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Journal of Molecular Endocrinology Feb 2024The exact neural construct underlying the dynamic secretion of gonadotrophin-releasing hormone (GnRH) has only recently been identified despite the detection of... (Review)
Review
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.
Topics: Animals; Gonadotropin-Releasing Hormone; Luteinizing Hormone; Hypothalamus; Neurokinin B; Dynorphins; Kisspeptins; Arcuate Nucleus of Hypothalamus; Mammals
PubMed: 38085702
DOI: 10.1530/JME-23-0079 -
Nature Communications Nov 2023Ample evidence has suggested the stress etiology of depression, but the underlying mechanism is not fully understood yet. Here, we report that chronic social defeat...
Ample evidence has suggested the stress etiology of depression, but the underlying mechanism is not fully understood yet. Here, we report that chronic social defeat stress (CSDS) attenuates the excitatory output of the claustrum (CLA) to the prelimbic cortex (PL) through the dynorphin/κ-opioid receptor (KOR) signaling, being critical for depression-related behaviors in male mice. The CSDS preferentially impairs the excitatory output from the CLA onto the parvalbumin (PV) of the PL, leading to PL micronetwork dysfunction by disinhibiting pyramidal neurons (PNs). Optogenetic activation or inhibition of this circuit suppresses or promotes depressive-like behaviors, which is reversed by chemogenetic inhibition or activation of the PV neurons. Notably, manipulating the dynorphin/KOR signaling in the CLA-PL projecting terminals controls depressive-like behaviors that is suppressed or promoted by optogenetic activation or inhibition of CLA-PL circuit. Thus, this study reveals both mechanism of the stress etiology of depression and possibly therapeutic interventions by targeting CLA-PL circuit.
Topics: Male; Mice; Animals; Receptors, Opioid, kappa; Dynorphins; Depression; Claustrum; Signal Transduction; Mice, Inbred C57BL
PubMed: 38036497
DOI: 10.1038/s41467-023-43636-x -
Scientific Reports Nov 2023The gonadotropin-releasing hormone (GnRH) pulse and surge are considered to be generated by arcuate kisspeptin/neurokinin B/dynorphin A (KNDy) neurons and anteroventral...
The gonadotropin-releasing hormone (GnRH) pulse and surge are considered to be generated by arcuate kisspeptin/neurokinin B/dynorphin A (KNDy) neurons and anteroventral periventricular nucleus (AVPV) kisspeptin neurons, respectively, in female rodents. The majority of KNDy and AVPV kisspeptin neurons express κ-opioid receptors (KORs, encoded by Oprk1) in female rodents. Thus, this study aimed to investigate the effect of a conditional Oprk1-dependent Kiss1 deletion in kisspeptin neurons on the luteinizing hormone (LH) pulse/surge and fertility using Kiss1-floxed/Oprk1-Cre rats, in which Kiss1 was deleted in cells expressing or once expressed the Oprk1/Cre. The Kiss1-floxed/Oprk1-Cre female rats, with Kiss1 deleted in a majority of KNDy neurons, showed normal puberty while having a one-day longer estrous cycle and fewer pups than Kiss1-floxed controls. Notably, ovariectomized (OVX) Kiss1-floxed/Oprk1-Cre rats showed profound disruption of LH pulses in the presence of a diestrous level of estrogen but showed apparent LH pulses without estrogen treatment. Furthermore, Kiss1-floxed/Oprk1-Cre rats, with Kiss1 deleted in approximately half of AVPV kisspeptin neurons, showed a lower peak of the estrogen-induced LH surge than controls. These results suggest that arcuate and AVPV kisspeptin neurons expressing or having expressed Oprk1 have a role in maintaining normal GnRH pulse and surge generation, the normal length of the estrous cycle, and the normal offspring number in female rats.
Topics: Rats; Female; Animals; Kisspeptins; Luteinizing Hormone; Estrogens; Gonadotropin-Releasing Hormone; Neurokinin B; Dynorphins; Neurons; Arcuate Nucleus of Hypothalamus
PubMed: 37993510
DOI: 10.1038/s41598-023-47222-5 -
Endocrinology Nov 2023The mechanism by which arcuate kisspeptin (ARNKISS) neurons co-expressing glutamate, neurokinin B, and dynorphin intermittently synchronize their activity to drive...
The mechanism by which arcuate kisspeptin (ARNKISS) neurons co-expressing glutamate, neurokinin B, and dynorphin intermittently synchronize their activity to drive pulsatile hormone secretion remains unclear in females. In order to study spontaneous synchronization within the ARNKISS neuron network, acute brain slices were prepared from adult female Kiss1-GCaMP6 mice. Analysis of both spontaneous synchronizations and those driven by high frequency stimulation of individual ARNKISS neurons revealed that the network exhibits semi-random emergent excitation dependent upon glutamate signaling through AMPA receptors. No role for NMDA receptors was identified. In contrast to male mice, ongoing tachykinin receptor tone within the slice operated to promote spontaneous synchronizations in females. As previously observed in males, we found that ongoing dynorphin transmission in the slice did not contribute to synchronization events. These observations indicate that a very similar AMPA receptor-dependent mechanism underlies ARNKISS neuron synchronizations in the female mouse supporting the "glutamate two-transition" model for kisspeptin neuron synchronization. However, a potentially important sex difference appears to exist with a more prominent facilitatory role for tachykinin transmission in the female.
Topics: Mice; Female; Male; Animals; Kisspeptins; Dynorphins; Arcuate Nucleus of Hypothalamus; Neurokinin B; Brain; Neurons; Glutamates; Gonadotropin-Releasing Hormone
PubMed: 37936337
DOI: 10.1210/endocr/bqad167 -
Neuropharmacology Jan 2024Pain comorbidities include several psychological disorders, such as anxiety and anhedonia. However, the way pain affects male and female individuals and by which...
Pain comorbidities include several psychological disorders, such as anxiety and anhedonia. However, the way pain affects male and female individuals and by which mechanism is not well understood. Previous research shows that pain induces alterations in the dynorphinergic pathway within the mesocorticolimbic system (MCLS), together with a relationship between corticotropin-releasing system and dynorphin release in the MCLS. Here, we analyse the sex and time course-dependent effects of pain on negative affect. Additionally, we study the implication of dynorphinergic and corticotropin releasing factor in these pain related behaviours. We used behavioural pharmacology and biochemical tools to characterise negative affective states induced by inflammatory pain in male and female rats, and the alterations in the dynorphinergic and the corticotropin systems within the MCLS. Female rats showed persistent anxiety-like and reversible anhedonia-like behaviours derived from inflammatory pain. Additionally, we found alterations in dynorphin and corticotropin releasing factor in NAc and amygdala, which suggests sex-dependent dynamic adaptations. Finally blockade on the kappa opioid receptor in the NAc confirmed its role in pain-induced anxiety-like behaviour in female rats. Our results show sex and time-dependent anxiety- and anhedonia-like behaviours induced by the presence of pain in female rats. Furthermore, we replicated previous data, pointing to the KOR/DYN recruitment in the NAc as a key neurological substrate mediating pain-induced behavioural alterations. This research studies the mechanisms underlying these behaviours, to better understand the emotional dimension of pain.
Topics: Rats; Male; Female; Animals; Receptors, Opioid, kappa; Nucleus Accumbens; Dynorphins; Corticotropin-Releasing Hormone; Anhedonia; Pain; Adrenocorticotropic Hormone
PubMed: 37879455
DOI: 10.1016/j.neuropharm.2023.109764 -
BioRxiv : the Preprint Server For... Oct 2023The central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) are reciprocally connected nodes of the extended amygdala thought to play an important role in...
The central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) are reciprocally connected nodes of the extended amygdala thought to play an important role in alcohol consumption. Studies of immediate-early genes indicate that BNST and CeA are acutely activated following alcohol drinking and may signal alcohol reward in nondependent drinkers, while increased stress signaling in the extended amygdala following chronic alcohol exposure drives increased drinking via negative reinforcement. However, the temporal dynamics of neuronal activation in these regions during drinking behavior are poorly understood. In this study, we used fiber photometry and the genetically encoded calcium sensor GCaMP6s to assess acute changes in neuronal activity during alcohol consumption in BNST and CeA before and after a chronic drinking paradigm. Activity was examined in the pan-neuronal population and separately in dynorphinergic neurons. BNST and CeA showed increased pan-neuronal activity during acute consumption of alcohol and other fluid tastants of positive and negative valence, as well as highly palatable chow. Responses were greatest during initial consummatory bouts and decreased in amplitude with repeated consumption of the same tastant, suggesting modulation by stimulus novelty. Dynorphin neurons showed similar consumption-associated calcium increases in both regions. Following three weeks of continuous alcohol access (CA), calcium increases in dynorphin neurons during drinking were maintained, but pan-neuronal activity and BNST-CeA coherence were altered in a sex-specific manner. These results indicate that BNST and CeA, and dynorphin neurons specifically, are engaged during drinking behavior, and activity dynamics are influenced by stimulus novelty and chronic alcohol.
PubMed: 37873188
DOI: 10.1101/2023.10.10.561741 -
BioRxiv : the Preprint Server For... Sep 2023Binding events to elements of the cell membrane act as receptors which regulate cellular function and communication and are the targets of many small molecule drug...
Binding events to elements of the cell membrane act as receptors which regulate cellular function and communication and are the targets of many small molecule drug discovery efforts for agonists and antagonists. Conventional techniques to probe these interactions generally require labels and large amounts of receptor to achieve satisfactory sensitivity. Whispering gallery mode microtoroid optical resonators have demonstrated sensitivity to detect single-molecule binding events. Here, we demonstrate the use of frequency-locked optical microtoroids for characterization of membrane interactions at zeptomolar concentrations using a supported biomimetic membrane. Arrays of microtoroids were produced using photolithography and subsequently modified with a biomimetic membrane, providing high quality (Q) factors () in aqueous environments. Fluorescent recovery after photobleaching (FRAP) experiments confirmed the retained fluidity of the microtoroid supported-lipid membrane with a diffusion coefficient of . Utilizing this frequency-locked membrane-on-a-chip model combined with auto-balanced detection and non-linear post-processing techniques, we demonstrate zeptomolar detection levels The binding of Cholera Toxin B- monosialotetrahexosyl ganglioside (GM1) was monitored in real-time, with an apparent equilibrium dissociation constant . The measured affiny of the agonist dynorphin A 1-13 to the -opioid receptor revealed a using the same approach. Radioligand binding competition with dynorphin A 1-13 revealed a in agreement (1.1 nM) with the unlabeled method. The biosensing platform reported herein provides a highly sensitive real-time characterization of membrane embedded protein binding kinetics, that is rapid and label-free, for toxin screening and drug discovery, among other applications.
PubMed: 37786702
DOI: 10.1101/2023.09.20.558657 -
American Journal of Translational... 2023To analyze the effects of transcutaneous electrical nerve stimulation (TENS) combined with levofloxacin (0.1 g, twice daily) and tamsulosin (0.2 mg, once daily) on...
Transcutaneous electrical nerve stimulation combined with levofloxacin and tamsulosin for patients with chronic prostatitis: clinical efficacy and changes in serum factors.
OBJECTIVE
To analyze the effects of transcutaneous electrical nerve stimulation (TENS) combined with levofloxacin (0.1 g, twice daily) and tamsulosin (0.2 mg, once daily) on clinical efficacy and serum factors in patients with chronic prostatitis (CP).
METHODS
A retrospective analysis was conducted on 105 patients with CP who received treatment at Hangzhou Lin'an District Hospital of Traditional Chinese Medicine from February 2020 to December 2022. Among them, 47 patients received levofloxacin and tamsulosin were included in a drug group (DG), and 58 patients received additional TENS therapy (frequency: 1/4/1 Hz+80/120/80 Hz; pulse width: 270/230/270 μs+120/80/120 μs; waveform: square and continuous waveforms) were included in a joint group (JG). The changes in the National Institutes of Health chronic prostatitis symptom index (NIH-CPSI), international prostate symptom score (IPSS), and the levels of inflammatory and pain-causing factors were compared between the two groups before and after treatment. The clinical efficacy was compared between the two groups after treatment. Moreover, the incidence of adverse reactions was compared between the two groups.
RESULTS
After treatment, the scores of NIH-CPSI and IPSS, and the levels of IL-6, CRP, TNF-α, IL-1β, 5-hydroxytryptamine, substance P, and dynorphin in the JG were obviously lower than those in the DG (P<0.001). The clinical response rate in the DG was obviously lower than that in the JG (P=0.006, Table 2). There was no difference in total incidence of adverse reactions between the two groups (P=0.801).
CONCLUSION
Compared to medication alone (levofloxacin and tamsulosin), the combination of TENS with levofloxacin and tamsulosin can reduce the levels of inflammatory and pain-causing factors in patients, and improve the efficacy. Importantly, it has been observed that this combination therapy does not lead to an increase in adverse reactions and is considered to be safe for patients.
PubMed: 37692965
DOI: No ID Found -
Biology of Reproduction Nov 2023Kisspeptin (KP, encoded by Kiss1, binding to the Gpr54 receptor) is a neuropeptide conveying information on the metabolic status to the hypothalamic-pituitary-gonadal...
Maternal cafeteria diet influences kisspeptin (Kiss1), kisspeptin receptor(Gpr54), and sirtuin (Sirt1) genes, hormonal and metabolic profiles, and reproductive functions in rat offspring in a sex-specific manner†.
Kisspeptin (KP, encoded by Kiss1, binding to the Gpr54 receptor) is a neuropeptide conveying information on the metabolic status to the hypothalamic-pituitary-gonadal axis. KP acts together with dynorphin A (encoded by Pdyn) and neurokinin B (encoded by Tac2) to regulate reproduction. KP is crucial for the onset of puberty and is under the control of sirtuin (encoded by Sirt1). We hypothesize that the maternal cafeteria (CAF) diet has adverse effects on the offspring's hormonal, metabolic, and reproductive functions due to sex-specific alterations in the expression of Kiss1, Gpr54, Pdyn, Tac2, and Sirt1 in the hypothalamus, and Kiss1, Gpr54, and Sirt1 in the liver. Rats were fed a CAF diet before pregnancy, during pregnancy, and during lactation. The vaginal opening was monitored. Offspring were sacrificed in three age points: PND 30, PND 35, and PND 60 (females) and PND 40, PND 45, and PND 60 (males). Their metabolic and hormonal status was assessed. mRNA for Kiss1, Gpr54, Pdyn, Tac2, and Sirt1 were measured by real-time PCR in the hypothalamus and/or livers. We found that CAF offspring had lower weight and altered body composition; increased cholesterol and triglyceride levels, sex-specific changes in glucose and insulin levels; sex-dependent changes in Sirt1/Kiss1 mRNA ratio in the hypothalamus; sex-specific alterations in Kiss1 and Sirt1 mRNA in the liver with more diversity in males; and a delayed puberty onset in females. We concluded that the mother's CAF diet leads to sex-specific alterations in metabolic and reproductive outcomes via Kiss1/Gpr54 and Sirt1 systems in offspring.
Topics: Pregnancy; Female; Male; Rats; Animals; Kisspeptins; Sirtuin 1; Sexual Maturation; Receptors, Kisspeptin-1; Diet; Metabolome; RNA, Messenger
PubMed: 37665248
DOI: 10.1093/biolre/ioad101 -
Molecular Psychiatry Nov 2023The medial prefrontal cortex (mPFC) controls behavior via connections with limbic excitatory afferents that engage various inhibitory motifs to shape mPFC circuit...
The medial prefrontal cortex (mPFC) controls behavior via connections with limbic excitatory afferents that engage various inhibitory motifs to shape mPFC circuit function. The dynorphin (Dyn) / kappa-opioid receptor (KOR) system is highly enriched in the mPFC, and its dysregulation is implicated in neuropsychiatric disorders. However, it is unclear how the Dyn / KOR system modulates excitatory and inhibitory circuits that are integral for mPFC information processing and behavioral control. Here, we provide a circuit-based framework wherein mPFC Dyn / KOR signaling regulates excitation-inhibition balance by toggling which afferents drive mPFC neurons. Dyn / KOR regulation of afferent inputs is pathway-specific. Dyn acting on presynaptic KORs inhibits glutamate release from afferent inputs to the mPFC, including the basolateral amygdala (BLA), paraventricular nucleus of the thalamus, and contralateral cortex. The majority of excitatory synapses to mPFC neurons, including those from the ventral hippocampus (VH), do not express presynaptic KOR, rendering them insensitive to Dyn / KOR modulation. Dyn / KOR signaling also suppresses afferent-driven recruitment of specific inhibitory sub-networks, providing a basis for Dyn to disinhibit mPFC circuits. Specifically, Dyn / KOR signaling preferentially suppresses SST interneuron- relative to PV interneuron-mediated inhibition. Selective KOR action on afferents or within mPFC microcircuits gates how distinct limbic inputs drive spiking in mPFC neurons. Presynaptic Dyn / KOR signaling decreases KOR-positive input-driven (e.g. BLA) spiking of mPFC neurons. In contrast, KOR-negative input recruitment of mPFC neurons is enhanced by Dyn / KOR signaling via suppression of mPFC inhibitory microcircuits. Thus, by acting on distinct circuit elements, Dyn / KOR signaling shifts KOR-positive and negative afferent control of mPFC circuits, providing mechanistic insights into the role of neuropeptides in shaping mPFC function. Together, these findings highlight the utility of targeting the mPFC Dyn / KOR system as a means to treat neuropsychiatric disorders characterized by dysregulation in mPFC integration of long-range afferents with local inhibitory microcircuits.
Topics: Dynorphins; Receptors, Opioid, kappa; Prefrontal Cortex; Neurons; Basolateral Nuclear Complex
PubMed: 37644172
DOI: 10.1038/s41380-023-02226-5