcleo Arqueado del Hipotálamo/metabolismo , Electroacupuntura/métodos , betaendorfina/metabolismo , Masculino , Ratones Transgénicos , Ratones Endogámicos C57BL , Ratones , Proteínas Proto-Oncogénicas c-fos/metabolismo , Neuronas/metabolismo
3.
Mol Autism ; 15(1): 14, 2024 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-38570876

RESUMEN

BACKGROUND: SH3 and multiple ankyrin repeat domains protein 3 (SHANK3) monogenic mutations or deficiency leads to excessive stereotypic behavior and impaired sociability, which frequently occur in autism cases. To date, the underlying mechanisms by which Shank3 mutation or deletion causes autism and the part of the brain in which Shank3 mutation leads to the autistic phenotypes are understudied. The hypothalamus is associated with stereotypic behavior and sociability. p38α, a mediator of inflammatory responses in the brain, has been postulated as a potential gene for certain cases of autism occurrence. However, it is unclear whether hypothalamus and p38α are involved in the development of autism caused by Shank3 mutations or deficiency. METHODS: Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and immunoblotting were used to assess alternated signaling pathways in the hypothalamus of Shank3 knockout (Shank3-/-) mice. Home-Cage real-time monitoring test was performed to record stereotypic behavior and three-chamber test was used to monitor the sociability of mice. Adeno-associated viruses 9 (AAV9) were used to express p38α in the arcuate nucleus (ARC) or agouti-related peptide (AgRP) neurons. D176A and F327S mutations expressed constitutively active p38α. T180A and Y182F mutations expressed inactive p38α. RESULTS: We found that Shank3 controls stereotypic behavior and sociability by regulating p38α activity in AgRP neurons. Phosphorylated p38 level in hypothalamus is significantly enhanced in Shank3-/- mice. Consistently, overexpression of p38α in ARC or AgRP neurons elicits excessive stereotypic behavior and impairs sociability in wild-type (WT) mice. Notably, activated p38α in AgRP neurons increases stereotypic behavior and impairs sociability. Conversely, inactivated p38α in AgRP neurons significantly ameliorates autistic behaviors of Shank3-/- mice. In contrast, activated p38α in pro-opiomelanocortin (POMC) neurons does not affect stereotypic behavior and sociability in mice. LIMITATIONS: We demonstrated that SHANK3 regulates the phosphorylated p38 level in the hypothalamus and inactivated p38α in AgRP neurons significantly ameliorates autistic behaviors of Shank3-/- mice. However, we did not clarify the biochemical mechanism of SHANK3 inhibiting p38α in AgRP neurons. CONCLUSIONS: These results demonstrate that the Shank3 deficiency caused autistic-like behaviors by activating p38α signaling in AgRP neurons, suggesting that p38α signaling in AgRP neurons is a potential therapeutic target for Shank3 mutant-related autism.


Asunto(s)
Trastorno Autístico , Animales , Ratones , Proteína Relacionada con Agouti/genética , Proteína Relacionada con Agouti/metabolismo , Núcleo Arqueado del Hipotálamo/metabolismo , Trastorno Autístico/genética , Trastorno Autístico/metabolismo , Hipotálamo/metabolismo , Proteínas de Microfilamentos/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Proteína Quinasa 14 Activada por Mitógenos/metabolismo
4.
Neuropharmacology ; 253: 109951, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-38615749

RESUMEN

Microglia are the macrophages of the central nervous system (CNS), implying their role in maintaining brain homeostasis. To achieve this, these cells are sensitive to a plethora of endogenous and exogenous signals, such as neuronal activity, cellular debris, hormones, and pathological patterns, among many others. More recent research suggests that microglia are highly responsive to nutrients and dietary variations. In this context, numerous studies have demonstrated their significant role in the development of obesity under calorie surfeit. Because many reviews already exist on this topic, we have chosen to present the state of our reflections on various concepts put forth in the literature, bringing a new perspective whenever possible. Our literature review focuses on studies conducted in the arcuate nucleus of the hypothalamus, a key structure in the control of food intake. Specifically, we present the recent data available on the modifications of microglial energy metabolism following the consumption of an obesogenic diet and their consequences on hypothalamic neuron activity. We also highlight the studies unraveling the mechanisms underlying obesity-related sexual dimorphism. The review concludes with a list of questions that remain to be addressed in the field to achieve a comprehensive understanding of the role of microglia in the regulation of body energy metabolism. This article is part of the Special Issue on "Microglia".


Asunto(s)
Metabolismo Energético , Microglía , Obesidad , Microglía/metabolismo , Microglía/fisiología , Obesidad/metabolismo , Obesidad/fisiopatología , Obesidad/patología , Humanos , Animales , Metabolismo Energético/fisiología , Núcleo Arqueado del Hipotálamo/metabolismo , Caracteres Sexuales , Hipotálamo/metabolismo
5.
Curr Biol ; 34(8): 1646-1656.e4, 2024 04 22.
Artículo en Inglés | MEDLINE | ID: mdl-38518777

RESUMEN

The obesity epidemic is principally driven by the consumption of more calories than the body requires. It is therefore essential that the mechanisms underpinning feeding behavior are defined. Neurons within the brainstem dorsal vagal complex (DVC) receive direct information from the digestive system and project to second-order regions in the brain to regulate food intake. Although γ-aminobutyric acid is expressed in the DVC (GABADVC), its function in this region has not been defined. In order to discover the unique gene expression signature of GABADVC cells, we used single-nucleus RNA sequencing (Nuc-seq), and this revealed 19 separate clusters. We next probed the function of GABADVC cells and discovered that the selective activation of GABADVC neurons significantly controls food intake and body weight. Optogenetic interrogation of GABADVC circuitry identified GABADVC → hypothalamic arcuate nucleus (ARC) projections as appetite suppressive without creating aversion. Electrophysiological analysis revealed that GABADVC → ARC stimulation inhibits hunger-promoting neuropeptide Y (NPY) neurons via GABA release. Adopting an intersectional genetics strategy, we clarify that the GABADVC → ARC circuit curbs food intake. These data identify GABADVC as a new modulator of feeding behavior and body weight and a controller of orexigenic NPY neuron activity, thereby providing insight into the neural underpinnings of obesity.


Asunto(s)
Núcleo Arqueado del Hipotálamo , Tronco Encefálico , Conducta Alimentaria , Núcleo Arqueado del Hipotálamo/metabolismo , Núcleo Arqueado del Hipotálamo/fisiología , Animales , Tronco Encefálico/fisiología , Tronco Encefálico/metabolismo , Ratones , Masculino , Conducta Alimentaria/fisiología , Neuronas GABAérgicas/fisiología , Neuronas GABAérgicas/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Ingestión de Alimentos/fisiología , Ratones Endogámicos C57BL , Femenino
6.
Nature ; 628(8009): 826-834, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38538787

RESUMEN

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.


Asunto(s)
Tronco Encefálico , Células Ependimogliales , Conducta Alimentaria , Calor , Hipotálamo , Vías Nerviosas , Neuronas , Animales , Femenino , Masculino , Ratones , Proteína Relacionada con Agouti/metabolismo , Núcleo Arqueado del Hipotálamo/metabolismo , Núcleo Arqueado del Hipotálamo/citología , Tronco Encefálico/citología , Tronco Encefálico/fisiología , Dopamina/metabolismo , Ingestión de Alimentos/fisiología , Células Ependimogliales/citología , Células Ependimogliales/fisiología , Conducta Alimentaria/fisiología , Ácido Glutámico/metabolismo , Hipotálamo/citología , Hipotálamo/fisiología , Vías Nerviosas/metabolismo , Neuronas/metabolismo , Núcleos Parabraquiales/citología , Núcleos Parabraquiales/metabolismo , Núcleos Parabraquiales/fisiología , Sensación Térmica/fisiología , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/líquido cefalorraquídeo , Factor A de Crecimiento Endotelial Vascular/metabolismo
7.
Mol Cell Endocrinol ; 586: 112179, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38387703

RESUMEN

Neuropeptide Y (Npy) is an abundant neuropeptide expressed in the central and peripheral nervous systems. NPY-secreting neurons in the hypothalamic arcuate nucleus regulate energy homeostasis, and Npy mRNA expression is regulated by peripheral nutrient and hormonal signals like leptin, interleukin-6 (IL-6), and fatty acids. This study demonstrates that IL-6, which phosphorylates tyrosine 705 (Y705) of STAT3, decreased Npy mRNA in arcuate immortalized hypothalamic neurons. In parallel, inhibitors of STAT3-Y705 phosphorylation, stattic and cucurbitacin I, robustly upregulated Npy mRNA. Chromatin-immunoprecipitation showed high baseline total STAT3 binding to multiple regulatory regions of the Npy gene, which are decreased by IL-6 exposure. The STAT3-Npy interaction was further examined in obesity-related pathologies. Notably, in four different hypothalamic neuronal models where palmitate potently stimulated Npy mRNA, Socs3, a specific STAT3 activity marker, was downregulated and was negatively correlated with Npy mRNA levels (R2 = 0.40, p < 0.001), suggesting that disrupted STAT3 signaling is involved in lipotoxicity-mediated dysregulation of Npy. Finally, human NPY SNPs that map to human obesity or body mass index were investigated for potential STAT3 binding sites. Although none of the SNPs were linked to direct STAT3 binding, analysis show that rs17149106 (-602 G > T) is located on an upstream enhancer element of NPY, where the variant is predicted to disrupt validated binding of KLF4, a known inhibitory cofactor of STAT3 and downstream effector of leptin signaling. Collectively, this study demonstrates that STAT3 signaling negatively regulates Npy transcription, and that disruption of this interaction may contribute to metabolic disorders.


Asunto(s)
Leptina , Neuropéptido Y , Humanos , Neuropéptido Y/genética , Neuropéptido Y/metabolismo , Leptina/farmacología , Leptina/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Hipotálamo/metabolismo , Obesidad/metabolismo , Núcleo Arqueado del Hipotálamo/metabolismo , Neuronas/metabolismo , ARN Mensajero/genética , Factor de Transcripción STAT3/metabolismo
8.
Gen Physiol Biophys ; 43(3): 255-261, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38385362

RESUMEN

The arcuate nucleus (ARN) of the hypothalamus is involved in multiple biological functions, such as feeding, sexual activity, and the regulation of the cardiovascular system. It was reported that leptin increased c-Fos expression in the proopiomelanocortin (POMC)- and decreased it in the neuropeptide-Y (NPY)-positive neurons of the ARN, suggesting that it stimulates the former, and inhibits the later. This study aimed at the direct electrophysiological examination of the effect of leptin on ARN neurons and to investigate potential sex-dimorphic changes. Wistar rats were anesthetized with urethane and the electrodes were inserted into the ARN. After a spontaneous active neuron was recorded for at least one minute, leptin was administered intravenously, and the firing activity of the same neuron was recorded for two additional minutes. It was found that approximately half of the ARN neurons had an excitatory, and another half an inhibitory response to the leptin administration. The excitability of the neurons with excitatory response to leptin was not different between the sexes. The average firing rate of the neurons with inhibitory response to leptin in females was, however, significantly lower comparing to the males. The obtained results demonstrate that the ARN neurons with stimulatory response to leptin are POMC and those with inhibitory response are NPY neurons. NPY Y1 receptor be might responsible, at least in part, for the sex differences in the excitability of the neurons putatively identified as NPY neurons.


Asunto(s)
Núcleo Arqueado del Hipotálamo , Leptina , Neuronas , Neuropéptido Y , Proopiomelanocortina , Ratas Wistar , Animales , Núcleo Arqueado del Hipotálamo/metabolismo , Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Proopiomelanocortina/metabolismo , Masculino , Femenino , Ratas , Neuropéptido Y/metabolismo , Neuropéptido Y/farmacología , Leptina/farmacología , Leptina/metabolismo , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Caracteres Sexuales
9.
J Comp Neurol ; 532(1): e25586, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38289191

RESUMEN

The torus semicircularis (TS) of teleosts is a key midbrain center of the lateral line and acoustic sensory systems. To characterize the TS in adult zebrafish, we studied their connections using the carbocyanine tracers applied to the TS and to other related nuclei and tracts. Two main TS nuclei, central and ventrolateral, were differentiable by their afferent connections. From central TS, (TSc) numerous toropetal cells were labeled bilaterally in several primary octaval nuclei (anterior, magnocellular, descending, and posterior octaval nuclei), in the secondary octaval nucleus, in the caudal octavolateralis nucleus, and in the perilemniscular region. In the midbrain, numerous toropetal cells were labeled in the contralateral TSc. In the diencephalon, toropetal cells labeled from the TSc were observed ipsilaterally in the medial prethalamic nucleus and the periventricular posterior tubercle nucleus. TSc toropetal neurons were also labeled bilaterally in the hypothalamic anterior tuberal nucleus (ATN) and ipsilaterally in the parvicellular preoptic nucleus but not in the telencephalon. Tracer application to the medial octavolateralis nucleus revealed contralateral projections to the ventrolateral TS (TSvl), whereas tracer application to the secondary octaval nucleus labeled fibers bilaterally in TSc and neurons in rostral TSc. The TSc sends ascending fibers to the ipsilateral lateral preglomerular region that, in turn, projects to the pallium. Application of DiI to the optic tectum labeled cells and fibers in the TSvl, whereas application of DiI to the ATN labeled cells and fibers in the TSc. These results reveal that the TSvl and TSc are mainly related with the mechanosensory lateral line and acoustic centers, respectively, and that they show different higher order connections.


Asunto(s)
Neuronas , Pez Cebra , Animales , Acústica , Núcleo Arqueado del Hipotálamo , Colículos Superiores
10.
Endocrinology ; 165(3)2024 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-38279940

RESUMEN

The arcuate nucleus kisspeptin (ARNKISS) neurons represent the GnRH pulse generator that likely drives pulsatile gonadotropin secretion in all mammals. Using an improved GCaMP fiber photometry system enabling long-term continuous recordings, we aimed to establish a definitive profile of ARNKISS neuronal activity across the murine estrous cycle. As noted previously, a substantial reduction in the frequency of ARNKISS neuron synchronization events (SEs) occurs on late proestrus and extends into estrus. The SE amplitude remains constant throughout the cycle. During metestrus, we unexpectedly detected many multipeak SEs where many SEs occurred rapidly, within 160 seconds of each other. By applying a machine learning-based, k-means clustering analysis, we were further able to detect substantial within-stage variability in the patterns of pulse generator activity. Estrous cycle-dependent changes in SE activity occurred around the time of lights on and off. We also find that a mild stressor such as vaginal lavage reduces ARNKISS neuron SE frequency for up to 3 hours. These observations provide a comprehensive account of ARNKISS neuron activity across the estrous cycle, highlight a new pattern of multipeak SE activity, and introduce a new k-means clustering approach for analyzing ARNKISS neuron population behavior.


Asunto(s)
Hormona Liberadora de Gonadotropina , Hormona Luteinizante , Animales , Femenino , Ratones , Núcleo Arqueado del Hipotálamo/metabolismo , Ciclo Estral/fisiología , Hormona Liberadora de Gonadotropina/metabolismo , Kisspeptinas/metabolismo , Neuronas/metabolismo
11.
J Neurophysiol ; 131(2): 241-260, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38197176

RESUMEN

Perinatal exposure to a high-fat, high-sugar Western-style diet (WSD) is associated with altered neural circuitry in the melanocortin system. This association may have an underlying inflammatory component, as consumption of a WSD during pregnancy can lead to an elevated inflammatory environment. Our group previously demonstrated that prenatal WSD exposure was associated with increased markers of inflammation in the placenta and fetal hypothalamus in Japanese macaques. In this follow-up study, we sought to determine whether this heightened inflammatory state persisted into the postnatal period, as prenatal exposure to inflammation has been shown to reprogram offspring immune function and long-term neuroinflammation would present a potential means for prolonged disruptions to microglia-mediated neuronal circuit formation. Neuroinflammation was approximated in 1-yr-old offspring by counting resident microglia and peripherally derived macrophages in the region of the hypothalamus examined in the fetal study, the arcuate nucleus (ARC). Microglia and macrophages were immunofluorescently stained with their shared marker, ionized calcium-binding adapter molecule 1 (Iba1), and quantified in 11 regions along the rostral-caudal axis of the ARC. A mixed-effects model revealed main effects of perinatal diet (P = 0.011) and spatial location (P = 0.003) on Iba1-stained cell count. Perinatal WSD exposure was associated with a slight decrease in the number of Iba1-stained cells, and cells were more densely located in the center of the ARC. These findings suggest that the heightened inflammatory state experienced in utero does not persist postnatally. This inflammatory response trajectory could have important implications for understanding how neurodevelopmental disorders progress.NEW & NOTEWORTHY Prenatal Western-style diet exposure is associated with increased microglial activity in utero. However, we found a potentially neuroprotective reduction in microglia count during early postnatal development. This trajectory could inform the timing of disruptions to microglia-mediated neuronal circuit formation. Additionally, this is the first study in juvenile macaques to characterize the distribution of microglia along the rostral-caudal axis of the arcuate nucleus of the hypothalamus. Nearby neuronal populations may be greater targets during inflammatory insults.


Asunto(s)
Núcleo Arqueado del Hipotálamo , Macaca fuscata , Embarazo , Animales , Femenino , Microglía , Enfermedades Neuroinflamatorias , Estudios de Seguimiento , Hipotálamo , Dieta Alta en Grasa/efectos adversos , Macaca
12.
Neuroendocrinology ; 114(5): 439-452, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38271999

RESUMEN

INTRODUCTION: Postweaning social isolation (PWSI) in rodents is an advanced psychosocial stress model in early life. Some psychosocial stress, such as restrain and isolation, disrupts reproductive physiology in young and adult periods. Mechanisms of early-life stress effects on central regulation of reproduction need to be elucidated. We have investigated the effects of PWSI on function of arcuate kisspeptin (ARCKISS1) neurons by using electrophysiological techniques combining with monitoring of puberty onset and estrous cycle in male and female Kiss1-Cre mice. METHODS: Female mice were monitored for puberty onset with vaginal opening examination during social isolation. After isolation, the estrous cycle of female mice was monitored with vaginal cytology. Anxiety-like behavior of mice was determined by an elevated plus maze test. Effects of PWSI on electrophysiology of ARCKISS1 neurons were investigated by the patch clamp method after intracranial injection of AAV-GFP virus into arcuate nucleus of Kiss1-Cre mice after the isolation period. RESULTS: We found that both male and female isolated mice showed anxiety-like behavior. PWSI caused delay in vaginal opening and extension in estrous cycle length. Spontaneous-firing rates of ARCKISS1 neurons were significantly lower in the isolated male and female mice. The peak amplitude of inhibitory postsynaptic currents to ARCKISS1 neurons was higher in the isolated mice, while frequency of excitatory postsynaptic currents was higher in group-housed mice. CONCLUSION: These findings demonstrate that PWSI alters pre- and postpubertal reproductive physiology through metabolic and electrophysiological pathways.


Asunto(s)
Núcleo Arqueado del Hipotálamo , Ciclo Estral , Kisspeptinas , Neuronas , Maduración Sexual , Aislamiento Social , Animales , Kisspeptinas/metabolismo , Femenino , Núcleo Arqueado del Hipotálamo/metabolismo , Neuronas/fisiología , Neuronas/metabolismo , Masculino , Maduración Sexual/fisiología , Ratones , Ciclo Estral/fisiología , Ratones Transgénicos , Ansiedad/fisiopatología , Estrés Psicológico/fisiopatología
13.
J Neuroendocrinol ; 36(2): e13366, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38279680

RESUMEN

The arcuate nucleus is a crucial hypothalamic brain region involved in regulating body weight homeostasis. Neurons within the arcuate nucleus respond to peripheral metabolic signals, such as leptin, and relay these signals via neuronal projections to brain regions both within and outside the hypothalamus, ultimately causing changes in an animal's behaviour and physiology. There is a substantial amount of evidence to indicate that leptin is intimately involved with the postnatal development of arcuate nucleus melanocortin circuitry. Further, it is clear that leptin signalling directly in the arcuate nucleus is required for circuitry development. However, as leptin receptor long isoform (Leprb) mRNA is expressed in multiple nuclei within the developing hypothalamus, including the postsynaptic target regions of arcuate melanocortin projections, this raises the possibility that leptin also signals in these nuclei to promote circuitry development. Here, we used RT-qPCR and RNAscope® to reveal the spatio-temporal pattern of Leprb mRNA in the early postnatal mouse hypothalamus. We found that Leprb mRNA expression increased significantly in the arcuate nucleus, ventromedial nucleus and paraventricular nucleus of the hypothalamus from P8, in concert with the leptin surge. In the dorsomedial nucleus of the hypothalamus, increases in Leprb mRNA were slightly later, increasing significantly from P12. Using duplex RNAscope®, we found Leprb co-expressed with Sim1, Pou3f2, Mc4r and Bdnf in the paraventricular nucleus at P8. Together, these data suggest that leptin may signal in a subset of neurons postsynaptic to arcuate melanocortin neurons, as well as within the arcuate nucleus itself, to promote the formation of arcuate melanocortin circuitry during the early postnatal period.


Asunto(s)
Leptina , Receptores de Leptina , Animales , Ratones , Leptina/metabolismo , Receptores de Leptina/genética , Receptores de Leptina/metabolismo , Hipotálamo/metabolismo , Núcleo Arqueado del Hipotálamo/metabolismo , Melanocortinas/metabolismo , ARN Mensajero/metabolismo
14.
J Mol Endocrinol ; 72(2)2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38085702

RESUMEN

The exact neural construct underlying the dynamic secretion of gonadotrophin-releasing hormone (GnRH) has only recently been identified despite the detection of multiunit electrical activity volleys associated with pulsatile luteinising hormone (LH) secretion four decades ago. Since the discovery of kisspeptin/neurokinin B/dynorphin neurons in the mammalian hypothalamus, there has been much research into the role of this neuronal network in controlling the oscillatory secretion of gonadotrophin hormones. In this review, we provide an update of the progressive application of cutting-edge techniques combined with mathematical modelling by the neuroendocrine community, which are transforming the functional investigation of the GnRH pulse generator. Understanding the nature and function of the GnRH pulse generator can greatly inform a wide range of clinical studies investigating infertility treatments.


Asunto(s)
Hormona Liberadora de Gonadotropina , Hormona Luteinizante , Animales , Hormona Liberadora de Gonadotropina/metabolismo , Hipotálamo/metabolismo , Neuroquinina B/metabolismo , Dinorfinas/metabolismo , Kisspeptinas/metabolismo , Núcleo Arqueado del Hipotálamo/metabolismo , Mamíferos/metabolismo
15.
Biol Reprod ; 110(1): 90-101, 2024 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-37774351

RESUMEN

Mammalian ovulation is induced by a luteinizing hormone surge, which is triggered by elevated plasma estrogen levels; however, chronic exposure to high levels of estradiol is known to inhibit luteinizing hormone secretion. In the present study, we hypothesized that the inhibition of the luteinizing hormone surge by chronic estradiol exposure is due to the downregulation of the estrogen receptor alpha in kisspeptin neurons at hypothalamic anteroventral periventricular nucleus, which is known as the gonadotropin-releasing hormone/luteinizing hormone surge generator. Animals exposed to estradiol for 2 days showed an luteinizing hormone surge, whereas those exposed for 14 days showed a significant suppression of luteinizing hormone. Chronic estradiol exposure did not affect the number of kisspeptin neurons and the percentage of kisspeptin neurons with estrogen receptor alpha or c-Fos in anteroventral periventricular nucleus, but it did affect the number of kisspeptin neurons in arcuate nucleus. Furthermore, chronic estradiol exposure did not affect gonadotropin-releasing hormone neurons. In the pituitary, 14-day estradiol exposure significantly reduced the expression of Lhb mRNA and LHß-immunoreactive areas. Gonadotropin-releasing hormone-induced luteinizing hormone release was also reduced significantly by 14-day estradiol exposure. We revealed that the suppression of an luteinizing hormone surge by chronic estradiol exposure was induced in association with the significant reduction in kisspeptin neurons in arcuate nucleus, luteinizing hormone expression in the pituitary, and pituitary responsiveness to gonadotropin-releasing hormone, and this was not caused by changes in the estrogen receptor alpha-expressing kisspeptin neurons in anteroventral periventricular nucleus and gonadotropin-releasing hormone neurons, which are responsible for estradiol positive feedback.


Asunto(s)
Estradiol , Hormona Luteinizante , Femenino , Animales , Hormona Luteinizante/metabolismo , Estradiol/farmacología , Estradiol/metabolismo , Kisspeptinas/genética , Kisspeptinas/metabolismo , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Hormona Liberadora de Gonadotropina/metabolismo , Hipotálamo Anterior/metabolismo , Núcleo Arqueado del Hipotálamo/metabolismo , Neuronas/metabolismo , Mamíferos/metabolismo
16.
J Neuroendocrinol ; 36(1): e13357, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38056947

RESUMEN

This study furthers the investigation of how pituitary adenylate cyclase activating polypeptide (PACAP) and the PAC1 receptor (PAC1R) regulate the homeostatic energy balance circuitry. We hypothesized that apoptotic ablation of PACAP neurones in the hypothalamic ventromedial nucleus (VMN) would affect both energy intake and energy expenditure. We also hypothesized that selective PAC1R knockdown would impair the PACAP-induced excitation in anorexigenic proopiomelanocortin (POMC) neurones and inhibition of orexigenic neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurones in the hypothalamic arcuate nucleus (ARC). The results show CASPASE-3-induced ablation of VMN PACAP neurones leads to increased energy intake and meal frequency as well as decreased energy expenditure in lean animals. The effects were more robust in obese males, whereas we saw the opposite effects in obese females. We then utilized visualized whole-cell patch clamp recordings in hypothalamic slices. PAC1R knockdown in POMC neurones diminishes the PACAP-induced depolarization, increase in firing, decreases in energy intake and meal size, as well as increases in CO2 production and O2 consumption. Similarly, the lack of expression of the PAC1R in NPY/AgRP neurones greatly attenuates the PACAP-induced hyperpolarization, suppression of firing, decreases in energy intake and meal frequency, as well as increases in energy expenditure. The PACAP response in NPY/AgRP neurones switched from predominantly inhibitory to excitatory in fasted animals. Finally, the anorexigenic effect of PACAP was potentiated when oestradiol was injected into the ARC in ovariectomized females. This study demonstrates the critical role of anorexigenic VMN PACAP neurones and the PAC1R in exciting POMC and inhibiting NPY/AgRP neurons to control homeostatic feeding.


Asunto(s)
Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Proopiomelanocortina , Animales , Masculino , Femenino , Proopiomelanocortina/metabolismo , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/metabolismo , Neuropéptido Y/metabolismo , Proteína Relacionada con Agouti/metabolismo , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/metabolismo , Núcleo Hipotalámico Ventromedial/metabolismo , Núcleo Arqueado del Hipotálamo/metabolismo , Dieta , Neuronas/metabolismo , Obesidad/metabolismo
17.
Aging Cell ; 23(2): e14047, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37994388

RESUMEN

Orexigenic neurons expressing agouti-related protein (AgRP) and neuropeptide Y in the arcuate nucleus (ARC) of the hypothalamus are activated in response to dynamic variations in the metabolic state, including exercise. We previously observed that carnitine palmitoyltransferase 1a (CPT1A), a rate-limiting enzyme of mitochondrial fatty acid oxidation, is a key factor in AgRP neurons, modulating whole-body energy balance and fluid homeostasis. However, the effect of CPT1A in AgRP neurons in aged mice and during exercise has not been explored yet. We have evaluated the physical and cognitive capacity of adult and aged mutant male mice lacking Cpt1a in AgRP neurons (Cpt1a KO). Adult Cpt1a KO male mice exhibited enhanced endurance performance, motor coordination, locomotion, and exploration compared with control mice. No changes were observed in anxiety-related behavior, cognition, and muscle strength. Adult Cpt1a KO mice showed a reduction in gastrocnemius and tibialis anterior muscle mass. The cross-sectional area (CSA) of these muscles were smaller than those of control mice displaying a myofiber remodeling from type II to type I fibers. In aged mice, changes in myofiber remodeling were maintained in Cpt1a KO mice, avoiding loss of physical capacity during aging progression. Additionally, aged Cpt1a KO mice revealed better cognitive skills, reduced inflammation, and oxidative stress in the hypothalamus and hippocampus. In conclusion, CPT1A in AgRP neurons appears to modulate health and protects against aging. Future studies are required to clarify whether CPT1A is a potential antiaging candidate for treating diseases affecting memory and physical activity.


Asunto(s)
Carnitina O-Palmitoiltransferasa , Envejecimiento Saludable , Animales , Masculino , Ratones , Proteína Relacionada con Agouti/genética , Proteína Relacionada con Agouti/metabolismo , Núcleo Arqueado del Hipotálamo/metabolismo , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , Hipotálamo/metabolismo , Neuronas/metabolismo
18.
Biol Reprod ; 110(2): 275-287, 2024 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-37930247

RESUMEN

The timing of puberty onset is reliant on increased gonadotropin-releasing hormone (GnRH). This elicits a corresponding increase in luteinizing hormone (LH) due to a lessening of sensitivity to the inhibitory actions of estradiol (E2). The mechanisms underlying the increase in GnRH release likely involve a subset of neurons within the arcuate (ARC) nucleus of the hypothalamus that contain kisspeptin, neurokinin B (NKB), and dynorphin (KNDy neurons). We aimed to determine if KNDy neurons in female sheep are critical for: timely puberty onset; the LH surge; and the response to an intravenous injection of the neurokinin-3 receptor (NK3R) agonist, senktide. Prepubertal ewes received injections aimed at the ARC containing blank-saporin (control, n = 5) or NK3-saporin (NK3-SAP, n = 6) to ablate neurons expressing NK3R. Blood samples taken 3/week for 65 days following surgery were assessed for progesterone to determine onset of puberty. Control ewes exhibited onset of puberty at 33.2 ± 3.9 days post sampling initiation, whereas 5/6 NK3-SAP treated ewes didn't display an increase in progesterone. After an artificial LH surge protocol, surge amplitude was lower in NK3-SAP ewes. Finally, ewes were treated with senktide to determine if an LH response was elicited. LH pulses were evident in both groups in the absence of injections, but the response to senktide vs saline was similar between groups. These results show that KNDy cells are necessary for timely puberty onset and for full expresson of the LH surge. The occurrence of LH pulses in NK3-SAP treated ewes may indicate a recovery from an apulsatile state.


Asunto(s)
Núcleo Arqueado del Hipotálamo , Hormona Luteinizante , Fragmentos de Péptidos , Sustancia P/análogos & derivados , Femenino , Animales , Ovinos , Hormona Luteinizante/farmacología , Núcleo Arqueado del Hipotálamo/metabolismo , Saporinas/farmacología , Progesterona/farmacología , Hormona Liberadora de Gonadotropina/farmacología , Hormona Liberadora de Gonadotropina/metabolismo , Neuroquinina B/metabolismo , Dinorfinas/farmacología , Dinorfinas/metabolismo , Kisspeptinas/metabolismo
19.
Reproduction ; 167(1)2024 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-37934722

RESUMEN

In brief: The transcriptional profiles of Kiss1 neurons from the arcuate and the rostral periventricular region of the third ventricle of the hypothalamus have been directly compared in diestrous female mice. Differentially expressed genes provide molecular signatures for these two populations of Kiss1 neurons and insights into their physiology. Abstract: The neuropeptide kisspeptin is produced by Kiss1 neurons and is required for normal mammalian fertility. The two main populations of Kiss1 neurons are located in the arcuate (ARC) and the rostral periventricular area of the third ventricle (RP3V) of the hypothalamus. To define the molecular signature of these Kiss1 populations, transcriptomics profiling was performed using purified Kiss1 neurons from diestrous stage female mice. From a data set of 7026 genes, 332 differentially expressed transcripts were identified between the Kiss1ARC and Kiss1RP3V neurons. These data have uncovered novel transcripts and expanded the receptor expression, co-transmitter and transcription factor profiles of Kiss1 neurons. Validation by quantitative RT-PCR confirmed differential expression of Cartpt, Ddc, Gal, Gda, Npy2r, Penk, Rasp18, Rxfp3, Slc18a2, and Th in Kiss1RP3V neurons and Gpr83, Hctr2, Nhlh2, Nmn, Npr3, Nr4a2, Nr5a2, Olfm2, Tac2 and Tacr3 in Kiss1ARC neurons. Enriched pathways common to both Kiss1 populations included the NF-kB, mTor, endocannabinoid, GPCR, Wnt and oestrogen signalling while some pathways (e.g. cytomegalovirus infection, dopaminergic and serotonergic biosynthesis) were specific to Kiss1RP3V neurons. Our gene expression data set augments the existing data sets describing the transcriptional profiles of Kiss1 neuronal populations.


Asunto(s)
Kisspeptinas , Neuronas , Neuropéptidos , Animales , Femenino , Ratones , Núcleo Arqueado del Hipotálamo/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Hipotálamo/metabolismo , Kisspeptinas/genética , Kisspeptinas/metabolismo , Neuronas/metabolismo , Neuropéptidos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal , Perfilación de la Expresión Génica
20.
Neurosci Lett ; 818: 137537, 2024 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-37898180

RESUMEN

INTRODUCTION: Development of the human medullary arcuate nucleus (AN) has not been sufficiently investigated. The present study provides morphometric data by examining the brains from preterm and perinatal infants. MATERIALS AND METHODS: Nine brains were obtained from infants aged 21-43 postmenstrual weeks (PW). Serial celloidin sections were cut and stained using the Klüver-Barrera method. After microscopic observations, morphometric parameters [AN volume, numerical density (Nv) and total number (Nt) of neurons, and neuronal profile area (PA)] were analyzed. RESULTS: The AN was found as a pair of neuronal masses on the ventral medullary surface at 21 PW. Caudally, it was ventrolateral to the pyramidal tract (PT), and rostrally, medial to the PT. In the middle, it was diminished in size or interrupted. The AN neurons were gradually enlarged with age, showing multiplicity in size and shape. The following findings had a marked asymmetry and individual variability: (1) complete or partial inclusion of the AN in the PT; (2) connection between the rostral AN and the pontine nuclei; (3) coexistence of pyknotic neurons. The AN volume increased exponentially with age, while the Nv decreased exponentially. The Nt changed along two phases (decrease-increase) after mid-gestation. The mean PA increased linearly with age. Asymmetry and/or individual variability were demonstrated in the AN volume, Nt, and mean PA. CONCLUSIONS: Asymmetry and individual variability in the AN morphology are present in fetal period. The AN may undergo neuron death and neuroblasts production in tandem after mid-gestation.


Asunto(s)
Núcleo Arqueado del Hipotálamo , Bulbo Raquídeo , Recién Nacido , Lactante , Humanos , Embarazo , Femenino , Neuronas , Puente , Muerte Celular
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