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Power EM, Ganeshan D, Paul J, Igarashi H, Inoue W, Iremonger KJ. Direct Modulation of CRH Nerve Terminal Function by Noradrenaline and Corticosterone. J Neurosci 2025; 45:e1092242024. [PMID: 39638558 PMCID: PMC11735660 DOI: 10.1523/jneurosci.1092-24.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 10/13/2024] [Accepted: 11/25/2024] [Indexed: 12/07/2024] Open
Abstract
Nerve terminals are the final point of regulation before neurosecretion. As such, neuromodulators acting on nerve terminals can exert significant influence on neural signaling. Hypothalamic corticotropin-releasing hormone (CRH) neurons send axonal projections to the median eminence where CRH is secreted to stimulate the hypothalamic-pituitary-adrenal (HPA) axis. Noradrenaline and corticosterone are two of the most important neuromodulators of HPA axis function; noradrenaline excites CRH neurons and corticosterone inhibits CRH neurons by negative feedback. Here, we used GCaMP6f Ca2+ imaging and measurement of nerve terminal CRH secretion using sniffer cells to determine whether these neuromodulators act directly on CRH nerve terminals in male mice. Contrary to expectations, noradrenaline inhibited action potential-dependent Ca2+ elevations in CRH nerve terminals and suppressed evoked CRH secretion. This inhibitory effect was blocked by α2-adrenoreceptor antagonism. Corticosterone also suppressed evoked CRH peptide secretion from nerve terminals, independent of action potential-dependent Ca2+ levels. This inhibition was prevented by the glucocorticoid receptor antagonist, RU486, and indicates that CRH nerve terminals may be a site of fast glucocorticoid negative feedback. Together these findings establish median eminence nerve terminals as a key site for regulation of the HPA axis.
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Affiliation(s)
- Emmet M Power
- Centre for Neuroendocrinology and Department of Physiology, School of Biomedical Sciences, University of Otago, Dunedin 9016, New Zealand
| | - Dharshini Ganeshan
- Centre for Neuroendocrinology and Department of Physiology, School of Biomedical Sciences, University of Otago, Dunedin 9016, New Zealand
| | - Jamieson Paul
- Centre for Neuroendocrinology and Department of Physiology, School of Biomedical Sciences, University of Otago, Dunedin 9016, New Zealand
| | - Hiroyuki Igarashi
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario N6A 5B7, Canada
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan
| | - Wataru Inoue
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario N6A 5B7, Canada
| | - Karl J Iremonger
- Centre for Neuroendocrinology and Department of Physiology, School of Biomedical Sciences, University of Otago, Dunedin 9016, New Zealand
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Krolick KN, Cao J, Gulla EM, Bhardwaj M, Marshall SJ, Zhou EY, Kiss AJ, Choueiry F, Zhu J, Shi H. Subregion-specific transcriptomic profiling of rat brain reveals sex-distinct gene expression impacted by adolescent stress. Neuroscience 2024; 553:19-39. [PMID: 38977070 PMCID: PMC11444371 DOI: 10.1016/j.neuroscience.2024.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 05/14/2024] [Accepted: 07/02/2024] [Indexed: 07/10/2024]
Abstract
Stress during adolescence clearly impacts brain development and function. Sex differences in adolescent stress-induced or exacerbated emotional and metabolic vulnerabilities could be due to sex-distinct gene expression in hypothalamic, limbic, and prefrontal brain regions. However, adolescent stress-induced whole-genome expression changes in key subregions of these brain regions were unclear. In this study, female and male adolescent Sprague Dawley rats received one-hour restraint stress daily from postnatal day (PD) 32 to PD44. Corticosterone levels, body weights, food intake, body composition, and circulating adiposity and sex hormones were measured. On PD44, brain and blood samples were collected. Using RNA-sequencing, sex-specific differences in stress-induced differentially expressed (DE) genes were identified in subregions of the hypothalamus, limbic system, and prefrontal cortex. Canonical pathways reflected well-known sex-distinct maladies and diseases, substantiating the therapeutic potential of the DE genes found in the current study. Thus, we proposed specific sex distinct, adolescent stress-induced transcriptional changes found in the current study as examples of the molecular bases for sex differences witnessed in stress induced or exacerbated emotional and metabolic disorders. Future behavioral studies and single-cell studies are warranted to test the implications of the DE genes identified in this study in sex-distinct stress-induced susceptibilities.
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Affiliation(s)
| | - Jingyi Cao
- Department of Biology, Miami University, Oxford, OH 45056, USA.
| | - Evelyn M Gulla
- Department of Biology, Miami University, Oxford, OH 45056, USA.
| | - Meeta Bhardwaj
- Department of Biology, Miami University, Oxford, OH 45056, USA.
| | | | - Ethan Y Zhou
- Department of Biology, Miami University, Oxford, OH 45056, USA.
| | - Andor J Kiss
- Center for Bioinformatics & Functional Genomics, Miami University, Oxford, OH 45056, USA.
| | - Fouad Choueiry
- Department of Human Sciences, The Ohio State University, Columbus, OH 43210, USA.
| | - Jiangjiang Zhu
- Department of Human Sciences, The Ohio State University, Columbus, OH 43210, USA; James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
| | - Haifei Shi
- Department of Biology, Miami University, Oxford, OH 45056, USA.
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Zheng JY, Zhu J, Wang Y, Tian ZZ. Effects of acupuncture on hypothalamic-pituitary-adrenal axis: Current status and future perspectives. JOURNAL OF INTEGRATIVE MEDICINE 2024; 22:445-458. [PMID: 38955651 DOI: 10.1016/j.joim.2024.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 05/08/2024] [Indexed: 07/04/2024]
Abstract
The hypothalamic-pituitary-adrenal (HPA) axis is a critical component of the neuroendocrine system, playing a central role in regulating the body's stress response and modulating various physiological processes. Dysregulation of HPA axis function disrupts the neuroendocrine equilibrium, resulting in impaired physiological functions. Acupuncture is recognized as a non-pharmacological type of therapy which has been confirmed to play an important role in modulating the HPA axis and thus favorably targets diseases with abnormal activation of the HPA axis. With numerous studies reporting the promising efficacy of acupuncture for neuroendocrine disorders, a comprehensive review in terms of the underlying molecular mechanism for acupuncture, especially in regulating the HPA axis, is currently in need. This review fills the need and summarizes recent breakthroughs, from the basic principles and the pathological changes of HPA axis dysfunction, to the molecular mechanisms by which acupuncture regulates the HPA axis. These mechanisms include the modulation of multiple neurotransmitters and their receptors, neuropeptides and their receptors, and microRNAs in the paraventricular nucleus, hippocampus, amygdala and pituitary gland, which alleviate the hyperfunctioning of the HPA axis. This review comprehensively summarizes the mechanism of acupuncture in regulating HPA axis dysfunction for the first time, providing new targets and prospects for further exploration of acupuncture. Please cite this article as: Zheng JY, Zhu J, Wang Y, Tian ZZ. Effects of acupuncture on hypothalamic-pituitary-adrenal axis: Current status and future perspectives. J Integr Med. 2024; 22(4): 446-459.
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Affiliation(s)
- Jia-Yuan Zheng
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, Institutes of Brain Science, Institute of Acupuncture Research, Academy of Integrative Medicine, Shanghai Key Laboratory for Acupuncture Mechanism and Acupoint Function, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Jing Zhu
- Department of Human Anatomy, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yu Wang
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, Institutes of Brain Science, Institute of Acupuncture Research, Academy of Integrative Medicine, Shanghai Key Laboratory for Acupuncture Mechanism and Acupoint Function, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Zhan-Zhuang Tian
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, Institutes of Brain Science, Institute of Acupuncture Research, Academy of Integrative Medicine, Shanghai Key Laboratory for Acupuncture Mechanism and Acupoint Function, Shanghai Medical College, Fudan University, Shanghai 200032, China.
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Watanabe M, Sinha AS, Shinmyo Y, Fukuda A. Early establishment of chloride homeostasis in CRH neurons is altered by prenatal stress leading to fetal HPA axis dysregulation. Front Mol Neurosci 2024; 17:1373337. [PMID: 38577026 PMCID: PMC10994000 DOI: 10.3389/fnmol.2024.1373337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 03/05/2024] [Indexed: 04/06/2024] Open
Abstract
Corticotropin-releasing hormone (CRH) neurons play an important role in the regulation of neuroendocrine responses to stress. The excitability of CRH neurons is regulated by inhibitory GABAergic inputs. However, it is unclear when GABAergic regulation of CRH neurons is established during fetal brain development. Furthermore, the exact progression of the developmental shift of GABA action from depolarization to hyperpolarization remains unelucidated. Considering the importance of CRH neuron function in subsequent hypothalamic-pituitary-adrenal (HPA) axis regulation during this critical phase of development, we investigated the ontogeny of GABAergic inputs to CRH neurons and consequent development of chloride homeostasis. Both CRH neuron soma in the paraventricular nucleus (PVN) and axons projecting to the median eminence could be identified at embryonic day 15 (E15). Using acute slices containing the PVN of CRF-VenusΔNeo mice, gramicidin perforated-patch clamp-recordings of CRH neurons at E15, postnatal day 0 (P0), and P7 were performed to evaluate the developmental shift of GABA action. The equilibrium potential of GABA (EGABA) was similar between E15 and P0 and showed a further hyperpolarizing shift between P0 and P7 that was comparable to EGABA values in adult CRH neurons. GABA primarily acted as an inhibitory signal at E15 and KCC2 expression was detected in CRH neurons at this age. Activation of the HPA axis has been proposed as the primary mechanism through which prenatal maternal stress shapes fetal development and subsequent long-term disease risk. We therefore examined the impact of maternal food restriction stress on the development of chloride homeostasis in CRH neurons. We observed a depolarization shift of EGABA in CRH neurons of pups exposed to maternal food restriction stress. These results suggest that Cl- homeostasis in early developmental CRH neurons attains mature intracellular Cl- levels, GABA acts primarily as inhibitory, and CRH neurons mature and function early compared with neurons in other brain regions, such as the cortex and hippocampus. Maternal food restriction stress alters chloride homeostasis in CRH neurons of pups, reducing their inhibitory control by GABA. This may contribute to increased CRH neuron activity and cause activation of the HPA axis in pups.
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Affiliation(s)
| | | | - Yohei Shinmyo
- Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Atsuo Fukuda
- Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Japan
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Li L, Su Y, Wang S, Wang C, Ruan N, Hu Z, Cheng X, Chen J, Yuan K, Li P, Fan P. Neonatal di-(2-ethylhexyl)phthalate exposure induces permanent alterations in secretory CRH neuron characteristics in the hypothalamus paraventricular region of adult male rats. Exp Neurol 2024; 372:114616. [PMID: 38007208 DOI: 10.1016/j.expneurol.2023.114616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 10/31/2023] [Accepted: 11/19/2023] [Indexed: 11/27/2023]
Abstract
Corticotrophin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) play a critical role in the modulation of the hypothalamic-pituitary-adrenal (HPA) axis. Early-life exposure to di-(2-ethylhexyl) phthalate (DEHP) has been associated with an increased risk of developing psychiatric disorders in adulthood. The present work was designed to explore the impact of neonatal exposure to DEHP on adult PVN CRH neuronal activity. DEHP or vehicle was given to male rat pups from PND16 to PND22. Then, anxiety-like behaviors, serum corticosterone and testosterone, immunohistochemistry, western blotting, fluorescence in situ hybridization and acute ex vivo slice electrophysiological recordings were used to evaluate the influence of DEHP on adult PVN secretory CRH neurons. Neonatal DEHP-exposed rats exhibited enhanced anxiety-like behaviors in adults, with an increase in CORT. Secretory CRH neurons showed higher spontaneous firing activity but could be inhibited by GABAAR blockers. CRH neurons displayed fewer firing spikes, prolonged first-spike latency, depolarizing shifts in GABA reversal potential and strengthened GABAergic inputs, as indicated by increases in the frequency and amplitude of sIPSCs. Enhancement of GABAergic transmission was accompanied by upregulated expression of GAD67 and downregulated expression of GABABR1, KCC2 and GAT1. These findings suggest that neonatal exposure to DEHP permanently altered the characteristics of secretory CRH neurons in the PVN, which may contribute to the development of psychiatric disorders later in life.
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Affiliation(s)
- Li Li
- Key Laboratory of Anesthesiology of Zhejiang Province, Department of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Ying Su
- Key Laboratory of Anesthesiology of Zhejiang Province, Department of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Siyuan Wang
- Key Laboratory of Anesthesiology of Zhejiang Province, Department of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Brain Injury Center, Department of Neurosurgery, RenJi Hospital, Shanghai JiaoTong University, School of Medicine, Shanghai 200127, China
| | - Chengyu Wang
- Key Laboratory of Anesthesiology of Zhejiang Province, Department of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Naqi Ruan
- Key Laboratory of Anesthesiology of Zhejiang Province, Department of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Zhiyan Hu
- Key Laboratory of Anesthesiology of Zhejiang Province, Department of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Xin Cheng
- Key Laboratory of Anesthesiology of Zhejiang Province, Department of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Jiajia Chen
- Key Laboratory of Anesthesiology of Zhejiang Province, Department of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Kaiming Yuan
- Key Laboratory of Anesthesiology of Zhejiang Province, Department of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
| | - Peijun Li
- Department of Neurology, Institute of Geriatric Neurology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
| | - Pei Fan
- Zhejiang Provincial Key Laboratory of Orthopedics, Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
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Yu J, Li XF, Tsaneva-Atanasova K, Zavala E, O’Byrne KT. Chemogenetic activation of PVN CRH neurons disrupts the estrous cycle and LH dynamics in female mice. Front Endocrinol (Lausanne) 2024; 14:1322662. [PMID: 38264285 PMCID: PMC10803550 DOI: 10.3389/fendo.2023.1322662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 12/20/2023] [Indexed: 01/25/2024] Open
Abstract
Introduction The impact of stress on reproductive function is significant. Hypothalamic paraventricular nucleus (PVN) corticotrophin-releasing hormone (CRH) plays a major role in regulating the stress response. Understanding how the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonadal (HPG) axis interact is crucial for comprehending how stress can lead to reproductive dysfunction. However, whether stress influences reproductive function via modulating PVN CRH or HPA sequelae is not fully elucidated. Methods In this study, we investigated the impact of chemogenetic activation of PVN CRH neurons on reproductive function. We chronically and selectively stimulated PVN CRH neurons in female CRH-Cre mice using excitatory designer receptor exclusively activated by designer drugs (DREADDs) viral constructs, which were bilaterally injected into the PVN. The agonist compound-21 (C21) was delivered through the drinking water. We determined the effects of DREADDs activation of PVN CRH neurons on the estrous cycles, LH pulse frequency in diestrus and metestrus and LH surge in proestrus mice. The effect of long-term C21 administration on basal corticosterone secretion and the response to acute restraint stress during metestrus was also examined. Additionally, computer simulations of a mathematical model were used to determine the effects of DREADDs activation of PVN CRH neurons, simulating chronic stress, on the physiological parameters examined experimentally. Results As a result, and consistent with our mathematical model predictions, the length of the estrous cycle was extended, with an increase in the time spent in estrus and metestrus, and a decrease in proestrus and diestrus. Additionally, the frequency of LH pulses during metestrus was decreased, but unaffected during diestrus. The occurrence of the preovulatory LH surge during proestrus was disrupted. The basal level of corticosterone during metestrus was not affected, but the response to acute restraint stress was diminished after long-term C21 application. Discussion These data suggest that PVN CRH neurons play a functional role in disrupting ovarian cyclicity and the preovulatory LH surge, and that the activity of the GnRH pulse generator remains relatively robust during diestrus but not during metestrus under chronic stress exposure in accordance with our mathematical model predictions.
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Affiliation(s)
- Junru Yu
- Department of Women and Children’s Health, School of Life Course and Population Sciences, Faculty of Life Science and Medicine, King’s College London, London, United Kingdom
| | - Xiao-Feng Li
- Department of Women and Children’s Health, School of Life Course and Population Sciences, Faculty of Life Science and Medicine, King’s College London, London, United Kingdom
| | - Krasimira Tsaneva-Atanasova
- Department of Mathematics and Statistics, Faculty of Environment, Science and Economy, University of Exeter, Exeter, United Kingdom
- Living Systems Institute, University of Exeter, Exeter, United Kingdom
| | - Eder Zavala
- Centre for Systems Modelling and Quantitative Biomedicine, University of Birmingham, Edgbaston, United Kingdom
| | - Kevin T. O’Byrne
- Department of Women and Children’s Health, School of Life Course and Population Sciences, Faculty of Life Science and Medicine, King’s College London, London, United Kingdom
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Pol E, Côme E, Merlaud Z, Gouhier J, Russeau M, Scotto-Lomassese S, Moutkine I, Marques X, Lévi S. NKCC1 and KCC2 Chloride Transporters Have Different Membrane Dynamics on the Surface of Hippocampal Neurons. Cells 2023; 12:2363. [PMID: 37830575 PMCID: PMC10571912 DOI: 10.3390/cells12192363] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 09/12/2023] [Accepted: 09/20/2023] [Indexed: 10/14/2023] Open
Abstract
Na-K-2Cl cotransporter 1 (NKCC1) regulates chloride influx in neurons and thereby GABAA receptor activity in normal and pathological conditions. Here, we characterized in hippocampal neurons the membrane expression, distribution and dynamics of exogenous NKCC1a and NKCC1b isoforms and compared them to those of the chloride extruder K-Cl cotransporter 2 (KCC2). We found that NKCC1a and NKCC1b behave quite similarly. NKCC1a/1b but not KCC2 are present along the axon initial segment where they are confined. Moreover, NKCC1a/1b are detected in the somato-dendritic compartment at a lower level than KCC2, where they form fewer, smaller and less compact clusters at perisynaptic and extrasynaptic sites. Interestingly, ~60% of dendritic clusters of NKCC1a/1b are colocalized with KCC2. They are larger and brighter than those devoid of KCC2, suggesting a particular NKCC1a/1b-KCC2 relationship. In agreement with the reduced dendritic clustering of NKCC1a/1b compared with that of KCC2, NKCC1a/1b are more mobile on the dendrite than KCC2, suggesting weaker cytoskeletal interaction. NKCC1a/b are confined to endocytic zones, where they spend more time than KCC2. However, they spend less time in these compartments than at the synapses, suggesting that they can rapidly leave endocytic zones to increase the membrane pool, which can happen in pathological conditions. Thus, NKCC1a/b have different membrane dynamics and clustering from KCC2, which helps to explain their low level in the neuronal membrane, while allowing a rapid increase in the membrane pool under pathological conditions.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Sabine Lévi
- Institut du Fer à Moulin, Institut National de la Santé Et de la Recherche Médicale (INSERM) UMR-S 1270, Sorbonne Université, 75005 Paris, France; (E.P.); (E.C.); (Z.M.); (J.G.); (M.R.); (S.S.-L.); (I.M.); (X.M.)
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Watanabe K, Ishibashi M, Suzuki T, Otsuka A, Yoshimura N, Miyake H, Fukuda A. Therapeutic effects of KCC2 chloride transporter activation on detrusor overactivity in mice with spinal cord injury. Am J Physiol Renal Physiol 2023; 324:F353-F361. [PMID: 36656987 DOI: 10.1152/ajprenal.00271.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
This study aimed to clarify whether downregulation of K+-Cl- cotransporter 2 (KCC2) in the sacral parasympathetic nucleus (SPN) of the lumbosacral spinal cord, from which the efferent pathway innervating the bladder originates, causes cellular hyperexcitability and triggers detrusor overactivity (DO) in spinal cord injury (SCI). SCI was produced by Th8-9 spinal cord transection in female C57BL/6 mice. At 4 wk after SCI, CLP290, a KCC2 activator, was administered, and cystometry was performed. Thereafter, neuronal activity with c-fos staining and KCC2 expression in cholinergic preganglionic parasympathetic neurons in the SPN was examined using immunohistochemistry. Firing properties of neurons in the SPN region were evaluated by extracellular recordings in the spinal cord slice preparations. DO evident as nonvoiding contractions was significantly reduced by CLP290 treatment in SCI mice. The number of c-fos-positive cells and coexpression of c-fos in choline acetyltransferase-positive cells were decreased in the SPN region of the SCI CLP290-treated group versus the SCI vehicle-treated group. KCC2 immunoreactivity was present on the cell membrane of SPN neurons and normalized fluorescence intensity of KCC2 in choline acetyltransferase-positive SPN neurons was decreased in the SCI vehicle-treated group versus the spinal intact vehicle-treated group but recovered in the SCI CLP290-treated group. Extracellular recordings showed that CLP290 suppressed the high-frequency firing activity of SPN neurons in SCI mice. These results indicated that SCI-induced DO is associated with downregulation of KCC2 in preganglionic parasympathetic neurons and that activation of KCC2 transporters can reduce DO, increase KCC2 expression in preganglionic parasympathetic neurons, and decrease neuronal firing of SPN neurons in SCI mice.NEW & NOTEWORTHY This study is the first report to suggest that activation of the Cl- transporter K+-Cl- cotransporter 2 may be a therapeutic modality for the treatment of spinal cord injury-induced detrusor overactivity by targeting bladder efferent pathways.
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Affiliation(s)
- Kyohei Watanabe
- Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Japan
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Masaru Ishibashi
- Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takahisa Suzuki
- Department of Urology, Kanagawa Rehabilitation Hospital, Atsugi, Japan
- Department of Urology, Yokohama City University, Yokohama, Japan
| | - Atsushi Otsuka
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Naoki Yoshimura
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
| | - Hideaki Miyake
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Atsuo Fukuda
- Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Japan
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Corticotropin-Releasing Hormone: Biology and Therapeutic Opportunities. BIOLOGY 2022; 11:biology11121785. [PMID: 36552294 PMCID: PMC9775501 DOI: 10.3390/biology11121785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/16/2022] [Accepted: 12/06/2022] [Indexed: 12/13/2022]
Abstract
In 1981, Wylie Vale, Joachim Spiess, Catherine Rivier, and Jean Rivier reported on the characterization of a 41-amino-acid peptide from ovine hypothalamic extracts with high potency and intrinsic activity stimulating the secretion of adrenocorticotropic hormone and β-endorphin by cultured anterior pituitary cells. With its sequence known, this neuropeptide was determined to be a hormone and consequently named corticotropin-releasing hormone (CRH), although the term corticotropin-releasing factor (CRF) is still used and preferred in some circumstances. Several decades have passed since this seminal contribution that opened a new research era, expanding the understanding of the coding of stress-related processes. The characterization of CRH receptors, the availability of CRH agonists and antagonists, and advanced immunocytochemical staining techniques have provided evidence that CRH plays a role in the regulation of several biological systems. The purpose of this review is to summarize the present knowledge of this 41-amino-acid peptide.
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Liu X, Porteous R, Herbison AE. Robust GABAergic Regulation of the GnRH Neuron Distal Dendron. Endocrinology 2022; 164:6862923. [PMID: 36458869 PMCID: PMC9749702 DOI: 10.1210/endocr/bqac194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 11/16/2022] [Accepted: 11/18/2022] [Indexed: 12/04/2022]
Abstract
The amino acid transmitter γ-aminobutyric acid (GABA) is suspected to play an important role in regulating the activity of the gonadotropin-releasing hormone (GnRH) neurons controlling fertility. Rodent GnRH neurons have a novel dendritic compartment termed the "distal dendron" through which action potentials pass to the axon terminals and where inputs from the kisspeptin pulse generator drive pulsatile GnRH secretion. Combining Gnrh1-Cre mice with the Cre-dependent calcium sensor GCaMP6 and confocal imaging of acute brain slices, we examined whether GABA regulated intracellular calcium concentrations ([Ca2+]) in the GnRH neuron distal dendron. Short puffs of GABA on the dendron evoked either a monophasic sustained suppression of [Ca2+] or a biphasic acute elevation in [Ca2+] followed by the sustained suppression. Application of muscimol to the dendron replicated the acute elevation in [Ca2+] while baclofen generated the sustained suppression. Robust GABAB receptor-mediated inhibition was observed in 80% to 100% of dendrons recorded from females across the estrous cycle and from approximately 70% of dendrons in males. In contrast, the GABAA receptor-mediated excitation was rare in males and varied across the estrous cycle, being most prominent at proestrus. The activation of GABAB receptors potently suppressed the stimulatory effect of kisspeptin on the dendron. These observations demonstrate that the great majority of GnRH neuron distal dendrons are regulated by GABAergic inputs in a sex- and estrous cycle-dependent manner, with robust GABAB receptor-mediated inhibition being the primary mode of signaling. This provides a new, kisspeptin-independent, pathway for the regulation of pulsatile and surge modes of GnRH secretion in the rodent.
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Affiliation(s)
- Xinhuai Liu
- Centre for Neuroendocrinology and Department of Physiology, University of Otago School of Biomedical Sciences, Dunedin 9054, New Zealand
| | - Robert Porteous
- Centre for Neuroendocrinology and Department of Physiology, University of Otago School of Biomedical Sciences, Dunedin 9054, New Zealand
| | - Allan E Herbison
- Correspondence: Allan E. Herbison, PhD, Department of Physiology, Development and Neuroscience, Downing Site, University of Cambridge, Cambridge CB2 3EG, UK.
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Yesmin R, Watanabe M, Sinha AS, Ishibashi M, Wang T, Fukuda A. A subpopulation of agouti-related peptide neurons exciting corticotropin-releasing hormone axon terminals in median eminence led to hypothalamic-pituitary-adrenal axis activation in response to food restriction. Front Mol Neurosci 2022; 15:990803. [PMID: 36245920 PMCID: PMC9557964 DOI: 10.3389/fnmol.2022.990803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Accepted: 09/13/2022] [Indexed: 11/17/2022] Open
Abstract
The excitatory action of gamma-aminobutyric-acid (GABA) in the median-eminence (ME) led to the steady-state release of corticotropin-releasing hormone (CRH) from CRH axon terminals, which modulates the hypothalamic-pituitary-adrenal (HPA) axis. However, in ME, the source of excitatory GABAergic input is unknown. We examined agouti-related peptide (AgRP) expressing neurons in the arcuate nucleus as a possible source for excitatory GABAergic input. Here, we show that a subpopulation of activated AgRP neurons directly project to the CRH axon terminals in ME elevates serum corticosterone levels in 60% food-restricted mice. This increase in serum corticosterone is not dependent on activation of CRH neuronal soma in the paraventricular nucleus. Furthermore, conditional deletion of Na+-K+-2Cl– cotransporter-1 (NKCC1), which promotes depolarizing GABA action, from the CRH axon terminals results in significantly lower corticosterone levels in response to food restriction. These findings highlight the important role of a subset of AgRP neurons in HPA axis modulation via NKCC1-dependent GABAergic excitation in ME.
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Affiliation(s)
- Ruksana Yesmin
- Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Miho Watanabe
- Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Adya Saran Sinha
- Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Masaru Ishibashi
- Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Tianying Wang
- Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Atsuo Fukuda
- Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
- Advanced Research Facilities and Services, Preeminent Medical Photonics Education and Research Center, Hamamatsu University School of Medicine, Hamamatsu, Japan
- *Correspondence: Atsuo Fukuda,
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12
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Kawabe M, Nishida T, Horita C, Ikeda A, Takahashi R, Inui A, Shiozaki K. Ninjinyoeito improves social behavior disorder in neuropeptide Y deficient zebrafish. Front Pharmacol 2022; 13:905711. [PMID: 36034826 PMCID: PMC9411948 DOI: 10.3389/fphar.2022.905711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 07/07/2022] [Indexed: 11/13/2022] Open
Abstract
Sociability is an essential component of the linkage structure in human and other vertebrate communication. Low sociability is defined as a poor social approach, including social withdrawal and apathy, and is implicated in a variety of psychiatric disorders. Ninjinyoeito (NYT), a traditional Japanese herbal medicine, has been used in the medical field. This study aimed to determine the effect of NYT on low sociality in NPY-KO zebrafish. NPY-KO zebrafish were fed a 3% NYT-supplemented diet for 4 days and subjected to behavioral tests. In the mirror test, NPY-KO zebrafish fed a control diet showed avoidance behavior toward their mirror counterparts. In contrast, the treatment of NPY-KO zebrafish with NYT significantly increased their interaction with their counterparts in the mirror. In addition, a 3-chambers test was conducted to confirm the effect of NYT on the low sociality of NPY-KO zebrafish. NPY-KO zebrafish fed the control diet showed less interaction with fish chambers, while NYT treatment increased the interaction. Phosphorylation of ERK, a marker of neuronal activity, was significantly reduced in the whole brain of NYT-fed NPY-KO zebrafish, compared to the control diet. NYT treatment significantly suppressed hypothalamic-pituitary-adrenal-related genes (gr, pomc, and crh) and sympathetic-adrenal-medullary-related genes (th1, th2, and cck) in NPY-KO zebrafish. NYT administration significantly reduced mRNA levels of gad1b compared to the control diet, suggesting the involvement of GABAergic neurons in NYT-induced improvement of low sociability. Furthermore, the expression of CREB was suppressed when NPY-KO zebrafish were fed NYT. Next, we attempted to identify the effective herb responsible for the NYT-induced improvement of low sociability. NPY-KO zebrafish were fed an experimental diet containing the target herb for 4 days, and its effect on sociability was evaluated using the 3-chambers test. Results showed that Cinnamon Bark and Polygala Root treatments significantly increased time spent in the fish tank area compared to the control diet, while the other 10 herbs did not. We confirmed that these two herbs suppressed the activity of HPA-, SAM-, and GABAergic neurons, as well as NYT-treated zebrafish, accompanied by downregulation of CREB signaling. This study suggests the potential use of NYT as a drug for sociability disorders.
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Affiliation(s)
- Momoko Kawabe
- Course of Biological Science and Technology, The United Graduate School of Agricultural Sciences, Kagoshima University, Kagoshima, Japan
| | - Takumi Nishida
- Department of Food Life Sciences, Faculty of Fisheries, Kagoshima University, Kagoshima, Japan
| | - Chihoko Horita
- Department of Food Life Sciences, Faculty of Fisheries, Kagoshima University, Kagoshima, Japan
| | - Asami Ikeda
- Course of Biological Science and Technology, The United Graduate School of Agricultural Sciences, Kagoshima University, Kagoshima, Japan
| | - Ryuji Takahashi
- Kampo Research Laboratories, Kracie Pharma Ltd., Toyama, Japan
| | - Akio Inui
- Pharmacological Department of Herbal Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Kazuhiro Shiozaki
- Course of Biological Science and Technology, The United Graduate School of Agricultural Sciences, Kagoshima University, Kagoshima, Japan
- Department of Food Life Sciences, Faculty of Fisheries, Kagoshima University, Kagoshima, Japan
- *Correspondence: Kazuhiro Shiozaki,
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13
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Fernandes ACA, de Oliveira FP, Fernandez G, da Guia Vieira L, Rosa CG, do Nascimento T, de Castro França S, Donato J, Vella KR, Antunes-Rodrigues J, Mecawi AS, Perello M, Elias LLK, Rorato R. Arcuate AgRP, but not POMC neurons, modulate paraventricular CRF synthesis and release in response to fasting. Cell Biosci 2022; 12:118. [PMID: 35902915 PMCID: PMC9331576 DOI: 10.1186/s13578-022-00853-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 07/14/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The activation of the hypothalamic-pituitary-adrenal (HPA) axis is essential for metabolic adaptation in response to fasting. However, the neurocircuitry connecting changes in the peripheral energy stores to the activity of hypothalamic paraventricular corticotrophin-releasing factor (CRFPVN) neurons, the master controller of the HPA axis activity, is not completely understood. Our main goal was to determine if hypothalamic arcuate nucleus (ARC) POMC and AgRP neurons can communicate fasting-induced changes in peripheral energy stores, associated to a fall in plasma leptin levels, to CRFPVN neurons to modulate the HPA axis activity in mice. RESULTS We observed increased plasma corticosterone levels associate with increased CRFPVN mRNA expression and increased CRFPVN neuronal activity in 36 h fasted mice. These responses were associated with a fall in plasma leptin levels and changes in the mRNA expression of Agrp and Pomc in the ARC. Fasting-induced decrease in plasma leptin partially modulated these responses through a change in the activity of ARC neurons. The chemogenetic activation of POMCARC by DREADDs did not affect fasting-induced activation of the HPA axis. DREADDs inhibition of AgRPARC neurons reduced the content of CRFPVN and increased its accumulation in the median eminence but had no effect on corticosterone secretion induced by fasting. CONCLUSION Our data indicate that AgRPARC neurons are part of the neurocircuitry involved in the coupling of PVNCRF activity to changes in peripheral energy stores induced by prolonged fasting.
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Affiliation(s)
| | - Franciane Pereira de Oliveira
- Department of Biophysics, Paulista Medical School, Federal University of Sao Paulo, São Paulo, SP, CEP 04023-062, Brazil
| | - Gimena Fernandez
- Laboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology [IMBICE, Argentine Research Council (CONICET) and Scientific Research Commission, Province of Buenos Aires (CIC-PBA), National University of La Plata, La Plata, 403, Buenos Aires, Argentina
| | - Luane da Guia Vieira
- Department of Biotechnology, University of Ribeirao Preto, Ribeirão Prêto, SP, 14096-900, Brazil
| | - Cristiane Gugelmin Rosa
- Department of Biotechnology, University of Ribeirao Preto, Ribeirão Prêto, SP, 14096-900, Brazil
| | - Taís do Nascimento
- Department of Biotechnology, University of Ribeirao Preto, Ribeirão Prêto, SP, 14096-900, Brazil
| | - Suzelei de Castro França
- Department of Biotechnology, University of Ribeirao Preto, Ribeirão Prêto, SP, 14096-900, Brazil
| | - Jose Donato
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, SP, 05508-000, Brazil
| | - Kristen R Vella
- Department of Endocrinology, Diabetes and Metabolism and the Weill Center for Metabolic Health, Weill Cornell Medical College, New York, NY, 10021, USA
| | - Jose Antunes-Rodrigues
- Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirão Prêto, SP, 14049-900, Brazil
| | - André Souza Mecawi
- Department of Biophysics, Paulista Medical School, Federal University of Sao Paulo, São Paulo, SP, CEP 04023-062, Brazil
| | - Mario Perello
- Laboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology [IMBICE, Argentine Research Council (CONICET) and Scientific Research Commission, Province of Buenos Aires (CIC-PBA), National University of La Plata, La Plata, 403, Buenos Aires, Argentina
| | - Lucila Leico Kagohara Elias
- Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirão Prêto, SP, 14049-900, Brazil
| | - Rodrigo Rorato
- Department of Biotechnology, University of Ribeirao Preto, Ribeirão Prêto, SP, 14096-900, Brazil.
- Department of Biophysics, Paulista Medical School, Federal University of Sao Paulo, São Paulo, SP, CEP 04023-062, Brazil.
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14
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Zhao X, Huang X, Peng W, Han M, Zhang X, Zhu K, Shao B. Chlorine disinfection byproduct of diazepam affects nervous system function and possesses gender-related difference in zebrafish. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 238:113568. [PMID: 35490575 DOI: 10.1016/j.ecoenv.2022.113568] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 04/19/2022] [Accepted: 04/25/2022] [Indexed: 06/14/2023]
Abstract
Chlorinated disinfection byproducts in water posed potential health threat to humans. Nowadays, chlorinated derivatives of diazepam were ubiquitously detected in drinking water. Among these derivatives, 2-methylamino-5-chlorobenzophenone (MACB) was capable of penetrating the blood-brain barrier (BBB) and induced microglial phagocytosis of neurons in zebrafish. However, little is known about the MACB metabolism in vivo. Here, we determined the metabolism of MACB in zebrafish and microglia cell model. We found that MACB mainly disrupted the metabolism of branched-chain amino acids (Leu, Ile and Val) in zebrafish model and gamma-aminobutyric acid (GABA) pathway-related amino acids in microglia model. Additionally, we demonstrated that MACB can be metabolized by the mixed-function oxidase CYP1A2 enzyme which could be inhibited by estrogen causing the gender-difference in the accumulation of MACB in vivo. These results indicated that MACB perturbed metabolism and induced neurological disorders, particularly in the female zebrafish.
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Affiliation(s)
- Xiaole Zhao
- College of Veterinary Medicine, China Agricultural University, No.2 Yuanmingyuan West Road, Beijing 100193, People's Republic of China; Institute of Food Science and Engineering, Wuhan Polytechnic University, Wuhan 430023, People's Republic of China
| | - Xiaoyong Huang
- College of Veterinary Medicine, China Agricultural University, No.2 Yuanmingyuan West Road, Beijing 100193, People's Republic of China; Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control, Beijing 100013, People's Republic of China
| | - Wenjing Peng
- College of Veterinary Medicine, China Agricultural University, No.2 Yuanmingyuan West Road, Beijing 100193, People's Republic of China
| | - Muke Han
- Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control, Beijing 100013, People's Republic of China
| | - Xin Zhang
- Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control, Beijing 100013, People's Republic of China
| | - Kui Zhu
- College of Veterinary Medicine, China Agricultural University, No.2 Yuanmingyuan West Road, Beijing 100193, People's Republic of China.
| | - Bing Shao
- College of Veterinary Medicine, China Agricultural University, No.2 Yuanmingyuan West Road, Beijing 100193, People's Republic of China; Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control, Beijing 100013, People's Republic of China.
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15
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Combined exposure to maternal high-fat diet and neonatal lipopolysaccharide disrupts stress-related signaling but normalizes spatial memory in juvenile rats. Brain Behav Immun 2022; 102:299-311. [PMID: 35259428 DOI: 10.1016/j.bbi.2022.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 02/27/2022] [Accepted: 03/03/2022] [Indexed: 10/18/2022] Open
Abstract
Both neonatal infections and exposure to maternal obesity are inflammatory stressors in early life linked to increased rates of psychopathologies related to mood and cognition. Epidemiological studies indicate that neonates born to mothers with obesity have a higher likelihood of developing neonatal infections, however effects on offspring physiology and behavior resulting from the combination of these stressors have yet to be investigated. The aim of this study was to explore immediate and persistent phenotypes resulting from neonatal lipopolysaccharide (nLPS) administration in rat offspring born to dams consuming a high-fat diet (HFD). Neural transcript abundance of genes involved with stress regulation and spatial memory were examined alongside related behaviors. At the juvenile age point, unlike offspring exposed to maternal HFD (mHFD) or nLPS alone, offspring with combined exposure to mHFD + nLPS displayed altered transcript abundances of stress-related genes in the ventral hippocampus (HPC) in a manner conducive to potentiating stress responses. For memory-related phenotypes, juveniles exposed to mHFD + nLPS exhibited normalized spatial memory and levels of memory-related gene expression in the dorsal HPC similar to control diet offspring, while control diet + nLPS, and mHFD offspring exhibited reduced levels of memory-related gene expression and impaired spatial memory. These findings suggest that dual exposure to unique inflammatory stressors in early life can disrupt neural stress regulation but normalize spatial memory processes.
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16
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So SY, Savidge TC. Gut feelings: the microbiota-gut-brain axis on steroids. Am J Physiol Gastrointest Liver Physiol 2022; 322:G1-G20. [PMID: 34730020 PMCID: PMC8698538 DOI: 10.1152/ajpgi.00294.2021] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/26/2021] [Accepted: 10/29/2021] [Indexed: 01/31/2023]
Abstract
The intricate connection between central and enteric nervous systems is well established with emerging evidence linking gut microbiota function as a significant new contributor to gut-brain axis signaling. Several microbial signals contribute to altered gut-brain communications, with steroids representing an important biological class that impacts central and enteric nervous system function. Neuroactive steroids contribute pathologically to neurological disorders, including dementia and depression, by modulating the activity of neuroreceptors. However, limited information is available on the influence of neuroactive steroids on the enteric nervous system and gastrointestinal function. In this review, we outline how steroids can modulate enteric nervous system function by focusing on their influence on different receptors that are present in the intestine in health and disease. We also highlight the potential role of the gut microbiota in modulating neuroactive steroid signaling along the gut-brain axis.
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Affiliation(s)
- Sik Yu So
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas
| | - Tor C Savidge
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas
- Department of Pathology, Texas Children's Microbiome Center, Texas Children's Hospital, Houston, Texas
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17
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Thorsdottir D, Einwag Z, Erdos B. BDNF shifts excitatory-inhibitory balance in the paraventricular nucleus of the hypothalamus to elevate blood pressure. J Neurophysiol 2021; 126:1209-1220. [PMID: 34406887 DOI: 10.1152/jn.00247.2021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Presympathetic neurons in the paraventricular nucleus of the hypothalamus (PVN) play a key role in cardiovascular regulation. We have previously shown that brain-derived neurotrophic factor (BDNF), acting in the PVN, increases sympathetic activity and blood pressure and serves as a key regulator of stress-induced hypertensive responses. BDNF is known to alter glutamatergic and GABA-ergic signaling broadly in the central nervous system, but whether BDNF has similar actions in the PVN remains to be investigated. Here, we tested the hypothesis that increased BDNF expression in the PVN elevates blood pressure by enhancing N-methyl-d-aspartate (NMDA) receptor (NMDAR)- and inhibiting GABAA receptor (GABAAR)-mediated signaling. Sprague-Dawley rats received bilateral PVN injections of AAV2 viral vectors expressing green fluorescent protein (GFP) or BDNF. Three weeks later, cardiovascular responses to PVN injections of NMDAR and GABAAR agonists and antagonists were recorded under α-chloralose-urethane anesthesia. In addition, expressions of excitatory and inhibitory signaling components in the PVN were assessed using immunofluorescence. Our results showed that NMDAR inhibition led to a greater decrease in blood pressure in the BDNF vs. GFP group, while GABAAR inhibition led to greater increases in blood pressure in the GFP group compared to BDNF. Conversely, GABAAR activation decreased blood pressure significantly more in GFP vs. BDNF rats. In addition, immunoreactivity of NMDAR1 was upregulated, while GABAAR-α1 and K+/Cl- cotransporter 2 were downregulated by BDNF overexpression in the PVN. In summary, our findings indicate that hypertensive actions of BDNF within the PVN are mediated, at least in part, by augmented NMDAR and reduced GABAAR signaling.NEW & NOTEWORTHY We have shown that BDNF, acting in the PVN, elevates blood pressure in part by augmenting NMDA receptor-mediated excitatory input and by diminishing GABAA receptor-mediated inhibitory input to PVN neurons. In addition, we demonstrate that elevated BDNF expression in the PVN upregulates NMDA receptor immunoreactivity and downregulates GABAA receptor as well as KCC2 transporter immunoreactivity.
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Affiliation(s)
| | - Zachary Einwag
- Department of Pharmacology, University of Vermont, Burlington, Vermont
| | - Benedek Erdos
- Department of Pharmacology, University of Vermont, Burlington, Vermont
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18
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Martynyuk AE, Ju LS, Morey TE. The potential role of stress and sex steroids in heritable effects of sevoflurane. Biol Reprod 2021; 105:735-746. [PMID: 34192761 DOI: 10.1093/biolre/ioab129] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/17/2021] [Accepted: 06/25/2021] [Indexed: 12/11/2022] Open
Abstract
Most surgical procedures require general anesthesia, which is a reversible deep sedation state lacking all perception. The induction of this state is possible because of complex molecular and neuronal network actions of general anesthetics (GAs) and other pharmacological agents. Laboratory and clinical studies indicate that the effects of GAs may not be completely reversible upon anesthesia withdrawal. The long-term neurocognitive effects of GAs, especially when administered at the extremes of ages, are an increasingly recognized health concern and the subject of extensive laboratory and clinical research. Initial studies in rodents suggest that the adverse effects of GAs, whose actions involve enhancement of GABA type A receptor activity (GABAergic GAs), can also extend to future unexposed offspring. Importantly, experimental findings show that GABAergic GAs may induce heritable effects when administered from the early postnatal period to at least young adulthood, covering nearly all age groups that may have children after exposure to anesthesia. More studies are needed to understand when and how the clinical use of GAs in a large and growing population of patients can result in lower resilience to diseases in the even larger population of their unexposed offspring. This minireview is focused on the authors' published results and data in the literature supporting the notion that GABAergic GAs, in particular sevoflurane, may upregulate systemic levels of stress and sex steroids and alter expressions of genes that are essential for the functioning of these steroid systems. The authors hypothesize that stress and sex steroids are involved in the mediation of sex-specific heritable effects of sevoflurane.
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Affiliation(s)
- Anatoly E Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA.,McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA
| | - Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA
| | - Timothy E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA
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19
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Lee J, Kim K, Cho JH, Bae JY, O'Leary TP, Johnson JD, Bae YC, Kim EK. Insulin synthesized in the paraventricular nucleus of the hypothalamus regulates pituitary growth hormone production. JCI Insight 2020; 5:135412. [PMID: 32644973 PMCID: PMC7455129 DOI: 10.1172/jci.insight.135412] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 07/02/2020] [Indexed: 01/11/2023] Open
Abstract
Evidence has mounted that insulin can be synthesized in various brain regions, including the hypothalamus. However, the distribution and functions of insulin-expressing cells in the hypothalamus remain elusive. Herein, we show that in the mouse hypothalamus, the perikarya of insulin-positive neurons are located in the paraventricular nucleus (PVN) and their axons project to the median eminence; these findings define parvocellular neurosecretory PVN insulin neurons. Contrary to corticotropin-releasing hormone expression, insulin expression in the PVN was inhibited by restraint stress (RS) in both adult and young mice. Acute RS–induced inhibition of PVN insulin expression in adult mice decreased both pituitary growth hormone (Gh) mRNA level and serum GH concentration, which were attenuated by overexpression of PVN insulin. Notably, PVN insulin knockdown or chronic RS in young mice hindered normal growth via the downregulation of GH gene expression and secretion, whereas PVN insulin overexpression in young mice prevented chronic RS–induced growth retardation by elevating GH production. Our results suggest that in both normal and stressful conditions, insulin synthesized in the parvocellular PVN neurons plays an important role in the regulation of pituitary GH production and body length, unveiling a physiological function of brain-derived insulin. Insulin produced in the paraventricular nucleus regulates body length by modulating pituitary growth hormone expression and secretion under both normal and stress conditions.
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Affiliation(s)
- Jaemeun Lee
- Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, South Korea
| | - Kyungchan Kim
- Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, South Korea
| | - Jae Hyun Cho
- Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, South Korea
| | - Jin Young Bae
- Department of Oral Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu, South Korea
| | - Timothy P O'Leary
- Diabetes Research Group, Life Sciences Institute, Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - James D Johnson
- Diabetes Research Group, Life Sciences Institute, Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Yong Chul Bae
- Department of Oral Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu, South Korea
| | - Eun-Kyoung Kim
- Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, South Korea.,Neurometabolomics Research Center, Daegu Gyeongbuk Institute of Science and Technology, Daegu, South Korea
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20
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Hou X, Rong C, Wang F, Liu X, Sun Y, Zhang HT. GABAergic System in Stress: Implications of GABAergic Neuron Subpopulations and the Gut-Vagus-Brain Pathway. Neural Plast 2020; 2020:8858415. [PMID: 32802040 PMCID: PMC7416252 DOI: 10.1155/2020/8858415] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 07/03/2020] [Accepted: 07/06/2020] [Indexed: 02/07/2023] Open
Abstract
Stress can cause a variety of central nervous system disorders, which are critically mediated by the γ-aminobutyric acid (GABA) system in various brain structures. GABAergic neurons have different subsets, some of which coexpress certain neuropeptides that can be found in the digestive system. Accumulating evidence demonstrates that the gut-brain axis, which is primarily regulated by the vagus nerve, is involved in stress, suggesting a communication between the "gut-vagus-brain" pathway and the GABAergic neuronal system. Here, we first summarize the evidence that the GABAergic system plays an essential role in stress responses. In addition, we review the effects of stress on different brain regions and GABAergic neuron subpopulations, including somatostatin, parvalbumin, ionotropic serotonin receptor 5-HT3a, cholecystokinin, neuropeptide Y, and vasoactive intestinal peptide, with regard to signaling events, behavioral changes, and pathobiology of neuropsychiatric diseases. Finally, we discuss the gut-brain bidirectional communications and the connection of the GABAergic system and the gut-vagus-brain pathway.
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Affiliation(s)
- Xueqin Hou
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, Shandong 271016, China
| | - Cuiping Rong
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Fugang Wang
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, Shandong 271016, China
| | - Xiaoqian Liu
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, Shandong 271016, China
| | - Yi Sun
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, Shandong 271016, China
| | - Han-Ting Zhang
- Departments of Neuroscience and Behavioral Medicine & Psychiatry, The Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV 26506, USA
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21
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Martynyuk AE, Ju LS, Morey TE, Zhang JQ. Neuroendocrine, epigenetic, and intergenerational effects of general anesthetics. World J Psychiatry 2020; 10:81-94. [PMID: 32477904 PMCID: PMC7243620 DOI: 10.5498/wjp.v10.i5.81] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 03/18/2020] [Accepted: 03/26/2020] [Indexed: 02/05/2023] Open
Abstract
The progress of modern medicine would be impossible without the use of general anesthetics (GAs). Despite advancements in refining anesthesia approaches, the effects of GAs are not fully reversible upon GA withdrawal. Neurocognitive deficiencies attributed to GA exposure may persist in neonates or endure for weeks to years in the elderly. Human studies on the mechanisms of the long-term adverse effects of GAs are needed to improve the safety of general anesthesia but they are hampered not only by ethical limitations specific to human research, but also by a lack of specific biological markers that can be used in human studies to safely and objectively study such effects. The latter can primarily be attributed to an insufficient understanding of the full range of the biological effects induced by GAs and the molecular mechanisms mediating such effects even in rodents, which are far more extensively studied than any other species. Our most recent experimental findings in rodents suggest that GAs may adversely affect many more people than is currently anticipated. Specifically, we have shown that anesthesia with the commonly used GA sevoflurane induces in exposed animals not only neuroendocrine abnormalities (somatic effects), but also epigenetic reprogramming of germ cells (germ cell effects). The latter may pass the neurobehavioral effects of parental sevoflurane exposure to the offspring, who may be affected even at levels of anesthesia that are not harmful to the exposed parents. The large number of patients who require general anesthesia, the even larger number of their future unexposed offspring whose health may be affected, and a growing number of neurodevelopmental disorders of unknown etiology underscore the translational importance of investigating the intergenerational effects of GAs. In this mini review, we discuss emerging experimental findings on neuroendocrine, epigenetic, and intergenerational effects of GAs.
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Affiliation(s)
- Anatoly E Martynyuk
- Department of Anesthesiology and the McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Timothy E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Jia-Qiang Zhang
- Department of Anesthesiology and Perioperative Medicine, Henan Provincial People’s Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450003, Henan Province, China
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Chakraborty A, Banerjee S, Mukherjee B, Poddar MK. Calorie restriction improves aging-induced impairment of cognitive function in relation to deregulation of corticosterone status and brain regional GABA system. Mech Ageing Dev 2020; 189:111248. [PMID: 32339520 DOI: 10.1016/j.mad.2020.111248] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 03/16/2020] [Accepted: 04/05/2020] [Indexed: 12/21/2022]
Abstract
Aging is known to affect adversely the corticosterone status and the brain function including cognition. Calorie restricted (CR) diet has been found to improve brain aging. The objective of the present investigation is to study the effect of short-term CR diet without any food deprivation on aging-induced impairment of cognitive function in relation to the corticosterone status and the brain regional GABA system. The result showed that aging-induced deregulation of the brain regional GABA system, increase in plasma and adrenal corticosterone levels and cognitive impairment were attenuated with short-term CR diet supplementation for consecutive 1 and 2 months to the aged (18 and 24 months) rats. But in young rats (4 months) consumption of the same CR diet under similar conditions reversibly affected those above-mentioned parameters. These results, thus suggest that (a) aging down-regulates brain regional GABA system with an up-regulation of corticosterone status and impairment of cognitive function, (b) CR diet consumption improves this aging-induced deregulation of brain regional GABA system, corticosterone status, and cognitive function, (c) these attenuating effects of CR diet are greater with a longer period of consumption but (d) CR diet consumption is harmful to young rats as observed in those parameters.
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Affiliation(s)
- Apala Chakraborty
- Department of Pharmaceutical Technology, Jadavpur University, 188, Raja S.C. Mallick Road, Kolkata, 700032, India
| | - Soumyabrata Banerjee
- Department of Pharmaceutical Technology, Jadavpur University, 188, Raja S.C. Mallick Road, Kolkata, 700032, India
| | - Biswajit Mukherjee
- Department of Pharmaceutical Technology, Jadavpur University, 188, Raja S.C. Mallick Road, Kolkata, 700032, India
| | - Mrinal Kanti Poddar
- Department of Pharmaceutical Technology, Jadavpur University, 188, Raja S.C. Mallick Road, Kolkata, 700032, India.
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Romanov RA, Alpár A, Hökfelt T, Harkany T. Unified Classification of Molecular, Network, and Endocrine Features of Hypothalamic Neurons. Annu Rev Neurosci 2019; 42:1-26. [DOI: 10.1146/annurev-neuro-070918-050414] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Peripheral endocrine output relies on either direct or feed-forward multi-order command from the hypothalamus. Efficient coding of endocrine responses is made possible by the many neuronal cell types that coexist in intercalated hypothalamic nuclei and communicate through extensive synaptic connectivity. Although general anatomical and neurochemical features of hypothalamic neurons were described during the past decades, they have yet to be reconciled with recently discovered molecular classifiers and neurogenetic function determination. By interrogating magnocellular as well as parvocellular dopamine, GABA, glutamate, and phenotypically mixed neurons, we integrate available information at the molecular, cellular, network, and endocrine output levels to propose a framework for the comprehensive classification of hypothalamic neurons. Simultaneously, we single out putative neuronal subclasses for which future research can fill in existing gaps of knowledge to rationalize cellular diversity through function-determinant molecular marks in the hypothalamus.
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Affiliation(s)
- Roman A. Romanov
- Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria
| | - Alán Alpár
- Department of Anatomy, Histology, and Embryology, and SE NAP Research Group of Experimental Neuroanatomy and Developmental Biology, Semmelweis University, H-1085 Budapest, Hungary
| | - Tomas Hökfelt
- Department of Neuroscience, Biomedicum, Karolinska Institutet, SE-17165 Stockholm, Sweden
| | - Tibor Harkany
- Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria
- Department of Neuroscience, Biomedicum, Karolinska Institutet, SE-17165 Stockholm, Sweden
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24
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Malikowska-Racia N, Salat K. Recent advances in the neurobiology of posttraumatic stress disorder: A review of possible mechanisms underlying an effective pharmacotherapy. Pharmacol Res 2019; 142:30-49. [PMID: 30742899 DOI: 10.1016/j.phrs.2019.02.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 01/24/2019] [Accepted: 02/01/2019] [Indexed: 12/24/2022]
Abstract
Recent progress in the field of neurobiology supported by clinical evidence gradually reveals the mystery of human brain functioning. So far, many psychiatric disorders have been described in great detail, although there are still plenty of cases that are misunderstood. These include posttraumatic stress disorder (PTSD), which is a unique disease that combines a wide range of neurobiological changes, which involve disturbances of the hypothalamic-pituitary-adrenal gland axis, hyperactivation of the amygdala complex, and attenuation of some hippocampal and cortical functions. Such multiplicity results in differential symptomatology, including elevated anxiety, nightmares, fear retrieval episodes that may trigger delusions and hallucinations, sleep disturbances, and many others that strongly interfere with the quality of the patient's life. Because of widespread neurological changes and the disease manifestation, the pharmacotherapy of PTSD remains unclear and requires a multidimensional approach and involvement of polypharmacotherapy. Hopefully, more and more neuroscientists and clinicians will study PTSD, which will provide us with new information that would possibly accelerate establishment of well-tolerated and effective pharmacotherapy. In this review, we have focused on neurobiological changes regarding PTSD, addressing the most disturbed brain structures and neurotransmissions, as well as discussing in detail the recently taken and novel therapeutic paths.
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Affiliation(s)
- Natalia Malikowska-Racia
- Department of Pharmacodynamics, Chair of Pharmacodynamics, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland.
| | - Kinga Salat
- Department of Pharmacodynamics, Chair of Pharmacodynamics, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland
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25
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Alpár A, Benevento M, Romanov RA, Hökfelt T, Harkany T. Hypothalamic cell diversity: non-neuronal codes for long-distance volume transmission by neuropeptides. Curr Opin Neurobiol 2018; 56:16-23. [PMID: 30471413 DOI: 10.1016/j.conb.2018.10.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 10/24/2018] [Indexed: 11/24/2022]
Abstract
Volume transmission is a mode of intercellular communication using cerebral liquor to deliver signal molecules over long distances and allow their action for extended periods. For hypothalamic neuropeptides, nerve endings amongst ependymal cells are seen as a site of release into the cerebrospinal fluid. Recent single-cell RNA-seq data identify tanycytes and ventricular ependyma as alternative sources by being unexpectedly rich in neuroactive substances. This notion, coupled with circuit analysis showing regionalized innervation of periventricular ependyma by intrahypothalamic neurons, could allow for the integration of hypothalamic neuronal activity patterns with brain-wide activity changes upon metabolic challenges through phasic volume transmission primed by neuron-ependyma coupling. Here, we discuss emerging data for an ependymal interface and its breaches in neuropsychiatric disease.
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Affiliation(s)
- Alán Alpár
- SE NAP Research Group of Experimental Neuroanatomy and Developmental Biology, Semmelweis University, H-1085 Budapest, Hungary; Department of Anatomy, Histology, and Embryology, Semmelweis University, H-1085 Budapest, Hungary
| | - Marco Benevento
- Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria
| | - Roman A Romanov
- Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria
| | - Tomas Hökfelt
- Department of Neuroscience, Karolinska Institutet, SE-17165 Solna, Sweden
| | - Tibor Harkany
- Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria; Department of Neuroscience, Karolinska Institutet, SE-17165 Solna, Sweden.
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26
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Foradori CD, Healy JE, Zimmerman AD, Kemppainen RJ, Jones MA, Read CC, White BD, Yi KD, Hinds LR, Lacagnina AF, Quihuis AM, Breckenridge CB, Handa RJ. Characterization of Activation of the Hypothalamic-Pituitary-Adrenal Axis by the Herbicide Atrazine in the Female Rat. Endocrinology 2018; 159:3378-3388. [PMID: 30060079 DOI: 10.1210/en.2018-00474] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 07/19/2018] [Indexed: 11/19/2022]
Abstract
Atrazine (ATR) is a commonly used pre-emergence and early postemergence herbicide. Rats gavaged with ATR and its chlorometabolites desethylatrazine (DEA) and deisopropylatrazine (DIA) respond with a rapid and dose-dependent rise in plasma corticosterone, whereas the major chlorometabolite, diaminochlorotriazine (DACT), has little or no effect on corticosterone levels. In this study, we investigated the possible sites of ATR activation of the hypothalamic-pituitary-adrenal (HPA) axis. ATR treatment had no effect on adrenal weights but altered adrenal morphology. Hypophysectomized rats or rats under dexamethasone suppression did not respond to ATR treatment, suggesting that ATR does not directly stimulate the adrenal gland to induce corticosterone synthesis. Immortalized mouse corticotrophs (AtT-20) and primary rat pituitary cultures were treated with ATR, DEA, DIA, or DACT. None of the compounds induced an increase in ACTH secretion or potentiated ACTH release in conjunction with CRH on ACTH release. In female rats gavaged with ATR, pretreatment with the CRH receptor antagonist astressin completely blocked the ATR-induced rise in corticosterone concentrations, implicating CRH release in ATR-induced HPA activation. Intracerebroventricular infusion of ATR, DEA, and DIA but not DACT at concentrations equivalent to peak plasma concentrations after gavage dosing resulted in an elevation of plasma corticosterone concentrations. However, ATR did not induce c-Fos immunoreactivity in the paraventricular nucleus of the hypothalamus. These results indicate that ATR activates the HPA axis centrally and requires CRH receptor activation, but it does not stimulate cellular pathways associated with CRH neuronal excitation.
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Affiliation(s)
- Chad D Foradori
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama
| | - Jessica E Healy
- Department of Basic Medical Sciences, College of Medicine-Phoenix, University of Arizona, Phoenix, Arizona
| | - Arthur D Zimmerman
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama
| | - Robert J Kemppainen
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama
| | - Melaney A Jones
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama
| | - Casey C Read
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama
| | - B Douglas White
- Nutrition, Dietetics, and Hospitality Management, College of Human Sciences, Auburn University, Auburn, Alabama
| | - Kun Don Yi
- Syngenta Crop Protection LLC, Greensboro, North Carolina
| | - Laura R Hinds
- Department of Basic Medical Sciences, College of Medicine-Phoenix, University of Arizona, Phoenix, Arizona
| | - Anthony F Lacagnina
- Department of Basic Medical Sciences, College of Medicine-Phoenix, University of Arizona, Phoenix, Arizona
| | - Alicia M Quihuis
- Department of Basic Medical Sciences, College of Medicine-Phoenix, University of Arizona, Phoenix, Arizona
| | | | - Robert J Handa
- Department of Basic Medical Sciences, College of Medicine-Phoenix, University of Arizona, Phoenix, Arizona
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27
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Yang J, Ju L, Yang C, Xue J, Setlow B, Morey TE, Gravenstein N, Seubert CN, Vasilopoulos T, Martynyuk AE. Effects of combined brief etomidate anesthesia and postnatal stress on amygdala expression of Cl - cotransporters and corticotropin-releasing hormone and alcohol intake in adult rats. Neurosci Lett 2018; 685:83-89. [PMID: 30125644 DOI: 10.1016/j.neulet.2018.08.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 08/09/2018] [Accepted: 08/16/2018] [Indexed: 01/18/2023]
Abstract
Early life stressors, including general anesthesia, can have adverse effects on adult neural and behavioral outcomes, such as disruptions in inhibitory signaling, stress responsivity and increased risk of psychiatric disorders. Here we used a rat model to determine the effects of combined exposure to etomidate (ET) neonatal anesthesia and maternal separation on adult amygdala expression of genes for corticotropin-releasing hormone (Crh) and the chloride co-transporters Nkcc1 and Kcc2, as well as ethanol intake. Male and female Sprague-Dawley rats were subjected to 2 h of ET anesthesia on postnatal days (P) 4, 5, or 6 followed by maternal separation for 3 h on P10 (ET + SEP). During the P91-P120 period rats had daily 2 h access to three 0.05% saccharin solutions containing 0%, 5%, or 10% ethanol, followed by gene expression analyses. The ET + SEP group had increased Crh mRNA levels and Nkcc1/Kcc2 mRNA ratios in the amygdala, with greater increases in Nkcc1/Kcc2 mRNA ratios in males. A moderate increase in 5% ethanol intake was evident in the ET + SEP males, but not females, after calculation of the ratio of alcohol intake between the last week and first week of exposure. In contrast, control males tended to decrease alcohol consumption during the same period. A brief exposure to ET combined with a subsequent episode of stress early in life induced significant alterations in expression of amygdala Crh, Nkcc1 and Kcc2 with greater changes in the Cl- transporter expression in males. The possibility of increased alcohol intake in the exposed males requires further confirmation using different alcohol intake paradigms.
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Affiliation(s)
- Jiaojiao Yang
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Lingsha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Chunyao Yang
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Jinhu Xue
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Barry Setlow
- The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States; Department of Psychiatry, University of Florida College of Medicine, Gainesville, FL, United States
| | - Timothy E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Nikolaus Gravenstein
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States
| | - Christoph N Seubert
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Terrie Vasilopoulos
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Anatoly E Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States.
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28
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Farokhnia M, Sheskier MB, Lee MR, Le AN, Singley E, Bouhlal S, Ton T, Zhao Z, Leggio L. Neuroendocrine response to GABA-B receptor agonism in alcohol-dependent individuals: Results from a combined outpatient and human laboratory experiment. Neuropharmacology 2018; 137:230-239. [PMID: 29665351 PMCID: PMC6050109 DOI: 10.1016/j.neuropharm.2018.04.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 04/05/2018] [Accepted: 04/10/2018] [Indexed: 12/13/2022]
Abstract
Gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the nervous system, plays an important role in biobehavioral processes that regulate alcohol seeking, food intake, and stress response. The metabotropic GABA-B receptor has been investigated as a potential therapeutic target for alcohol use disorder, by using orthosteric agonists (e.g., baclofen) and positive allosteric modulators. Whether and how pharmacological manipulation of the GABA-B receptor, in combination with alcohol intake, may affect feeding- and stress-related neuroendocrine pathways remains unknown. In the present randomized, double-blind, placebo-controlled study, thirty-four alcohol-dependent individuals received baclofen (30 mg/day) or placebo in a naturalistic outpatient setting for one week, and then performed a controlled laboratory experiment which included alcohol cue-reactivity, fixed-dose priming, and self-administration procedures. Blood samples were collected, and the following neuroendocrine markers were measured: ghrelin, leptin, amylin, glucagon-like peptide-1 (GLP-1), insulin, prolactin, thyroid-stimulating hormone, growth hormone, cortisol, and adrenocorticotropic hormone (ACTH). During the outpatient phase, baclofen significantly increased blood concentrations of acyl-ghrelin (p = 0.01), leptin (p = 0.01), amylin (p = 0.004), and GLP-1 (p = 0.02). Significant drug × time-point interaction effects for amylin (p = 0.001) and insulin (p = 0.03), and trend-level interaction effects for GLP-1 (p = 0.06) and ACTH (p = 0.10) were found during the laboratory experiment. Baclofen, compared to placebo, had no effect on alcohol drinking in this study (p's ≥ 0.05). Together with previous studies, these findings shed light on the role of the GABAergic system and GABA-B receptors in the shared neurobiology of alcohol-, feeding-, and stress-related behaviors.
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Affiliation(s)
- Mehdi Farokhnia
- Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA
| | - Mikela B Sheskier
- Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA
| | - Mary R Lee
- Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA
| | - April N Le
- Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA
| | - Erick Singley
- Clinical Core Laboratory, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Sofia Bouhlal
- Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA
| | - Timmy Ton
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Zhen Zhao
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Lorenzo Leggio
- Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA; Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI, USA.
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29
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Yang Y, Yang K, Hao T, Zhu G, Ling R, Zhou X, Li P. Prediction of Molecular Mechanisms for LianXia NingXin Formula: A Network Pharmacology Study. Front Physiol 2018; 9:489. [PMID: 29867541 PMCID: PMC5952186 DOI: 10.3389/fphys.2018.00489] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Accepted: 04/17/2018] [Indexed: 12/27/2022] Open
Abstract
Objectives: Network pharmacological methods were used to investigate the underlying molecular mechanisms of LianXia NingXin (LXNX) formula, a Chinese prescription, to treat coronary heart disease (CHD) and disease phenotypes (CHD related diseases and symptoms). Methods: The different seed gene lists associated with the herbs of LXNX formula, the CHD co-morbid diseases and symptoms which were relieved by the LXNX formula (co-morbid diseases and symptoms) were curated manually from biomedical databases and published biomedical literatures. Module enrichment analysis was used to identify CHD-related disease modules in the protein–protein interaction (PPI) network which were also associated to the targets of LXNX formula (LXNX formula’s CHD modules). The molecular characteristics of LXNX formula’s CHD modules were investigated via functional enrichment analysis in terms of gene ontology and pathways. We performed shortest path analysis to explore the interactions between the drug targets of LXNX formula and CHD related disease phenotypes (e.g., co-morbid diseases and symptoms). Results: We identified two significant CHD related disease modules (i.e., M146 and M203), which were targeted by the herbs of LXNX formula. Pathway and GO term functional analysis results indicated that G-protein coupled receptor signaling pathways (GPCR) of M146 and cellular protein metabolic process of M203 are important functional pathways for the respective module. This is further confirmed by the shortest path analysis between the drug targets of LXNX formula and the aforementioned disease modules. In addition, corticotropin releasing hormone (CRH) and natriuretic peptide precursor A (NPPA) are the only two LXNX formula target proteins with the low shortest path length (on average shorter than 3) to their respective CHD module and co-morbid disease and symptom gene groups. Conclusion: G-protein coupled receptor signaling pathway and cellular protein metabolic process are the key LXNX formula’s pathways to treat CHD disease phenotypes, in which CRH and NPPA are the two key drug targets of LXNX formula. Further evidences from Chinese herb pharmacological databases indicate that Pinellia ternata (Banxia) has relatively strong adjustive functions on the two key targets.
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Affiliation(s)
- Yang Yang
- The Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Kuo Yang
- Beijing Key Lab of Traffic Data Analysis and Mining, School of Computer and Information Technology, Beijing Jiaotong University, Beijing, China
| | - Teng Hao
- Department of Psychiatry, Beijing ChaoYang Hospital of Traditional Chinese Medicine, Beijing, China
| | - Guodong Zhu
- Department of Cardiovascular, Beijing Chaoyang Integrative Medicine Emergency Medical Center, Beijing, China
| | - Ruby Ling
- The Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xuezhong Zhou
- Beijing Key Lab of Traffic Data Analysis and Mining, School of Computer and Information Technology, Beijing Jiaotong University, Beijing, China
| | - Ping Li
- The Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
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30
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den Boon FS, Sarabdjitsingh RA. Circadian and ultradian patterns of HPA-axis activity in rodents: Significance for brain functionality. Best Pract Res Clin Endocrinol Metab 2017; 31:445-457. [PMID: 29223280 DOI: 10.1016/j.beem.2017.09.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
The hypothalamo-pituitary-adrenal (HPA) axis comprises interactions between the hypothalamus, the pituitary and the adrenal glands and its activation results in the release of corticosteroid hormones. Corticosteroids are secreted from the adrenal gland in a distinct 24-h circadian rhythm overarching an ultradian rhythm, which consists of hourly corticosteroid pulses exposing target tissues to rapidly changing steroid levels. On top of these rhythms surges can take place after stress. HPA-axis rhythms promote adaptation to predictable (i.e. the earth's rotation) and unpredictable (i.e. stressors) changes in environmental factors. Two steroid hormone receptors, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), are activated by corticosteroids and mediate effects at fast and slow timescales on e.g. glucose availability, gene transcription and synaptic plasticity. The current review discusses the origin of the circadian and ultradian corticosteroid rhythms and their relevance for gene regulation, neuroendocrine and physiological responses to stress and the involvement in the maintenance of brain functionality in rodents.
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Affiliation(s)
- Femke S den Boon
- Dept. Translational Neuroscience, Brain Center Rudolf Magnus, UMC Utrecht, The Netherlands
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31
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Simultaneous two-photon imaging of intracellular chloride concentration and pH in mouse pyramidal neurons in vivo. Proc Natl Acad Sci U S A 2017; 114:E8770-E8779. [PMID: 28973889 DOI: 10.1073/pnas.1702861114] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Intracellular chloride ([Cl-]i) and pH (pHi) are fundamental regulators of neuronal excitability. They exert wide-ranging effects on synaptic signaling and plasticity and on development and disorders of the brain. The ideal technique to elucidate the underlying ionic mechanisms is quantitative and combined two-photon imaging of [Cl-]i and pHi, but this has never been performed at the cellular level in vivo. Here, by using a genetically encoded fluorescent sensor that includes a spectroscopic reference (an element insensitive to Cl- and pH), we show that ratiometric imaging is strongly affected by the optical properties of the brain. We have designed a method that fully corrects for this source of error. Parallel measurements of [Cl-]i and pHi at the single-cell level in the mouse cortex showed the in vivo presence of the widely discussed developmental fall in [Cl-]i and the role of the K-Cl cotransporter KCC2 in this process. Then, we introduce a dynamic two-photon excitation protocol to simultaneously determine the changes of pHi and [Cl-]i in response to hypercapnia and seizure activity.
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32
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Tanycytes control the hormonal output of the hypothalamic-pituitary-thyroid axis. Nat Commun 2017; 8:484. [PMID: 28883467 PMCID: PMC5589884 DOI: 10.1038/s41467-017-00604-6] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Accepted: 07/13/2017] [Indexed: 12/29/2022] Open
Abstract
The hypothalamic–pituitary–thyroid (HPT) axis maintains circulating thyroid hormone levels in a narrow physiological range. As axons containing thyrotropin-releasing hormone (TRH) terminate on hypothalamic tanycytes, these specialized glial cells have been suggested to influence the activity of the HPT axis, but their exact role remained enigmatic. Here, we demonstrate that stimulation of the TRH receptor 1 increases intracellular calcium in tanycytes of the median eminence via Gαq/11 proteins. Activation of Gαq/11 pathways increases the size of tanycyte endfeet that shield pituitary vessels and induces the activity of the TRH-degrading ectoenzyme. Both mechanisms may limit the TRH release to the pituitary. Indeed, blocking TRH signaling in tanycytes by deleting Gαq/11 proteins in vivo enhances the response of the HPT axis to the chemogenetic activation of TRH neurons. In conclusion, we identify new TRH- and Gαq/11-dependent mechanisms in the median eminence by which tanycytes control the activity of the HPT axis. The hypothalamic-pituitary-thyroid (HPT) axis regulates a wide range of physiological processes. Here the authors show that hypothalamic tanycytes play a role in the homeostatic regulation of the HPT axis; activation of TRH signaling in tanycytes elevates their intracellular Ca2+ via Gαq/11 pathway, ultimately resulting in reduced TRH release into the pituitary vessels.
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Ben-Ari Y. NKCC1 Chloride Importer Antagonists Attenuate Many Neurological and Psychiatric Disorders. Trends Neurosci 2017; 40:536-554. [PMID: 28818303 DOI: 10.1016/j.tins.2017.07.001] [Citation(s) in RCA: 136] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 07/03/2017] [Accepted: 07/10/2017] [Indexed: 12/23/2022]
Abstract
In physiological conditions, adult neurons have low intracellular Cl- [(Cl-)I] levels underlying the γ-aminobutyric acid (GABA)ergic inhibitory drive. In contrast, neurons have high (Cl-)I levels and excitatory GABA actions in a wide range of pathological conditions including spinal cord lesions, chronic pain, brain trauma, cerebrovascular infarcts, autism, Rett and Down syndrome, various types of epilepsies, and other genetic or environmental insults. The diuretic highly specific NKCC1 chloride importer antagonist bumetanide (PubChem CID: 2461) efficiently restores low (Cl-)I levels and attenuates many disorders in experimental conditions and in some clinical trials. Here, I review the mechanisms of action, therapeutic effects, promises, and pitfalls of bumetanide.
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Affiliation(s)
- Yehezkel Ben-Ari
- New INMED, Aix-Marseille University, Campus Scientifique de Luminy, Marseilles, France.
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Spike and Neuropeptide-Dependent Mechanisms Control GnRH Neuron Nerve Terminal Ca 2+ over Diverse Time Scales. J Neurosci 2017; 37:3342-3351. [PMID: 28235895 DOI: 10.1523/jneurosci.2925-16.2017] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2016] [Revised: 02/14/2017] [Accepted: 02/17/2017] [Indexed: 01/30/2023] Open
Abstract
Fast cell-to-cell communication in the brain is achieved by action potential-dependent synaptic release of neurotransmitters. The fast kinetics of transmitter release are determined by transient Ca2+ elevations in presynaptic nerve terminals. Neuromodulators have previously been shown to regulate transmitter release by inhibiting presynaptic Ca2+ influx. Few studies to date have demonstrated the opposite, that is, neuromodulators directly driving presynaptic Ca2+ rises and increases in nerve terminal excitability. Here we use GCaMP Ca2+ imaging in brain slices from mice to address how nerve terminal Ca2+ is controlled in gonadotropin-releasing hormone (GnRH) neurons via action potentials and neuromodulators. Single spikes and bursts of action potentials evoked fast, voltage-gated Ca2+ channel-dependent Ca2+ elevations. In contrast, brief exposure to the neuropeptide kisspeptin-evoked long-lasting Ca2+ plateaus that persisted for tens of minutes. Neuropeptide-mediated Ca2+ elevations were independent of action potentials, requiring Ca2+ entry via voltage-gated Ca2+ channels and transient receptor potential channels in addition to release from intracellular store mechanisms. Together, these data reveal that neuromodulators can exert powerful and long-lasting regulation of nerve terminal Ca2+ independently from actions at the soma. Thus, GnRH nerve terminal function is controlled over disparate timescales via both classical spike-dependent and nonclassical neuropeptide-dependent mechanisms.SIGNIFICANCE STATEMENT Nerve terminals are highly specialized regions of a neuron where neurotransmitters and neurohormones are released. Many neuroendocrine neurons release neurohormones in long-duration bursts of secretion. To understand how this is achieved, we have performed live Ca2+ imaging in the nerve terminals of gonadotropin-releasing hormone neurons. We find that bursts of action potentials and local neuropeptide signals are both capable of evoking large increases in nerve terminal Ca2+ Increases in Ca2+ driven by spike bursts last seconds; however, the increases in nerve terminal Ca2+ driven by neuropeptides can persist for tens of minutes. These findings reveal new mechanisms by which neuroendocrine nerve terminal Ca2+ can be controlled in the brain.
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