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Journal of Functional Morphology and... Dec 2022Physical activity (PA) is a non-invasive, cost-effective means of reducing chronic disease. Most US citizens fail to meet PA guidelines, and individuals experiencing...
Physical activity (PA) is a non-invasive, cost-effective means of reducing chronic disease. Most US citizens fail to meet PA guidelines, and individuals experiencing chronic stress are less likely to be physically active. To better understand the barriers to maintaining active lifestyles, we sought to determine the extent to which short- versus long-term PA increases stress- and aversion-related markers in wild-type (WT) and low voluntary running (LVR) rats, a unique genetic model of low physical activity motivation. Here, we tested the effects of 1 and 4 weeks of voluntary wheel-running on physiological, behavioral, and molecular measures of stress and Hypothalamic Pituitary Adrenal (HPA)-axis responsiveness (corticosterone levels, adrenal wet weights, and fecal boli counts). We further determined measures of aversion-related signaling (kappa opioid receptor, dynorphin, and corticotropin releasing hormone mRNA expression) in the basolateral amygdala (BLA), a brain region well characterized for its role in anxiety and aversion. Compared to sedentary values, 1, but not 4 weeks of voluntary wheel-running increased adrenal wet weights and plasma corticosterone levels, suggesting that HPA responsiveness normalizes following long-term PA. BLA mRNA expression of prodynorphin () was significantly elevated in WT and LVR rats following 1 week of wheel-running compared to sedentary levels, suggesting that aversion-related signaling is elevated following short- but not long-term wheel-running. In all, it appears that the stress effects of acute PA may increase molecular markers associated with aversion in the BLA, and that LVR rats may be more sensitive to these effects, providing a potential neural mechanism for their low PA motivation.
PubMed: 36648898
DOI: 10.3390/jfmk8010006 -
Cell Reports Jan 2023The mechanism by which arcuate nucleus kisspeptin (ARN) neurons co-expressing glutamate, neurokinin B, and dynorphin intermittently synchronize their activity to...
The mechanism by which arcuate nucleus kisspeptin (ARN) neurons co-expressing glutamate, neurokinin B, and dynorphin intermittently synchronize their activity to generate pulsatile hormone secretion remains unknown. An acute brain slice preparation maintaining synchronized ARN neuron burst firing was used alongside in vivo GCaMP GRIN lens microendoscope and fiber photometry imaging coupled with intra-ARN microinfusion. Studies in intact and gonadectomized male mice revealed that ARN neuron synchronizations result from near-random emergent network activity within the population and that this was critically dependent on local glutamate-AMPA signaling. Whereas neurokinin B operated to potentiate glutamate-generated synchronizations, dynorphin-kappa opioid tone within the network served as a gate for synchronization initiation. These observations force a departure from the existing "KNDy hypothesis" for ARN neuron synchronization. A "glutamate two-transition" mechanism is proposed to underlie synchronizations in this key hypothalamic central pattern generator driving mammalian fertility.
Topics: Mice; Male; Animals; Neurokinin B; Dynorphins; Kisspeptins; Arcuate Nucleus of Hypothalamus; Neurons; Glutamates; Hormones; Mammals
PubMed: 36640343
DOI: 10.1016/j.celrep.2022.111914 -
Endocrinology Jan 2023
Topics: Mice; Animals; Dynorphins; Gonadotropin-Releasing Hormone; Kisspeptins; Rodentia; Sexual Maturation; Neurokinin B; Fertility
PubMed: 36639244
DOI: 10.1210/endocr/bqad005 -
Cell Jan 2023Opioids are effective analgesics, but their use is beset by serious side effects, including addiction and respiratory depression, which contribute to the ongoing opioid...
Opioids are effective analgesics, but their use is beset by serious side effects, including addiction and respiratory depression, which contribute to the ongoing opioid crisis. The human opioid system contains four opioid receptors (μOR, δOR, κOR, and NOPR) and a set of related endogenous opioid peptides (EOPs), which show distinct selectivity toward their respective opioid receptors (ORs). Despite being key to the development of safer analgesics, the mechanisms of molecular recognition and selectivity of EOPs to ORs remain unclear. Here, we systematically characterize the binding of EOPs to ORs and present five structures of EOP-OR-G complexes, including β-endorphin- and endomorphin-bound μOR, deltorphin-bound δOR, dynorphin-bound κOR, and nociceptin-bound NOPR. These structures, supported by biochemical results, uncover the specific recognition and selectivity of opioid peptides and the conserved mechanism of opioid receptor activation. These results provide a structural framework to facilitate rational design of safer opioid drugs for pain relief.
Topics: Humans; Analgesics, Opioid; Opioid Peptides; Receptors, Opioid, mu; Receptors, Opioid
PubMed: 36638794
DOI: 10.1016/j.cell.2022.12.026 -
Current Opinion in Endocrine and... Dec 2022The pulsatile release of gonadotropin-releasing hormone (GnRH) and its frequency are crucial for healthy reproductive function. To understand what drives GnRH pulses, a... (Review)
Review
The pulsatile release of gonadotropin-releasing hormone (GnRH) and its frequency are crucial for healthy reproductive function. To understand what drives GnRH pulses, a combination of experimental and mathematical modelling approaches has been used. Early work focussed on the possibility that GnRH pulse generation is an intrinsic feature of GnRH neurons, with autocrine feedback generating pulsatility. However, there is now ample evidence suggesting that a network of upstream neurons secreting kisspeptin, neurokinin-B and dynorphin are the source of this GnRH pulse generator. The interplay of slow positive and negative feedback via neurokinin-B and dynorphin, respectively, allows the network to act as a relaxation oscillator, driving pulsatile secretion of kisspeptin, and consequently, of GnRH and LH. Here, we review the mathematical modelling approaches exploring both scenarios and suggest that with pulsatile GnRH secretion driven by the KNDy pulse generator, autocrine feedback still has the potential to modulate GnRH output.
PubMed: 36632147
DOI: 10.1016/j.coemr.2022.100407 -
Frontiers in Endocrinology 2022In vertebrates, the tachykinin system includes tachykinin genes, which encode one or two peptides each, and tachykinin receptors. The complexity of this system is... (Review)
Review
In vertebrates, the tachykinin system includes tachykinin genes, which encode one or two peptides each, and tachykinin receptors. The complexity of this system is reinforced by the massive conservation of gene duplicates after the whole-genome duplication events that occurred in vertebrates and furthermore in teleosts. Added to this, the expression of the tachykinin system is more widespread than first thought, being found beyond the brain and gut. The discovery of the co-expression of neurokinin B, encoded by the tachykinin 3 gene, and kisspeptin/dynorphin in neurons involved in the generation of GnRH pulse, in mammals, put a spotlight on the tachykinin system in vertebrate reproductive physiology. As food intake and reproduction are linked processes, and considering that hypothalamic hormones classically involved in the control of reproduction are reported to regulate also appetite and energy homeostasis, it is of interest to look at the potential involvement of tachykinins in these two major physiological functions. The purpose of this review is thus to provide first a general overview of the tachykinin system in mammals and teleosts, before giving a state of the art on the different levels of action of tachykinins in the control of reproduction and food intake. This work has been conducted with a comparative point of view, highlighting the major similarities and differences of tachykinin systems and actions between mammals and teleosts.
Topics: Animals; Tachykinins; Reproduction; Neurokinin B; Mammals; Eating
PubMed: 36589829
DOI: 10.3389/fendo.2022.1056939 -
Neuron Dec 2022In this issue of Neuron, Pomrenze and colleagues report a novel mechanism behind sociability deficits in mice during protracted withdrawal from morphine. Dorsal raphe...
In this issue of Neuron, Pomrenze and colleagues report a novel mechanism behind sociability deficits in mice during protracted withdrawal from morphine. Dorsal raphe dynorphin neurons terminating in the nucleus accumbens suppress local serotonin release through kappa opioid receptors. These findings likely have important clinical implications.
Topics: Mice; Animals; Loneliness; Morphine; Dorsal Raphe Nucleus; Nucleus Accumbens; Receptors, Opioid, kappa
PubMed: 36549267
DOI: 10.1016/j.neuron.2022.12.002 -
Neurobiology of Stress Nov 2022Extensive preclinical and emerging clinical evidence point to an involvement of the kappa opioid receptor (KOR) in brain networks that promotes neurobehavioral...
Extensive preclinical and emerging clinical evidence point to an involvement of the kappa opioid receptor (KOR) in brain networks that promotes neurobehavioral stability. KOR expression in mesolimbic and mesocortical pathways has been the basis for characterizing the role of this receptor system in regulating motivation and emotion; however, the involvement of the KOR system in higher-order executive processes such as working memory (WM) is not well-understood. WM is readily impaired with uncontrollable stress exposure and is dysregulated in many neurobehavioral disorders. To empirically evaluate the role of the KOR system on WM performance, we administered a selective KOR antagonist, NMRA-140 (0, 0.1, 0.3, 1.0 mg/kg, intramuscular) to monkeys under both stress and non-stress conditions. In this study, NMRA-140 was co-administered with FG7142, a benzodiazepine inverse agonist, known to produce a mild stress response and to impair WM function in monkeys. NMRA-140 protected WM performance from the detrimental effects of FG7142-induced stress and exhibited no significant effect under non-stress conditions. Collectively, these data highlight the functional influence of the KOR system in mediating stress-induced dysfunction of executive processes and suggest that modulating KOR activity could offer therapeutic benefit in stress-related neurobehavioral disorders.
PubMed: 36532373
DOI: 10.1016/j.ynstr.2022.100493 -
The Journal of Physiology May 2023Ion channels of the degenerin (DEG)/epithelial Na channel (ENaC) family serve diverse functions ranging from mechanosensation over Na reabsorption to H sensing and... (Review)
Review
Ion channels of the degenerin (DEG)/epithelial Na channel (ENaC) family serve diverse functions ranging from mechanosensation over Na reabsorption to H sensing and neurotransmission. However, several diverse DEG/ENaCs interact with neuropeptides; some are directly activated, whereas others are modulated by neuropeptides. Two questions arise: does this interaction have a common structural basis and does it have an ancient origin? Current evidence suggests that RFamide neuropeptides activate the FMRFamide-activated Na channels (FaNaCs) of invertebrates via binding to a pocket at the external face of their large extracellular domain. It is likely that RFamides might activate DEG/ENaCs from the freshwater polyp Hydra (the HyNaCs) via binding to a similar pocket, although there is not yet any experimental evidence. In contrast, RFamide neuropeptides modulate acid-sensing ion channels (ASICs) from vertebrates via binding to a central cavity enclosed by β-sheets of the extracellular domain. Dynorphin opioid peptides, for their part, bind to the acidic pocket of ASICs, which might be evolutionarily related to the peptide binding pocket of FaNaCs, but instead of opening the channels they work as antagonists to stabilize its closed state. Moreover, peptides interacting with DEG/ENaCs from animals of different phyla, although having similar sequences, are evolutionarily unrelated to each other. Collectively, it appears that despite a seemingly similar interaction with similar peptides, the interaction of DEG/ENaCs with neuropeptides has diverse structural bases and many origins.
Topics: Animals; Degenerin Sodium Channels; Cnidaria; Neuropeptides; Peptides; Acid Sensing Ion Channels; Ions; Mammals; Epithelial Sodium Channels
PubMed: 36479972
DOI: 10.1113/JP282309 -
Frontiers in Endocrinology 2022Feedback from oestradiol (E2) plays a critical role in the regulation of major events in the physiological menstrual cycle including the release of gonadotrophins to... (Review)
Review
Feedback from oestradiol (E2) plays a critical role in the regulation of major events in the physiological menstrual cycle including the release of gonadotrophins to stimulate follicular growth, and the mid-cycle luteinising hormone (LH) surge that leads to ovulation. E2 predominantly exerts its action oestrogen receptor-alpha (ERα), however, as gonadotrophin releasing hormone (GnRH) neurons lack ERα, E2-feedback is posited to be indirectly mediated upstream neurons. Kisspeptin (KP) is a neuropeptide expressed in hypothalamic KP-neurons that control GnRH secretion and plays a key role in the central mechanism regulating the hypothalamic-pituitary-gonadal (HPG) axis. In the rodent arcuate (ARC) nucleus, KP is co-expressed with Neurokinin B and Dynorphin; and thus, these neurons are termed 'Kisspeptin-Neurokinin B-Dynorphin' (KNDy) neurons. ARC KP-neurons function as the 'GnRH pulse generator' to regulate GnRH pulsatility, as well as mediating negative feedback from E2. A second KP neuronal population is present in the rostral periventricular area of the third ventricle (RP3V), which includes anteroventral periventricular (AVPV) nucleus and preoptic area neurons. These RP3V KP-neurons mediate positive feedback to induce the mid-cycle luteinising hormone (LH) surge and subsequent ovulation. Here, we describe the role of KP-neurons in these two regions in mediating this differential feedback from oestrogens. We conclude by considering reproductive diseases for which exploitation of these mechanisms could yield future therapies.
Topics: Kisspeptins; Neurokinin B; Dynorphins; Luteinizing Hormone; Gonadotropin-Releasing Hormone; Neurons
PubMed: 36479214
DOI: 10.3389/fendo.2022.951938