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Journal of the Endocrine Society Aug 20235α-reductase-1 catalyzes production of various steroids, including neurosteroids. We reported previously that expression of its encoding gene, drops in murine ovaries...
5α-reductase-1 catalyzes production of various steroids, including neurosteroids. We reported previously that expression of its encoding gene, drops in murine ovaries and hypothalamic preoptic area (POA) after early-life immune stress, seemingly contributing to delayed puberty and ovarian follicle depletion, and in the ovaries the first intron was more methylated at two CpGs. Here, we hypothesized that this CpG-containing locus comprises a methylation-sensitive transcriptional enhancer for . We found that ovarian mRNA increased 8-fold and methylation of the same two CpGs decreased up to 75% between postnatal days 10 and 30. Estradiol (E) levels rise during this prepubertal stage, and exposure of ovarian cells to E increased expression. Chromatin immunoprecipitation in an ovarian cell line confirmed ESR1 binding to this differentially methylated genomic region and enrichment of the enhancer modification, H3K4me1. Targeting dCas9-DNMT3 to this locus increased CpG2 methylation 2.5-fold and abolished the response to E. In the POA, mRNA levels decreased 70% between postnatal days 7 and 10 and then remained constant without correlation to CpG methylation levels. mRNA levels did not respond to E in hypothalamic GT1-7 cells, even after dCas9-TET1 reduced CpG1 methylation by 50%. The neonatal drop in POA expression occurs at a time of increasing glucocorticoids, and treatment of GT1-7 cells with dexamethasone reduced mRNA levels; chromatin immunoprecipitation confirmed glucocorticoid receptor binding at the enhancer. Our findings on the tissue-specific regulation of and its methylation-sensitive control by E in the ovaries illuminate epigenetic mechanisms underlying reproductive phenotypic variation that impact life-long health.
PubMed: 37646011
DOI: 10.1210/jendso/bvad108 -
Annals of the New York Academy of... Dec 2023Male songbirds produce female-directed songs in spring that convey a state of sexual motivation. Many songbirds also sing in fall flocks in affiliative/gregarious...
Male songbirds produce female-directed songs in spring that convey a state of sexual motivation. Many songbirds also sing in fall flocks in affiliative/gregarious contexts in which song is linked to an intrinsic positive affective state. The periaqueductal gray (PAG) in mammals, which is organized into functional columns, integrates information from multiple brain regions and relays this information to vocal motor areas so that an animal emits a vocal signal reflective of its affective state. Here, we test the hypothesis that distinct columns in the songbird PAG play roles in the distinct affective states communicated by sexually motivated and gregarious song. We quantified the numbers of immediate early gene ZENK-positive cells in 16 PAG subregions in male European starlings (Sturnus vulgaris) after singing gregarious or sexually motivated song. Results suggest that distinct PAG columns in songbirds context-specifically regulate song, agonistic, and courtship behaviors. A second exploratory, functional tract-tracing study also demonstrated that inputs to the PAG from specific subregions of the medial preoptic nucleus may contribute to gregarious song and behaviors indicative of social dominance. Together, findings suggest that conserved PAG columns and inputs from the preoptic nucleus may play a role in context-specific vocal and other social behaviors.
Topics: Animals; Male; Female; Periaqueductal Gray; Sexual Behavior, Animal; Vocalization, Animal; Brain; Motivation; Starlings; Mammals
PubMed: 37800392
DOI: 10.1111/nyas.15066 -
Neuroscience Research Sep 2023In many mammalian species, females exhibit higher sociability and gregariousness than males, presumably due to the benefit of group living for maternal care. We have...
In many mammalian species, females exhibit higher sociability and gregariousness than males, presumably due to the benefit of group living for maternal care. We have previously reported that adult female mice exhibit contact-seeking behaviors upon acute social isolation via amylin-calcitonin receptor (Calcr) signaling in the medial preoptic area (MPOA). In this study, we examined the sex differences in the behavioral responses to acute social isolation and reunion, and the levels of amylin and Calcr expression in the MPOA. We found that male mice exhibited significantly less contact-seeking upon social isolation. Upon reunion, male mice contacted each other to a similar extent as females, but their interactions were more aggressive and less affiliative compared with females. While Calcr-expressing neurons were activated during social contacts in males as in females, the amylin and Calcr expression were significantly lower in males than in females. Together with our previous findings, these findings suggested that the lower expression of both amylin and Calcr may explain the lower contact-seeking and social affiliation of male mice.
Topics: Mice; Animals; Female; Male; Islet Amyloid Polypeptide; Preoptic Area; Social Isolation; Sex Characteristics; Mammals
PubMed: 37030575
DOI: 10.1016/j.neures.2023.04.001 -
Communications Biology Dec 2023Calcitonin receptor (Calcr) and its brain ligand amylin in the medial preoptic area (MPOA) are found to be critically involved in infant care and social contact...
Calcitonin receptor (Calcr) and its brain ligand amylin in the medial preoptic area (MPOA) are found to be critically involved in infant care and social contact behaviors in mice. In primates, however, the evidence is limited to an excitotoxic lesion study of the Calcr-expressing MPOA subregion (cMPOA) in a family-living primate species, the common marmoset. The present study utilized pharmacological manipulations of the cMPOA and shows that reversible inactivation of the cMPOA abolishes infant-care behaviors in sibling marmosets without affecting other social or non-social behaviors. Amylin-expressing neurons in the marmoset MPOA are distributed in the vicinity of oxytocin neurons in the anterior paraventricular nucleus of the hypothalamus. While amylin infusion facilitates infant carrying selectively, an oxytocin's inverse agonist, atosiban, reduces physical contact with non-infant family members without grossly affecting infant care. These data suggest that the amylin and oxytocin signaling mediate intrafamilial social interactions in a complementary manner in marmosets.
Topics: Humans; Mice; Animals; Preoptic Area; Oxytocin; Callithrix; Islet Amyloid Polypeptide; Drug Inverse Agonism; Social Behavior
PubMed: 38052969
DOI: 10.1038/s42003-023-05593-5 -
Molecular Metabolism Jun 2024Hypothalamic signals potently stimulate energy expenditure by engaging peripheral mechanisms to restore energy homeostasis. Previous studies have identified several...
OBJECTIVE
Hypothalamic signals potently stimulate energy expenditure by engaging peripheral mechanisms to restore energy homeostasis. Previous studies have identified several critical hypothalamic sites (e.g. preoptic area (POA) and ventromedial hypothalamic nucleus (VMN)) that could be part of an interconnected neurocircuit that controls tissue thermogenesis and essential for body weight control. However, the key neurocircuit that can stimulate energy expenditure has not yet been established.
METHODS
Here, we investigated the downstream mechanisms by which VMN neurons stimulate adipose tissue thermogenesis. We manipulated subsets of VMN neurons acutely as well as chronically and studied its effect on tissue thermogenesis and body weight control, using Sf1 and Adcyap1 mice and measured physiological parameters under both high-fat diet and standard chow diet conditions. To determine the node efferent to these VMN neurons, that is involved in modulating energy expenditure, we employed electrophysiology and optogenetics experiments combined with measurements using tissue-implantable temperature microchips.
RESULTS
Activation of the VMN neurons that express the steroidogenic factor 1 (Sf1; VMN neurons) reduced body weight, adiposity and increased energy expenditure in diet-induced obese mice. This function is likely mediated, at least in part, by the release of the pituitary adenylate cyclase-activating polypeptide (PACAP; encoded by the Adcyap1 gene) by the VMN neurons, since we previously demonstrated that PACAP, at the VMN, plays a key role in energy expenditure control. Thus, we then shifted focus to the subpopulation of VMN neurons that contain the neuropeptide PACAP (VMN neurons). Since the VMN neurons do not directly project to the peripheral tissues, we traced the location of the VMN neurons' efferents. We identified that VMN neurons project to and activate neurons in the caudal regions of the POA whereby these projections stimulate tissue thermogenesis in brown and beige adipose tissue. We demonstrated that selective activation of caudal POA projections from VMN neurons induces tissue thermogenesis, most potently in negative energy balance and activating these projections lead to some similar, but mostly unique, patterns of gene expression in brown and beige tissue. Finally, we demonstrated that the activation of the VMN neurons' efferents that lie at the caudal POA are necessary for inducing tissue thermogenesis in brown and beige adipose tissue.
CONCLUSIONS
These data indicate that VMN connections with the caudal POA neurons impact adipose tissue function and are important for induction of tissue thermogenesis. Our data suggests that the VMN → caudal POA neurocircuit and its components are critical for controlling energy balance by activating energy expenditure and body weight control.
Topics: Animals; Ventromedial Hypothalamic Nucleus; Thermogenesis; Preoptic Area; Mice; Neurons; Energy Metabolism; Male; Steroidogenic Factor 1; Pituitary Adenylate Cyclase-Activating Polypeptide; Diet, High-Fat; Mice, Inbred C57BL; Body Weight; Adipose Tissue, Brown
PubMed: 38729241
DOI: 10.1016/j.molmet.2024.101951 -
Anatomical Record (Hoboken, N.J. : 2007) Feb 2024Serotonin (5-HT) is an evolutionarily conserved monoaminergic neurotransmitter found in the central nervous system and peripheral nervous system across invertebrates and...
Serotonin (5-HT) is an evolutionarily conserved monoaminergic neurotransmitter found in the central nervous system and peripheral nervous system across invertebrates and vertebrates. Although the distribution of 5-HT-immunoreactive (5-HT-ir) neurons is investigated in various fish species, the organization of these neurons in cichlid fishes is poorly understood. These fish are known for their adaptability to diverse environments, food habits, and complex mating and breeding behaviors, including parental care. In this paper, we describe the organization of 5-HT-ir neurons in the brain of the cichlid fish Oreochromis mossambicus. Aggregations of 5-HT-ir neurons were spotted in the granule cell layer of the olfactory bulb and near the ventricular border in the preoptic area and magnocellular subdivisions of the nucleus preopticus. Although the presence of 5-HT-ir cells and fibers in the hypothalamic and thalamic regions, cerebellum, and raphe nuclei was comparable to that of other teleosts, the current study reveals the occurrence of 5-HT-ir cells and fibers for the first time in some areas, such as the nucleus posterior tuberis, nucleus oculomotorius, and nucleus paracommissuralis in the tilapia. While the presence of 5-HT-ir cells and fibers in gustatory centers suggests a role for serotonin in the processing of gustatory signals, distinctive pattern of 5-HT immunoreactivity was seen in the telencephalon, pretectal areas, mesencephalic, and rhombencephalic regions, suggesting a cichlid fish specific organization of the serotonergic system. In conclusion, the 5-HT system in the tilapia brain may serve several neuroendocrine and neuromodulatory roles, including regulation of reproduction and sensorimotor processes.
Topics: Animals; Tilapia; Cichlids; Serotonin; Brain; Neurons
PubMed: 36938774
DOI: 10.1002/ar.25204 -
Cell Reports May 2024The preoptic area of the hypothalamus (POA) is essential for sleep regulation. However, the cellular makeup of the POA is heterogeneous, and the molecular identities of...
The preoptic area of the hypothalamus (POA) is essential for sleep regulation. However, the cellular makeup of the POA is heterogeneous, and the molecular identities of the sleep-promoting cells remain elusive. To address this question, this study compares mice during recovery sleep following sleep deprivation to mice allowed extended sleep. Single-nucleus RNA sequencing (single-nucleus RNA-seq) identifies one galanin inhibitory neuronal subtype that shows upregulation of rapid and delayed activity-regulated genes during recovery sleep. This cell type expresses higher levels of growth hormone receptor and lower levels of estrogen receptor compared to other galanin subtypes. single-nucleus RNA-seq also reveals cell-type-specific upregulation of purinergic receptor (P2ry14) and serotonin receptor (Htr2a) during recovery sleep in this neuronal subtype, suggesting possible mechanisms for sleep regulation. Studies with RNAscope validate the single-nucleus RNA-seq findings. Thus, the combined use of single-nucleus RNA-seq and activity-regulated genes identifies a neuronal subtype functionally involved in sleep regulation.
Topics: Animals; Galanin; Neurons; Preoptic Area; Mice; Sleep Deprivation; Male; RNA-Seq; Mice, Inbred C57BL; Sleep; Single-Cell Analysis
PubMed: 38703367
DOI: 10.1016/j.celrep.2024.114192 -
Psychopharmacology Apr 2024Cabergoline (CAB) is an ergot derivative typically prescribed for the treatment of hyperprolactinemia. It suppresses the release of prolactin through agonist actions on...
RATIONALE
Cabergoline (CAB) is an ergot derivative typically prescribed for the treatment of hyperprolactinemia. It suppresses the release of prolactin through agonist actions on dopamine (DA) D2 receptors; however, it possesses binding affinity for other DA and 5-HT receptors. Side effects that exacerbate valvular heart disease can occur with high doses.
OBJECTIVE
The present study examined the acute, subchronic, and chronic dose-response effects of CAB and a derivative dimethylcabergoline (DMC) which acts as an antagonist instead of agonist at 5-HT 2B receptors, on appetitive and consummatory sexual behaviors of male rats.
METHODS
CAB (0, 0.03, 0.15, or 0.3 mg/kg/ml) was administered daily to sexually experienced male rats (N = 10/dose) by oral gavage for a total of 68 days. Sexual behavior was tested every 4 days during this period for a total of 16 trials. On the 17 trial, rats were administered their dose of CAB, and 4 h after were overdosed with sodium pentobarbital, perfused intracardially, and their brains processed for Fos immunohistochemistry. DMC (0, 0.03, 0.15, 0.3 mg/kg/ml) was administered daily to sexually experienced male rats (N = 10/dose) by oral gavage for a total of 36 days. Sexual behavior was tested every 4 days for a total of 9 trials.
RESULTS
CAB increased anticipatory level changes, intromissions, and ejaculations significantly across all timepoints, with the medium and high doses being most potent. The medium and high doses also increased Fos protein significantly within the medial preoptic area, whereas in the nucleus accumbens shell, the low and medium doses decreased Fos protein but the high dose increased it significantly from control. Similar to CAB, the medium and high doses of DMC increased the number of ejaculations significantly. Rats in all drug dose groups appeared healthy for the duration of the experiments.
CONCLUSIONS
Both CAB and DMC facilitate ejaculations, and CAB further facilitates measures of anticipatory sexual motivation and intromissions. These data suggest that both could be used as treatments for sexual arousal disorders and ejaculation/orgasm disorders with little or no untoward side effects at low doses.
Topics: Rats; Male; Animals; Cabergoline; Sexual Behavior, Animal; Copulation; Motivation; Brain; Gonadal Steroid Hormones; Receptors, Dopamine D2
PubMed: 37968530
DOI: 10.1007/s00213-023-06501-9 -
Hydrogen-rich water improves sleep consolidation and enhances forebrain neuronal activation in mice.Sleep Advances : a Journal of the Sleep... 2024Sleep loss contributes to various health issues and impairs neurological function. Molecular hydrogen has recently gained popularity as a nontoxic ergogenic and health...
STUDY OBJECTIVES
Sleep loss contributes to various health issues and impairs neurological function. Molecular hydrogen has recently gained popularity as a nontoxic ergogenic and health promoter. The effect of molecular hydrogen on sleep and sleep-related neural systems remains unexplored. This study investigates the impact of hydrogen-rich water (HRW) on sleep behavior and neuronal activation in sleep-deprived mice.
METHODS
Adult C57BL/6J mice were implanted with electroencephalography (EEG) and electromyography (EMG) recording electrodes and given HRW (0.7-1.4 mM) or regular water for 7 days ad libitum. Sleep-wake cycles were recorded under baseline conditions and after acute sleep loss. Neuronal activation in sleep- and wake-related regions was assessed using cFos immunostaining.
RESULTS
HRW increased sleep consolidation in undisturbed mice and increased non-rapid-eye movement and rapid-eye-movement sleep amount in sleep-deprived mice. HRW also decreased the average amount of time for mice to fall asleep after light onset. Neuronal activation in the lateral septum, medial septum, ventrolateral preoptic area, and median preoptic area was significantly altered in all mice treated with HRW.
CONCLUSIONS
HRW improves sleep consolidation and increases neuronal activation in sleep-related brain regions. It may serve as a simple, effective treatment to improve recovery after sleep loss.
PubMed: 38264142
DOI: 10.1093/sleepadvances/zpad057 -
Photochemical & Photobiological... Sep 2023Light has a very important function in the regulation of the normal physiology including the neuroendocrine system, biological rhythms, cognitive behavior, etc. The...
Withania somnifera inhibits photorefractoriness which triggers neuronal apoptosis in both pre-optic and paraventricular hypothalamic area of Coturnix coturnix japonica: involvement of oxidative stress induced p53 dependent Caspase-3 mediated low immunoreactivity of estrogen receptor alpha.
Light has a very important function in the regulation of the normal physiology including the neuroendocrine system, biological rhythms, cognitive behavior, etc. The variation in photoperiod acts as a stressor due to imbalance in endogenous hormones. Estrogen and its receptors ER alpha and beta play a vital role in the control of stress response in birds. The study investigates the estrogenic effects of a well-known medicinal plant Withania somnifera (WS), mediated by estrogen receptor alpha (ERα) in the hypothalamic pre-optic area (POA) and paraventricular nuclei (PVN). Further the study elucidates its anti-oxidants and anti-apoptotic activities in the brain of Japanese quail. To validate this hypothesis, mature male quails were exposed to long day length for 3 months and then transferred to intermediate day length to become photorefractory (PR) while controls were still continued under long daylength. Supplementation of WS root extract in PR quail increases plasma estrogen and lowers corticosterone. Further, in PR quail the variation in light downregulates immunoreactivity of ERα, oxidative stress and antioxidant enzyme activities i.e. superoxide dismutase and catalase in the brain. Neuronal apoptosis was observed in the POA and PVN of PR quail as indicated by the abundant expression of Caspase-3 and p53 which reduces after the administration of WS root extract. The neuronal population also found to decrease in PR although it increased in WS administered quails. Further, the study concluded that change in photoperiod from 3 months exposure of 16L: 8D to 13.5L: 10.5D directly activates neuronal apoptosis via expression of Caspase3 and p53 expression in the brain and increases neuronal and gonadal oxidative stress while WS root extract reverses them via enhanced estrogen and its receptor ERα expression in the hypothalamic pre-optic and PVN area of Japanese quail.
Topics: Animals; Coturnix; Estrogen Receptor alpha; Withania; Tumor Suppressor Protein p53; Caspase 3; Apoptosis; Estrogens; Oxidative Stress
PubMed: 37266906
DOI: 10.1007/s43630-023-00442-0