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Brain Research Dec 2018In recent years estradiol has emerged as a potential regulator of transient receptor potential vanilloid (TRPV) cationic channels in the peripheral tissues and sensory...
In recent years estradiol has emerged as a potential regulator of transient receptor potential vanilloid (TRPV) cationic channels in the peripheral tissues and sensory neurons, however, its analogous role in the CNS is poorly understood. TRPV channels modulate Ca signalling, neurotransmission and behaviour, and expression of these ion channels and estrogen receptors show a great degree of overlap in different brain regions. Herein, we probe if Trpv1-6 genes contain estrogen receptor-binding sites and if their expression in different brain regions is modulated during estrous cycle. Bioinformatics analysis of the mouse Trpv1-6 gene sequences showed presence of putative functional estrogen response element in their promoter regions. Using qRT-PCR, Trpv1-6 mRNA expression was observed in the olfactory bulb, cortex, hypothalamus, hippocampus, brainstem, and cerebellum of mouse. In these regions, compared to estrus, metestrus, and diestrus, reduced levels of Trpv1 and Trpv5 but elevated Trpv2 and Trpv6 mRNA levels were observed during proestrus. Lower levels of Trpv3 and Trpv4 mRNAs were seen during estrus but higher expression of Trpv3 during metestrus and diestrus, and Trpv4 during proestrus was observed. Estradiol seems to regulate Trpv1/Trpv5 and Trpv2/Trpv6 mRNA expression in opposite manner. Except Trpv4 mRNA expression in the hippocampus and Trpv6 expression in the olfactory bulb, hippocampus and brainstem, expression of other members of TRPV subfamily in distinct brain regions of male mice was comparable to those in metestrus and diestrus mice. We suggest that the circulating levels of estradiol during the estrous cycle may differentially regulate the activity of TRPV1-6 ion channels in the brain.
Topics: Animals; Brain; Brain Mapping; Calcium Channels; Estradiol; Estrogens; Estrous Cycle; Female; Gene Expression; Hippocampus; Male; Mice; Mice, Inbred BALB C; RNA, Messenger; Receptors, Estrogen; TRPV Cation Channels
PubMed: 30194920
DOI: 10.1016/j.brainres.2018.09.005 -
Neuroscience Letters Jan 2022Chronic social isolation stress (SIS) induces lasting negative effects on the brain, including memory deficits, cognitive impairments, and mood alterations such as...
Chronic social isolation stress (SIS) induces lasting negative effects on the brain, including memory deficits, cognitive impairments, and mood alterations such as depression and anxiety. All these symptoms, at least in part, reflect reduced hippocampal function. In both clinical and preclinical studies, subanesthetic doses of the NMDA receptor antagonist, ketamine (KET), was shown to have rapid and lasting antidepressant effects. Animal studies have shown that biological sex and levels of gonadal hormones alter the behavioral effects of KET, with ovarian hormones increasing sensitivity to the antidepressant-like effects of KET. Since the hippocampus plays a key role in mediating some of the effects of SIS, and considering that KET at low doses has been shown to rescue some of the behavioral deficits of isolation rearing this study aimed to assess the effects of isolation stress on pre- and post-synaptic hippocampal functions in male and female rats reared in SIS, as well as determine whether some of the physiological deficits can be rescued with a single injection of sub-anesthetic doses of KET. To do this, Sprague-Dawley rats were raised from weaning in either social isolation or with same-sex cage mate for 5 to 7 weeks. Male and female rats in either diestrus of proestrus received a single injection of KET (0, 2.5, or 5.0 mg/kg) three hours prior to termination and collection of acute hippocampal slices for ex vivo electrophysiological field potential recordings. Long-term potentiation (LTP) and paired pulse facilitation (PPF) outputs were assessed in a canonical CA3-CA1 dorsal hippocampal circuit. Our data show that SIS inhibits hippocampal LTP without affecting PPF in male rats, an effect that was rescued by KET. In female rats, isolation stress did not alter LTP, but did reduce PPF - especially when females were tested in diestrus-, an effect that was rescued by KET at the highest dose. Our data thus suggest sex differences in the contribution of pre-and postsynaptic hippocampal compartments in response to stress and KET.
Topics: Animals; Excitatory Amino Acid Antagonists; Female; Hippocampus; Ketamine; Male; Neuronal Plasticity; Rats; Rats, Sprague-Dawley; Sex Characteristics; Social Isolation; Stress, Psychological
PubMed: 34688854
DOI: 10.1016/j.neulet.2021.136301 -
Biochemical Pharmacology Apr 2022Opioids, and numerous centrally active drugs, are metabolized by cytochrome P450 2D (CYP2D). There are sex and estrous cycle differences in brain oxycodone analgesia....
Opioids, and numerous centrally active drugs, are metabolized by cytochrome P450 2D (CYP2D). There are sex and estrous cycle differences in brain oxycodone analgesia. Here we investigated the mechanism examining the selective role of CYP2D in the brain on sex, estrous cycle, and hormonal regulation. Propranolol, CYP2D-specific mechanism-based inhibitor, or vehicle was delivered into cerebral ventricles 24 h before administering oxycodone (or oxymorphone, negative control) orally to male and female (in estrus and diestrus) rats. Ovariectomized and sham-operated females received no treatment, estradiol, progesterone or vehicle. Analgesia was measured using tail-flick latency, and brain drug and metabolite concentrations were measured by microdialysis. Data were analyzed by two-way or mixed ANOVA. Following propranolol (versus vehicle) inhibition and oral oxycodone, there were greater increases in brain oxycodone concentrations and analgesia, and greater decreases in brain oxymorphone/oxycodone ratios (an in vivo phenotype of CYP2D in brain) in males and females in estrus, compared to females in diestrus; with no impact on plasma drug concentrations. There was no impact of propranolol pre-treatment, sex, or cycle after oral oxymorphone (non-CYP2D substrate) on brain oxymorphone concentrations or analgesia. There was no impact of propranolol pre-treatment following ovariectomy on brain oxycodone concentrations or analgesia, which was restored in ovariectomized females following estradiol, but not progesterone, treatment. Sex, cycle, and estradiol regulation of CYP2D in brain in turn altered brain oxycodone concentration and response, which may contribute to the large inter-individual variation in response to the numerous centrally acting CYP2D substrate drugs, including opioids.
Topics: Analgesia; Analgesics, Opioid; Animals; Brain; Cytochrome P-450 Enzyme System; Estradiol; Estrous Cycle; Female; Male; Oxycodone; Oxymorphone; Pain; Progesterone; Propranolol; Rats; Rats, Wistar
PubMed: 35143755
DOI: 10.1016/j.bcp.2022.114949 -
Journal of Circadian Rhythms Apr 2021Female reproductive success relies on proper integration of circadian- and ovarian- signals to the hypothalamic-pituitary-gonadal axis in order to synchronize the...
Female reproductive success relies on proper integration of circadian- and ovarian- signals to the hypothalamic-pituitary-gonadal axis in order to synchronize the preovulatory LH surge at the end of the ovarian follicular stage with the onset of the main active period. In this study, we used a combination of neuroanatomical and electrophysiological approaches to assess whether the hypothalamic neurons expressing Arg-Phe amide-related peptide (RFRP-3), a gonadotropin inhibitory peptide, exhibit daily and estrous stage dependent variations in female mice. Furthermore, we investigated whether arginine vasopressin (AVP), a circadian peptide produced by the suprachiamatic nucleus regulates RFRP-3 neurons. The number of c-Fos-positive RFRP-3 immunoreactive neurons is significantly reduced at the day-to-night transition with no difference between diestrus and proestrus. Contrastingly, RFRP neuron firing rate is higher in proestrus as compared to diestrus, independently of the time of the day. AVP immunoreactive fibers contact RFRP neurons with the highest density observed during the late afternoon of diestrus and proestrus. Application of AVP increases RFRP neurons firing in the afternoon (ZT6-10) of diestrus, but not at the same time point of proestrus, indicating that AVP signaling on RFRP neurons may depend on circulating ovarian steroids. Together, these studies show that RFRP neurons integrate both daily and estrogenic signals, which downstream may help to properly time the preovulatory LH surge.
PubMed: 33953780
DOI: 10.5334/jcr.212 -
Biology of Reproduction May 2023Some transmasculine individuals may be interested in pausing gender-affirming testosterone therapy and carrying a pregnancy. The ovarian impact of taking and pausing...
Some transmasculine individuals may be interested in pausing gender-affirming testosterone therapy and carrying a pregnancy. The ovarian impact of taking and pausing testosterone is not completely understood. The objective of this study was to utilize a mouse model mimicking transmasculine testosterone therapy to characterize the ovarian dynamics following testosterone cessation. We injected postpubertal 9-10-week-old female C57BL/6N mice once weekly with 0.9 mg of testosterone enanthate or a vehicle control for 6 weeks. All testosterone-treated mice stopped cycling and demonstrated persistent diestrus within 1 week of starting testosterone, while control mice cycled regularly. After 6 weeks of testosterone therapy, one group of testosterone-treated mice and age-matched vehicle-treated diestrus controls were sacrificed. Another group of testosterone-treated mice were maintained after stopping testosterone therapy and were sacrificed in diestrus four cycles after the resumption of cyclicity along with age-matched vehicle-treated controls. Ovarian histological analysis revealed stromal changes with clusters of large round cells in the post testosterone group as compared to both age-matched controls and mice at 6 weeks on testosterone. These clusters exhibited periodic acid-Schiff staining, which has been previously reported in multinucleated macrophages in aging mouse ovaries. Notably, many of these cells also demonstrated positive staining for macrophage markers CD68 and CD11b. Ovarian ribonucleic acid-sequencing found upregulation of immune pathways post testosterone as compared to age-matched controls and ovaries at 6 weeks on testosterone. Although functional significance remains unknown, further attention to the ovarian stroma may be relevant for transmasculine people interested in pausing testosterone to carry a pregnancy.
Topics: Pregnancy; Female; Mice; Animals; Humans; Ovary; Transgender Persons; Mice, Inbred C57BL; Testosterone; Disease Models, Animal; Mice, Inbred Strains
PubMed: 36790125
DOI: 10.1093/biolre/ioad019 -
Genetics and Molecular Research : GMR Jan 2016Frizzled 3 is an important receptor in the Wnt/β-catenin pathway, a conserved signaling pathway that regulates gene expression and controls diverse developmental...
Frizzled 3 is an important receptor in the Wnt/β-catenin pathway, a conserved signaling pathway that regulates gene expression and controls diverse developmental processes. However, the role of this protein during follicular development in the adult ovary is not known. The present study was designed to investigate the expression and localization of Frizzled 3 mRNA and protein during the estrous cycle in the mouse ovary through in situ hybridization (ISH), real-time quantitative polymerase chain reaction, immunohistochemistry and western blot. ISH results showed that in proestrus, high expression of Frizzled 3 was found in the granulosa and stroma with weak levels in the corpus luteum. In estrus and diestrus, the stroma had high Frizzled 3 expression, but levels were low in granulosa cells and corpus luteum. In the metestrus, moderate expression of Frizzled 3 was found in the stroma but low to no expression was found in luteal cells and follicles. The mRNA and protein levels of Frizzled 3 were found to be the highest in proestrus and diestrus compared to estrus and metestrus (P < 0.05), confirming the ISH results. During estrus and diestrus, high Frizzled 3 expression was observed in the stroma and moderate levels in granulosa cells, and during estrus and proestrus, low expression was seen in the oocyte cell membrane. The western blot results further confirmed this change during the estrous cycle. Together, these results indicate that Frizzled 3 is involved in regulating follicular development and oocyte maturation during the estrous cycle.
Topics: Animals; Corpus Luteum; Diestrus; Estrus; Female; Frizzled Receptors; Gene Expression Regulation, Developmental; In Situ Hybridization; Mice; Mice, Inbred ICR; Oocytes; Ovarian Follicle; Proestrus; Real-Time Polymerase Chain Reaction; Time Factors
PubMed: 26909900
DOI: 10.4238/gmr.15017152 -
Journal of Equine Veterinary Science Oct 2021The reproductive cycle and early pregnancy represent dynamic physiological states in mammals, but mechanisms involved in early pregnancy in the domestic horse remain...
The reproductive cycle and early pregnancy represent dynamic physiological states in mammals, but mechanisms involved in early pregnancy in the domestic horse remain poorly understood. Proteins in uterine secretions have been studied, but the proteome of peripheral serum during various reproductive states has not been investigated. This study characterized and compared the serum proteome in the domestic horse during various reproductive states. Serum was collected from three mares during: (1) estrus (day [d] -1; d 0 = ovulation), (2) diestrus (d 12.5, non-mated), (3) early pregnancy (d 12.5, pregnant), and (4) nonpregnant (d 12.5, unsuccessfully mated) states. Serum proteins in each sample were analyzed by Nano LC-MS/MS, and 308 proteins were identified. Differentially-expressed proteins (DEP; > 1.5-fold or < - 0.5-fold) were identified by comparison of protein relative abundance between reproductive states: (1) diestrus compared to estrus (DEP = 71), (2) pregnant compared to diestrus (DEP = 72), and (3) non-pregnant compared to pregnant (DEP = 81). DEPs were analyzed for biological function using PANTHER (pantherdb.org). Several pregnancy-specific proteins previously identified in equine pregnant histotroph, including Apolipoprotein A-I, Complement C3, and Histone H4, were detectable in the serum. The ability to detect these biomarkers in serum provides a more readily available option for investigating and understanding early equine pregnancy.
Topics: Animals; Diestrus; Estrus; Female; Horses; Ovulation; Pregnancy; Proteome; Tandem Mass Spectrometry
PubMed: 34607689
DOI: 10.1016/j.jevs.2021.103724 -
Animal Reproduction Science Dec 2017The cervix is a dynamic structure that undergoes dramatic changes during the estrous cycle, pregnancy and parturition. It is well established that hormonal changes,...
Sex-steroid receptors, prostaglandin E2 receptors, and cyclooxygenase in the equine cervix during estrus, diestrus and pregnancy: Gene expression and cellular localization.
The cervix is a dynamic structure that undergoes dramatic changes during the estrous cycle, pregnancy and parturition. It is well established that hormonal changes, including estrogens, progestogens and prostaglandins, regulate the expression of key proteins involved in cervical function. The arachidonic acid cascade is important in the remodeling and relaxation of the cervix in the days preceding parturition. Despite the complexity of this mechanism, regulation of cervical function has received little study in the mare. Therefore, the objective of this study was to compare the expression of estrogen receptor α (ESR1) and β (ESR2), progesterone receptor (PGR), prostaglandin E2 type 2 (PTGER2) and type 4 (PTGER4) receptors as well as cyclooxygenase-1 (PTGS1) and -2 (PTGS2) in the equine cervical mucosa and stroma during estrus, diestrus and late pregnancy using qPCR. Immunohistochemistry was used to localize ESR1, ESR2, PGR, PTGER2 and PTGER4 receptors in these regions of the cervix. Relative mRNA expression of ESR1 and PGR was greater during estrus and diestrus than in late pregnancy in both the mucosa and stroma of the cervix. Expression of PTGER2 was highest in the cervical stroma during late pregnancy compared to either estrus or diestrus. Moreover, PTGS1 expression in mucosa and PTGS2 in stroma was greater during late pregnancy compared with estrus, but not diestrus. Immunostaining for ESR1, ESR2, PGR, PTGER2 and PTGER4 was consistently detected in the nucleus and cytoplasm of epithelium of the endocervix as well as the smooth muscle cytoplasm of the cervix in all stages evaluated. Immunolabeling in smooth muscle nuclei was detected for ESR1 and PGR in estrus, diestrus and late pregnancy, and for ESR2 in estrus and late pregnancy stages. The changes noted in late gestation likely reflect preparation of the equine cervix for subsequent parturition.
Topics: Animals; Cervix Uteri; Diestrus; Estrus; Female; Gene Expression Regulation; Horses; Pregnancy; Prostaglandin-Endoperoxide Synthases; Receptors, Prostaglandin E; Receptors, Steroid
PubMed: 29100665
DOI: 10.1016/j.anireprosci.2017.10.018 -
Neuroscience and Biobehavioral Reviews Oct 2014Panic disorder (PD) patients are specifically sensitive to 5–7% carbon dioxide. Another startling feature of clinical panic is the counterintuitive lack of increments... (Review)
Review
Panic disorder (PD) patients are specifically sensitive to 5–7% carbon dioxide. Another startling feature of clinical panic is the counterintuitive lack of increments in ‘stress hormones’. PD is also more frequent in women and highly comorbid with childhood separation anxiety (CSA). On the other hand, increasing evidence suggests that panic is mediated at dorsal periaqueductal grey matter (DPAG). In line with prior studies showing that DPAG-evoked panic-like behaviours are attenuated by clinically-effective treatments with panicolytics, we show here that (i) the DPAG harbors a hypoxia-sensitive alarm system, which is activated by hypoxia and potentiated by hypercapnia, (ii) the DPAG suffocation alarm system is inhibited by clinically-effective treatments with panicolytics, (iii) DPAG stimulations do not increase stress hormones in the absence of physical exertion, (iv) DPAG-evoked panic-like behaviours are facilitated in neonatally-isolated adult rats, a model of CSA, and (v) DPAG-evoked responses are enhanced in the late diestrus of female rats. Data are consistent with the DPAG mediation of both respiratory and non-respiratory types of panic attacks.
Topics: Animals; Asphyxia; Disease Models, Animal; Panic Disorder; Periaqueductal Gray; Rats; Translational Research, Biomedical
PubMed: 25316571
DOI: 10.1016/j.neubiorev.2014.10.002 -
BMC Veterinary Research Jun 2018Uterine myoactivity is crucial for successful reproductive performance of the sow. Spontaneous contractions of the uterus are strictly controlled and coordinated....
BACKGROUND
Uterine myoactivity is crucial for successful reproductive performance of the sow. Spontaneous contractions of the uterus are strictly controlled and coordinated. Uterine electromyographic (EMG) activity undergoes hormonal regulation with rapid and long-term effects. What is more, interstitial Cajal-like Cells (ICLC) appear essential for smooth muscle contractility in the reproductive tract where they are suspected to be playing a major role in generating, coordinating, modulating and synchronizing slow triggering waves. The aim of this study was to investigate the myoelectrical activity of sow's uterus during estrus cycle.
RESULTS
Study was conducted on 10 Polish Landrace sows. Propagation mechanisms and their connection with the uterine EMG activity were considered in correlation with expression of c-kit, progesterone and oxytocin receptors of the non-pregnant sow. ICLC were labeled with antibody directed against c-kit receptor and visualized by confocal microscopy and scanning cytometer for positive cells percentage assessment. EMG signal was recorded directly from the myometrium with telemetry transmitters and electrodes located in different topographic regions of reproductive tracts. The stages of estrus cycle were determined by monitoring levels of luteinizing hormone, progesterone and estrogen with radioimmunoassays. Significant differences of the EMG signal parameters between diestrus and estrus and the correlations with density of labelled receptors were demonstrated. Moreover, the electrophysiological studies indicated that ICLC in the myometrium in the tip of uterine horn may participate in the regulation of slow waves duration and frequency.
CONCLUSIONS
The pattern of EMG signal propagation in the wall of the non-pregnant porcine uterus occurs in an orderly, bidirectional fashion and at distinctive speed, with no differences between diestrus and estrus.
Topics: Animals; Electromyography; Estrous Cycle; Female; Swine; Uterine Contraction; Uterus
PubMed: 29866204
DOI: 10.1186/s12917-018-1495-z