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International Journal of Molecular... Jun 2024The physiology of reproduction has been of interest to researchers for centuries. The purpose of this work is to review the development of our knowledge on the... (Review)
Review
The physiology of reproduction has been of interest to researchers for centuries. The purpose of this work is to review the development of our knowledge on the neuroendocrine background of the regulation of ovulation. We first describe the development of the pituitary gland, the structure of the median eminence (ME), the connection between the hypothalamus and the pituitary gland, the ovarian and pituitary hormones involved in ovulation, and the pituitary cell composition. We recall the pioneer physiological and morphological investigations that drove development forward. The description of the supraoptic-paraventricular magnocellular and tuberoinfundibular parvocellular systems and recognizing the role of the hypophysiotropic area were major milestones in understanding the anatomical and physiological basis of reproduction. The discovery of releasing and inhibiting hormones, the significance of pulse and surge generators, the pulsatile secretion of the gonadotropin-releasing hormone (GnRH), and the subsequent pulsatility of luteinizing (LH) and follicle-stimulating hormones (FSH) in the human reproductive physiology were truly transformative. The roles of three critical neuropeptides, kisspeptin (KP), neurokinin B (NKB), and dynorphin (Dy), were also identified. This review also touches on the endocrine background of human infertility and assisted fertilization.
Topics: Humans; Ovulation; Female; Neurosecretory Systems; Animals; Pituitary Gland; Kisspeptins; Neurokinin B; Luteinizing Hormone; Gonadotropin-Releasing Hormone; Dynorphins; Hypothalamus
PubMed: 38928237
DOI: 10.3390/ijms25126531 -
Genes Jun 2024Previous studies have demonstrated the essential role of the Kisspeptin/Neurokinin B/Dynorphin A (KNDy) pathway in female reproductive biology by regulating the activity...
Previous studies have demonstrated the essential role of the Kisspeptin/Neurokinin B/Dynorphin A (KNDy) pathway in female reproductive biology by regulating the activity of the hypothalamic-pituitary-gonadal axis. Identified loss-of-function mutations in these genes are linked to various reproductive disorders. This study investigated genetic disorders linked to mutations in the genes related to premature ovarian insufficiency (POI). A cohort of 14 Mexican POI patients underwent genetic screening using PCR-SSCP and Sanger sequencing, assessing the genetic variations' impact on protein function thereafter using multiple in silico tools. The PCR excluded extensive deletions, insertions, and duplications, while SSCP detected five genetic variants. Variations occurred in the (c.58G>A and c.242C>G), (c.1091A>T), (c.600C>T), and (c.36G>T) genes, whereas no genetic anomalies were found in genes. Each single-nucleotide variant underwent genotyping using PCR-SSCP in 100 POI-free subjects. Their allelic frequencies paralleled the patient group. These observations indicate that allelic variations in the genes may not contribute to POI etiology. Hence, screening for mutations in genes should not be a part of the diagnostic protocol for POI.
Topics: Humans; Female; Primary Ovarian Insufficiency; Mexico; Adult; Neurokinin B; Kisspeptins; Cohort Studies; Polymorphism, Single Nucleotide; Receptors, Kisspeptin-1; Enkephalins; Protein Precursors
PubMed: 38927724
DOI: 10.3390/genes15060788 -
Cells Jun 2024(1) Background: The effects of short-term social isolation during adulthood have not yet been fully established in rats behaviourally, and not at all transcriptomically...
(1) Background: The effects of short-term social isolation during adulthood have not yet been fully established in rats behaviourally, and not at all transcriptomically in the medial prefrontal cortex (mPFC). (2) Methods: We measured the behavioural effects of housing adult male rats in pairs or alone for 10 days. We also used RNA sequencing to measure the accompanying gene expression alterations in the mPFC of male rats. (3) Results: The isolated animals exhibited reduced sociability and social novelty preference, but increased social interaction. There was no change in their aggression, anxiety, or depression-like activity. Transcriptomic analysis revealed a differential expression of 46 genes between the groups. The KEGG pathway analysis showed that differentially expressed genes are involved in neuroactive ligand-receptor interactions, particularly in the dopaminergic and peptidergic systems, and addiction. Subsequent validation confirmed the decreased level of three altered genes: regulator of G protein signalling 9 (Rgs9), serotonin receptor 2c (Htr2c), and Prodynorphin (Pdyn), which are involved in dopaminergic, serotonergic, and peptidergic function, respectively. Antagonizing Htr2c confirmed its role in social novelty discrimination. (4) Conclusions: Social homeostatic regulations include monoaminergic and peptidergic systems of the mPFC.
Topics: Animals; Prefrontal Cortex; Male; Social Isolation; Rats; Signal Transduction; Biogenic Monoamines; Rats, Sprague-Dawley; Behavior, Animal; Receptor, Serotonin, 5-HT2C; Enkephalins; Protein Precursors; Transcriptome; Gene Expression Regulation
PubMed: 38920671
DOI: 10.3390/cells13121043 -
Menopause (New York, N.Y.) Jun 2024Sleep disturbance is one of the most common and debilitating symptoms experienced by women during the menopause transition. However, there are currently no therapies...
IMPORTANCE AND OBJECTIVES
Sleep disturbance is one of the most common and debilitating symptoms experienced by women during the menopause transition. However, there are currently no therapies specifically approved for sleep disturbance associated with the menopause. Here, we consider how to characterize sleep disturbance associated with the menopause and discuss its etiology, including the latest advances in our understanding of the neuronal circuits that regulate reproduction, body temperature, sleep, and mood; and reflect on its impact on women's health and well-being. We also examine the current treatment landscape and look to the future of treatment for this condition.
METHODS
We conducted a review of the literature and combined this with discussion with experts in the fields of sleep and menopause as well as experiences from our own clinical practices.
DISCUSSION AND CONCLUSIONS
Sleep disturbance associated with the menopause is characterized by frequent night-time awakenings and increased awake time after sleep onset. Its impacts are wide-ranging, negatively affecting health as well as personal and social relationships, productivity, and work performance. There is currently an unmet need for effective, safe, and well-tolerated treatments to address this important symptom, and wider recognition of the association between sleep disturbances and the menopause is needed. Sleep disturbances associated with the menopause can result from hormone changes as well as vasomotor and mood symptoms. Growing research has contributed to our knowledge of the role of hypothalamic estrogen-sensitive kisspeptin/neurokinin B/dynorphin neurons. These neurons are thought to integrate the gonadotropin-releasing hormone pathway and the pathways responsible for the homeostatic control of body temperature and the circadian regulation of sleep-wake cycles. Understanding these neurons offers the potential to create treatments that target a key cause of sleep disturbance associated with the menopause. Further research to understand their etiology and characterize the neuronal circuits responsible could benefit the development of these targeted treatment approaches.
PubMed: 38916279
DOI: 10.1097/GME.0000000000002386 -
BioRxiv : the Preprint Server For... Jun 2024Hypothalamic kisspeptin (Kiss1) neurons are vital for pubertal development and reproduction. Arcuate nucleus Kiss1 (Kiss1 ) neurons are responsible for the pulsatile...
Hypothalamic kisspeptin (Kiss1) neurons are vital for pubertal development and reproduction. Arcuate nucleus Kiss1 (Kiss1 ) neurons are responsible for the pulsatile release of Gonadotropin-releasing Hormone (GnRH). In females, the behavior of Kiss1 neurons, expressing Kiss1, Neurokinin B (NKB), and Dynorphin (Dyn), varies throughout the ovarian cycle. Studies indicate that 17β-estradiol (E2) reduces peptide expression but increases mRNA and glutamate neurotransmission in these neurons, suggesting a shift from peptidergic to glutamatergic signaling. To investigate this shift, we combined transcriptomics, electrophysiology, and mathematical modeling. Our results demonstrate that E2 treatment upregulates the mRNA expression of voltage-activated calcium channels, elevating the whole-cell calcium current and that contribute to high-frequency burst firing. Additionally, E2 treatment decreased the mRNA levels of Canonical Transient Receptor Potential (TPRC) 5 and G protein-coupled K (GIRK) channels. When TRPC5 channels in Kiss1 neurons were deleted using CRISPR, the slow excitatory postsynaptic potential (sEPSP) was eliminated. Our data enabled us to formulate a biophysically realistic mathematical model of the Kiss1 neuron, suggesting that E2 modifies ionic conductances in Kiss1 neurons, enabling the transition from high frequency synchronous firing through NKB-driven activation of TRPC5 channels to a short bursting mode facilitating glutamate release. In a low E2 milieu, synchronous firing of Kiss1 neurons drives pulsatile release of GnRH, while the transition to burst firing with high, preovulatory levels of E2 would facilitate the GnRH surge through its glutamatergic synaptic connection to preoptic Kiss1 neurons.
PubMed: 38915596
DOI: 10.1101/2024.02.20.581121 -
BioRxiv : the Preprint Server For... Jun 2024Stress has been shown to promote the development and persistence of binge eating behaviors. However, the neural circuit mechanisms for stress-induced binge-eating...
Stress has been shown to promote the development and persistence of binge eating behaviors. However, the neural circuit mechanisms for stress-induced binge-eating behaviors are largely unreported. The endogenous dynorphin (dyn)/kappa opioid receptor (KOR) opioid neuropeptide system has been well-established to be a crucial mediator of the anhedonic component of stress. Here, we aimed to dissect the basis of dynorphinergic control of stress-induced binge-like eating behavior. We first established a mouse behavioral model for stress-induced binge-like eating behaviors. We found that mice exposed to stress increased their food intake of familiar palatable food (high fat, high sugar, HPD) compared to non-stressed mice. Following a brain-wide analysis, we isolated robust cFos-positive cells in the Claustrum (CLA), a subcortical structure with highly abundant KOR expression, following stress-induced binge-eating behavior. We report that KOR signaling in CLA is necessary for this elevated stress-induced binge eating behavior using local pharmacology and local deletion of KOR. In vivo calcium recordings using fiber photometry revealed a disinhibition circuit structure in the CLA during the initiation of HPD feeding bouts. We further established the dynamics of endogenous dynorphinergic control of this behavior using a genetically encoded dynorphin biosensor, Klight. Combined with 1-photon single-cell calcium imaging, we report significant heterogeneity with the CLA population during stress-induced binge eating and such behavior attenuates local dynorphin tone. Furthermore, we isolate the anterior Insular cortex (aIC) as the potential source of endogenous dynorphin afferents in the CLA. By characterizing neural circuits and peptidergic mechanisms within the CLA, we uncover a pathway that implicates endogenous opioid regulation stress-induced binge eating.
PubMed: 38915527
DOI: 10.1101/2024.06.10.598168 -
Frontiers in Physiology 2024The neuropeptides kisspeptin, neurokinin B, and dynorphin A are imperative for the pulsatile secretion of gonadotropin-releasing hormone and luteinizing hormone to...
The neuropeptides kisspeptin, neurokinin B, and dynorphin A are imperative for the pulsatile secretion of gonadotropin-releasing hormone and luteinizing hormone to ultimately regulate reproductive cyclicity. A population of neurons co-expressing these neuropeptides, KNDy neurons, within the arcuate nucleus of the hypothalamus (ARC) are positioned to integrate energy status from afferent neuronal and glial cells. We hypothesized that KNDy-expressing neurons in the ARC of mature ewes are influenced by energy balance. To test this hypothesis, ovary-intact, mature ewes were fed to lose, maintain, or gain body weight and hypothalamic tissue harvested during the luteal phase of the estrous cycle. Fluorescent, multiplex immunohistochemistry with direct antibody conjugation was employed to identify and quantify neurons expressing a single neuropeptide, as well as for the first time report co-expression of kisspeptin, neurokinin B, and dynorphin A protein in the ARC. Previous reports using this population of ewes demonstrated that concentrations of insulin and leptin differed between ewes fed to achieve different body weights and that ewes fed to gain body weight had increased concentrations of progesterone. Moreover, within this population of ewes tanycyte density and cellular penetration into the ARC was increased in ewes fed to gain body weight. Within the current report we have revealed that the number of neurons in the ARC expressing kisspeptin, neurokinin B, and dynorphin A protein was increased in ewes fed to gain body weight. Moreover, the number of KNDy neurons in the ARC expressing all three neuropeptides within a single neuron was decreased in ewes fed to lose body weight and increased in ewes fed to gain body weight when compared to ewes fed to maintain body weight. The cumulative findings of this experimental model suggest that expression of kisspeptin, neurokinin B, and dynorphin A protein in the ARC during the luteal phase of the estrous cycle are influenced by energy balance-induced alterations in circulating concentrations of progesterone that drive changes in morphology and density of tanycytes to ultimately regulate central perception of global energy status. Moreover, these results demonstrate that changes in KNDy neurons within the ARC occur as an adaptation to energy balance, potentially regulated divergently by metabolic milieu via proopiomelanocortin afferents.
PubMed: 38911326
DOI: 10.3389/fphys.2024.1372944 -
Neuron Jun 2024The dynamic suppression of threat-related behavior as a function of environmental constraint is critical for survival in mammals, yet the neurobiological underpinnings...
The dynamic suppression of threat-related behavior as a function of environmental constraint is critical for survival in mammals, yet the neurobiological underpinnings remain largely unknown. In this issue of Neuron, Wang et al. identified prefrontal dynorphin-expressing neurons as key elements for tracking threat-related behavioral states and regulating fear suppression.
Topics: Dynorphins; Prefrontal Cortex; Neurons; Animals; Fear
PubMed: 38901400
DOI: 10.1016/j.neuron.2024.05.028 -
The Journal of Pain Jun 2024While early life adversity has been associated with a higher risk of developing chronic pain in adulthood, the cellular and molecular mechanisms by which chronic stress...
While early life adversity has been associated with a higher risk of developing chronic pain in adulthood, the cellular and molecular mechanisms by which chronic stress during the neonatal period can persistently sensitize developing nociceptive circuits remain poorly understood. Here we investigate the effects of early life stress (ELS) on synaptic integration and intrinsic excitability in dynorphin-lineage (DYN) interneurons within the adult mouse superficial dorsal horn (SDH) which are important for inhibiting mechanical pain and itch. The administration of neonatal limited bedding between postnatal days (P)2 and P9 evoked sex-dependent effects on spontaneous glutamatergic signaling, as female SDH neurons exhibited a higher amplitude of miniature excitatory postsynaptic currents (mEPSCs) after ELS while mEPSC frequency was reduced in DYN neurons of the male SDH. Furthermore, ELS decreased the frequency of miniature inhibitory postsynaptic currents (mIPSCs) selectively in female DYN neurons. As a result, ELS increased the balance of spontaneous excitation vs. inhibition (E:I ratio) in mature DYN neurons of the female, but not male, SDH network. Nonetheless, ELS weakened the total primary afferent-evoked glutamatergic drive onto adult DYN neurons selectively in females, without modifying afferent-evoked inhibitory signaling onto the DYN population. Finally, ELS failed to significantly change the intrinsic membrane excitability of mature DYN neurons in either males or females. Collectively, these data suggest that ELS exerts a long-term influence on the properties of synaptic transmission onto DYN neurons within the adult SDH, which includes a reduction in the overall strength of sensory input onto this important subset of inhibitory interneurons. PERSPECTIVE: This study suggests that chronic stress during the neonatal period influences synaptic function within adult spinal nociceptive circuits in a sex-dependent manner. These findings yield new insight into the potential mechanisms by which early life adversity might shape the maturation of pain pathways in the CNS.
PubMed: 38885917
DOI: 10.1016/j.jpain.2024.104609 -
Advances in Neurobiology 2024The function of endogenous opioids spans from initiating behaviors that are critical for survival, to responding to rapidly changing environmental conditions. A network...
The function of endogenous opioids spans from initiating behaviors that are critical for survival, to responding to rapidly changing environmental conditions. A network of interconnected systems throughout the body characterizes the endogenous opioid system (EOS). EOS receptors for beta-endorphin, enkephalin, dynorphin, and endomorphin underpin the diverse functions of the EOS across biological systems. This chapter presents a succinct yet comprehensive summary of the structure of the EOS, EOS receptors, and their relationship to other biological systems.
Topics: Animals; Humans; Analgesics, Opioid; beta-Endorphin; Dynorphins; Enkephalins; Opioid Peptides; Receptors, Opioid
PubMed: 38874716
DOI: 10.1007/978-3-031-45493-6_2