1
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Kukkonen JP, Turunen PM, Rinne MK. Detection of reduced orexin-A/hypocretin-1 and its fragments by orexin-A "gold-standard" radioimmunoassay. Sleep Med 2025; 131:106505. [PMID: 40250157 DOI: 10.1016/j.sleep.2025.106505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 04/02/2025] [Accepted: 04/03/2025] [Indexed: 04/20/2025]
Abstract
BACKGROUND Orexin-A/hypocretin-1 level is determined in the cerebrospinal fluid samples as a part of clinical narcolepsy diagnostics utilizing a specific commercial radioimmunoassay (RIA); this assay is also widely used in research of many other conditions. The specificity of RIAs is in general variable, and little has been firmly disclosed about the specificity of this RIA assay. Thus, the validity of many research results obtained using the kit is unclear. At least metabolites of orexin-A have been proposed as potential interfering substances. METHODS Since this issue has not been systematically assessed, we decided to investigate it using synthetic variants of orexin-A and -B (intact peptides and peptide fragments as well as reduced orexin-A). RESULTS Our synthetic orexin-A bound correspondingly to the orexin-A standard included in the kit while orexin-B did not bind even at 10000-fold higher concentrations. Reduction of the disulfide bridges in orexin-A (giving orexin-A-SS) decreased its binding 25-fold. C-terminal truncation of orexin-A-SS was well tolerated - some of the fragments actually bound better than orexin-A-SS - while N-terminal truncation was not allowed. CONCLUSIONS The results demonstrate that the RIA kit is fairly selective for intact orexin-A among the peptides tested. However, this does not as such prove that it measures intact orexin-A in the physiological samples, and further studies including identification of physiological orexin-A metabolites are thus required. We also suggest that the redox milieu of cerebrospinal fluid - that has been suggested to vary in different diseases - may have an impact on what is measured with the kit.
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Affiliation(s)
- Jyrki P Kukkonen
- Department of Pharmacology, Medicum, University of Helsinki, Helsinki, Finland.
| | - Pauli M Turunen
- Department of Physiology, Medicum, University of Helsinki, Helsinki, Finland
| | - Maiju K Rinne
- Department of Pharmacology, Medicum, University of Helsinki, Helsinki, Finland
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2
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Zhang D, Wei Y. Distinct Neural Mechanisms Between Anesthesia Induction and Emergence: A Narrative Review. Anesth Analg 2025; 141:162-171. [PMID: 38861419 PMCID: PMC12140560 DOI: 10.1213/ane.0000000000007114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/24/2024] [Indexed: 06/13/2024]
Abstract
Anesthesia induction and emergence are critical periods for perioperative safety in the clinic. Traditionally, the emergence from general anesthesia has been recognized as a simple inverse process of induction resulting from the elimination of general anesthetics from the central nervous system. However, accumulated evidence has indicated that anesthesia induction and emergence are not mirror-image processes because of the occurrence of hysteresis/neural inertia in both animals and humans. An increasing number of studies have highlighted the critical role of orexinergic neurons and their involved circuits in the selective regulation of emergence but not the induction of general anesthesia. Moreover, additional brain regions have also been implicated in distinct neural mechanisms for anesthesia induction and emergence, which extends the concept that anesthetic induction and emergence are not antiparallel processes. Here, we reviewed the current literature and summarized the evidence regarding the differential mechanism of neural modulation in anesthesia induction and emergence, which will facilitate the understanding of the underlying neural mechanism for emergence from general anesthesia.
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Affiliation(s)
- Donghang Zhang
- From the Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
- Department of Anesthesiology, Weill Cornell Medicine, New York, New York
| | - Yiyong Wei
- Department of Anesthesiology, Longgang District Maternity & Child Healthcare Hospital of Shenzhen City (Longgang Maternity and Child Institute of Shantou University Medical College), Shenzhen, China
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3
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Tonosaki M, Kushikata T, Nikaido Y, Takekawa D, Kinoshita H, Saito J, Hirota K. Roles of orexinergic and noradrenergic neuronal activity in ketamine-induced sedation: a study using an orexin-ataxin-3 transgenic rat model. J Anesth 2025:10.1007/s00540-025-03521-x. [PMID: 40490582 DOI: 10.1007/s00540-025-03521-x] [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] [Received: 03/14/2024] [Accepted: 05/18/2025] [Indexed: 06/11/2025]
Abstract
PURPOSE To investigate the role of brain noradrenergic and orexinergic activity in ketamine-induced sedation. METHODS We used orexin neuron-deficient transgenic rats (orexin/ataxin-3) and wild-type controls. Noradrenaline and orexin levels were measured in the pons, hypothalamus, and cerebral cortex. Ketamine-induced loss-of-righting reflex (LORR) was assessed under modulation of noradrenergic or orexinergic activity. RESULTS Wild-type rats had higher noradrenaline and orexin levels than transgenic rats across all regions except hypothalamic noradrenaline. Noradrenaline and orexin were correlated in the pons and cortex. Transgenic rats had a shorter LORR duration than wild-type rats (36.3 ± 10.4 vs. 46.7 ± 5.2 min, P = 0.002). Noradrenergic activation via intraperitoneal yohimbine prolonged LORR in both genotypes (wild-type: 38.8 ± 4.9 vs. 71.9 ± 15.3 min at 3.3 mg/kg, P = 0.002; transgenic: 28.1 ± 3.9 vs. 71.9 ± 24.8 min, P < 0.001). Noradrenergic deactivation by DSP4 reduced LORR duration (wild-type: 43.3 ± 2.18 vs. 36.4 ± 6.0 min, P = 0.005). Intracerebroventricular orexin (1.0 nmol) shortened LORR (44.0 ± 16.7 vs. 30.1 ± 15.5 min, P = 0.001), but co-administration of selective orexin type 1 receptor antagonist YNT-1310 (100 nmol) counteracted this effect. Notably, orexin or DSP4 reduced LORR duration in wild-type rats but prolonged it in transgenic rats (e.g., wild-type: 40.8 ± 6.2 vs. 32.5 ± 5.3 min with orexin, P = 0.0001; transgenic 28.6 ± 6.2 vs. 42.1 ± 5.6 min, P = 0.0026). CONCLUSION Orexin-preserved noradrenergic activity supports the typical ketamine-induced sedation profile, highlighting their interactive role in modulating anesthetic depth.
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Affiliation(s)
- Mitsuru Tonosaki
- Intensive Care Unit, Hirosaki University Hospital, Honcho 53, Hirosaki, Aomori, 0368563, Japan
| | - Tetsuya Kushikata
- Department of Anesthesiology, Hirosaki University Graduate School of Medicine, Zaifu 5, Hirosaki, Aomori, 0368562, Japan.
| | - Yoshikazu Nikaido
- Department of Metabolomics Innovation, Hirosaki University Graduate School of Medicine, Zaifu 5, Hirosaki, Aomori, 0368562, Japan
| | - Daiki Takekawa
- Department of Anesthesiology, Hirosaki University Hospital, Honcho 53, Hirosaki, Aomori, 0368563, Japan
| | - Hirotaka Kinoshita
- Department of Anesthesiology, Hirosaki University Hospital, Honcho 53, Hirosaki, Aomori, 0368563, Japan
| | - Jyunichi Saito
- Department of Anesthesiology, Hirosaki University Hospital, Honcho 53, Hirosaki, Aomori, 0368563, Japan
| | - Kazuyoshi Hirota
- Department of Anesthesiology, Hirosaki University Graduate School of Medicine, Zaifu 5, Hirosaki, Aomori, 0368562, Japan
- Department of Perioperative Medicine for Community Healthcare, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 0368562, Japan
- Department of Perioperative Stress Management, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan
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4
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Heinicke U, Talbot SR, Thanasis F, Adam EH, von Knethen A, Steinbicker AU, Zinn S, Zacharowski K, Flinspach AN. Systemic role of orexin A, substance P, bradykinin, and DABK in severe COVID-19 and 2.5-yr follow-ups: an observational study. BJA OPEN 2025; 14:100415. [PMID: 40529720 PMCID: PMC12173137 DOI: 10.1016/j.bjao.2025.100415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 03/20/2025] [Accepted: 04/09/2025] [Indexed: 06/20/2025]
Abstract
Background Orexin A regulates sleep-wake cycles, arousal, and energy homeostasis, linking it to the renin-angiotensin system and substance P. Dysfunction in these pathways occurs in acute and long-term COVID-19, including post-COVID syndrome. Methods This observational study analysed plasma orexin A, substance P, bradykinin, and des-Arg9-bradykinin (DABK) in 78 ICU COVID-19 patients, 14 survivors of severe COVID-19 (2.5-yr follow-ups), and 14 healthy controls. Results During acute COVID-19, bradykinin and substance P were significantly reduced, whereas DABK was elevated compared with healthy controls and 2.5-yr follow-ups. Orexin A concentration correlated with ICU survival (Cohen's d=0.4), length of stay (LOS; r=-0.26, P=0.02), and sedation concentrations. Intriguingly, substance P plasma concentrations were elevated in 2.5-yr follow-ups. Plasma orexin A, substance P, and bradykinin increased with lower Richmond Agitation-Sedation Score (RASS): a combination of orexin A, substance P, and bradykinin concentrations at RASS -3 to -5 distinguished survivors from non-survivors of COVID-19 when categorised by age. Conclusions Changes in the bradykinin axis, affecting substance P and orexin A signalling, are associated with severe COVID-19, ICU LOS, and survival. Elevated substance P concentrations in the 2.5-yr follow-up cohort may be associated with physical, cognitive, and neuropsychological impairments commonly seen in post-ICU syndrome and post-COVID syndrome. The predictive values of orexin A, substance P, bradykinin, and DABK and the complex interplay between the renin-angiotensin system and the orexinergic system in severe, critical illnesses or viral diseases will be investigated in future studies.
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Affiliation(s)
- Ulrike Heinicke
- Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, Goethe University, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Steven R. Talbot
- Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany
| | - Filippos Thanasis
- Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, Goethe University, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Elisabeth H. Adam
- Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, Goethe University, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Andreas von Knethen
- Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, Goethe University, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Andrea U. Steinbicker
- Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, Goethe University, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Sebastian Zinn
- Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, Goethe University, University Hospital Frankfurt, Frankfurt am Main, Germany
- Columbia University Medical Center, Department of Anesthesiology, New York, NY, USA
| | - Kai Zacharowski
- Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, Goethe University, University Hospital Frankfurt, Frankfurt am Main, Germany
- Fraunhofer – Institute for Translational Medicine and Pharmacology (ITMP), Frankfurt am Main, Germany
| | - Armin N. Flinspach
- Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, Goethe University, University Hospital Frankfurt, Frankfurt am Main, Germany
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5
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Saper CB. Targeting Orexin Receptors to Treat Narcolepsy. N Engl J Med 2025; 392:1968-1971. [PMID: 40367382 DOI: 10.1056/nejme2502806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/16/2025]
Affiliation(s)
- Clifford B Saper
- Department of Neurology, Division of Sleep Medicine and Program in Neuroscience, Beth Israel Deaconess Medical Center, Boston
- Harvard Medical School, Boston
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6
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Freeman SA, Ayoub I, Dauvilliers Y, Liblau RS. Unraveling the pathophysiology of narcolepsy type 1 through hypothesis-driven and hypothesis-generating approaches. Semin Immunol 2025; 78:101962. [PMID: 40373365 DOI: 10.1016/j.smim.2025.101962] [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: 03/25/2025] [Revised: 04/30/2025] [Accepted: 05/01/2025] [Indexed: 05/17/2025]
Abstract
Narcolepsy type 1 (NT1) is a chronic orphan neurological sleep disorder characterized by the loss of hypocretin-producing neurons in the lateral hypothalamus, which play a crucial role in wakefulness. Given the genetic association with the HLA-DQB1 * 06:02 allele and environmental links with the 2009 influenza pandemic, many lines of evidence point towards an immune mechanism, notably autoimmunity, underlying the disease pathophysiology. Autoreactive T cells are found in the blood of NT1 patients, and mouse models demonstrate their migratory capacity and contribution in the selective destruction of hypocretin-producing neurons. However, direct evidence for their role in human NT1 pathophysiology remains elusive. In complementing these findings, hypothesis-generating approaches-including multiparametric immune profiling, transcriptomic sequencing and large-scale proteomic of blood and cerebrospinal fluid-have uncovered promising new avenues into the immune system's involvement in NT1. In this review, we explore the mechanisms driving NT1 pathogenesis, emphasizing both hypothesis-driven and hypothesis-generating approaches, and discuss potential future directions that could pave the way for targeted immunotherapies.
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Affiliation(s)
- Sean A Freeman
- Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), University of Toulouse, CNRS, INSERM, UPS, Toulouse, France; Department of Neurology, Toulouse University Hospitals, Toulouse, France
| | - Ikram Ayoub
- Department of Neurosciences, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Yves Dauvilliers
- Institute of Neurosciences of Montpellier (INM), University of Montpellier, INSERM, Montpellier, France; Sleep-Wake Disorders Unit, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, France; National Reference Centre for Orphan Diseases, Narcolepsy, Idiopathic Hypersomnia, and Kleine-Levin Syndrome, Montpellier, France
| | - Roland S Liblau
- Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), University of Toulouse, CNRS, INSERM, UPS, Toulouse, France; Department of Immunology, Toulouse University Hospitals, Toulouse, France.
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7
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Ishikawa T, Kurimoto E, Joyal AA, Koike T, Kimura H, Scammell TE. An orexin agonist promotes wakefulness and inhibits cataplexy through distinct brain regions. Curr Biol 2025; 35:2088-2099.e4. [PMID: 40233754 DOI: 10.1016/j.cub.2025.03.040] [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: 11/15/2024] [Revised: 02/12/2025] [Accepted: 03/20/2025] [Indexed: 04/17/2025]
Abstract
Narcolepsy type 1, caused by selective loss of the orexin-producing neurons, is characterized by poor maintenance of wakefulness and cataplexy. Clinical trials show that orexin receptor 2 (OX2R) agonists substantially improve narcolepsy symptoms, but the key brain regions through which OX2R signaling produces these benefits are only partially understood. To address this question, we produced recombinant mice expressing the human diphtheria toxin receptor driven by the endogenous orexin promoter (orexinDTR mice). After injection with diphtheria toxin, orexinDTR mice had severe and selective loss of the orexin neurons, leading to narcolepsy symptoms, including poor maintenance of wakefulness and cataplexy; these symptoms were substantially improved by an OX2R-selective agonist OX-201. We then crossed orexinDTR mice with OX2R transcription-disrupted (TD) mice to produce a new model lacking orexin neurons and OX2R. We focally restored OX2R expression in specific brain regions of OX2R TD::orexinDTR mice and assessed whether OX-201 improves specific aspects of narcolepsy. In mice expressing OX2R only in the tuberomammillary nucleus (TMN) or basal forebrain (BF) regions, OX-201 improved maintenance of wakefulness but did not suppress cataplexy. In contrast, in mice expressing OX2R in the ventrolateral periaqueductal gray and lateral pontine tegmentum (vlPAG/LPT), OX-201 suppressed cataplexy without improving maintenance of wakefulness. These results suggest that OX2R signaling in the TMN and BF regions can stabilize wakefulness and OX2R signaling in the vlPAG/LPT region can suppress cataplexy, providing key insights into how orexins regulate wakefulness and muscle tone and how OX2R agonists improve the symptoms of narcolepsy. VIDEO ABSTRACT.
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Affiliation(s)
- Takashi Ishikawa
- Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan; Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
| | - Emi Kurimoto
- Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan; Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
| | - Adam A Joyal
- Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
| | - Tatsuki Koike
- Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Haruhide Kimura
- Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Thomas E Scammell
- Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
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8
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Somach RT, Lim MM, Cohen AS. Effects of Traumatic Brain Injury on the Orexin/Hypocretin System. Neurotrauma Rep 2025; 6:322-335. [PMID: 40309161 PMCID: PMC12040569 DOI: 10.1089/neur.2024.0111] [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] [Indexed: 05/02/2025] Open
Abstract
Traumatic Brain Injuries (TBIs) are known to cause a myriad of symptoms in patients. One common symptom after injury is sleep disruptions. One neuropeptide system has been studied repeatedly as a potential cause of sleep disruptions after TBI- the orexin/hypocretin system. Orexin promotes wakefulness and arousal while disrupting the orexin system causes increased sleepiness and narcolepsy. Studies of TBI in human and animal subjects have shown that TBI affects the orexin system. This review serves as an overview of how TBI affects the orexin/hypocretin system, including structural and functional changes to the neurons after injury. This review is the first to include studies that examine how TBI affects orexin/hypocretin receptors. This review also examines how sex is accounted for in the studies of the orexin system after TBI.
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Affiliation(s)
| | - Miranda M. Lim
- Oregon Health and Science University, Portland, Oregon, USA
- VA Portland Health Care System, Portland, Oregon, USA
| | - Akiva S. Cohen
- Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- University of Pennsylvania, Philadelphia, Pennsylvania, USA
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9
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Yates AG, Khamhoung A, Gaebel L, Jacob W, Radford-Smith DE, Kiss MG, Huynh P, Gerhardt T, Heiser M, Cohen O, Swirski FK, Anthony DC, Sumowski J, Katz Sand I, McAlpine CS. Myelopoiesis is temporally dynamic and is regulated by lifestyle to modify multiple sclerosis. Nat Commun 2025; 16:3683. [PMID: 40246882 PMCID: PMC12006503 DOI: 10.1038/s41467-025-59074-w] [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: 04/29/2024] [Accepted: 04/10/2025] [Indexed: 04/19/2025] Open
Abstract
Monocytes and neutrophils from the myeloid lineage contribute to multiple sclerosis (MS), but the dynamics of myelopoiesis during MS are unclear. Here we uncover a disease stage-specific relationship between lifestyle, myelopoiesis and neuroinflammation. In mice with relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE), myelopoiesis in the femur, vertebrae and spleen is elevated prior to disease onset and during remission, preceding the peaks of clinical disability and neuroinflammation. In progressive EAE (P-EAE), vertebral myelopoiesis rises steadily throughout disease, while femur and splenic myelopoiesis is elevated early before waning later during disease height. In parallel, sleep disruption or hyperlipidemia and cardiometabolic syndrome augment M-CSF generation and multi-organ myelopoiesis to worsen P-EAE clinical symptoms, neuroinflammation, and spinal cord demyelination, with M-CSF blockade abrogating these symptoms. Lastly, results from a previous trial show that Mediterranean diet restrains myelopoietic activity and myeloid lineage progenitor skewing and improves clinical symptomology of MS. Together, our data suggest that myelopoiesis in MS is dynamic and dependent on disease stage and location, and that lifestyle factors modulate disease by influencing M-CSF-mediated myelopoiesis.
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Affiliation(s)
- Abi G Yates
- Cardiovascular Research Institute and the Department of Medicine, Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Friedman Brain Institute and the Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Annie Khamhoung
- Cardiovascular Research Institute and the Department of Medicine, Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Friedman Brain Institute and the Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Lena Gaebel
- Cardiovascular Research Institute and the Department of Medicine, Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Friedman Brain Institute and the Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Walter Jacob
- Cardiovascular Research Institute and the Department of Medicine, Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Friedman Brain Institute and the Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Máté G Kiss
- Cardiovascular Research Institute and the Department of Medicine, Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Friedman Brain Institute and the Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Pacific Huynh
- Cardiovascular Research Institute and the Department of Medicine, Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Friedman Brain Institute and the Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Teresa Gerhardt
- Cardiovascular Research Institute and the Department of Medicine, Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Friedman Brain Institute and the Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Merlin Heiser
- Cardiovascular Research Institute and the Department of Medicine, Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Friedman Brain Institute and the Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Oren Cohen
- Cardiovascular Research Institute and the Department of Medicine, Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Filip K Swirski
- Cardiovascular Research Institute and the Department of Medicine, Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Friedman Brain Institute and the Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - James Sumowski
- The Corinne Goldsmith Dickinson Center for Multiple Sclerosis and the Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ilana Katz Sand
- The Corinne Goldsmith Dickinson Center for Multiple Sclerosis and the Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Cameron S McAlpine
- Cardiovascular Research Institute and the Department of Medicine, Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Friedman Brain Institute and the Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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10
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Stankiewicz KH, Guiglielmoni N, Kitchen SA, Flot JF, Barott KL, Davies SW, Finnerty JR, Grace SP, Kaufman LS, Putnam HM, Rotjan RD, Sharp KH, Peters EC, Baums IB. Genomic comparison of the temperate coral Astrangia poculata with tropical corals yields insights into winter quiescence, innate immunity, and sexual reproduction. G3 (BETHESDA, MD.) 2025; 15:jkaf033. [PMID: 39964876 PMCID: PMC12005167 DOI: 10.1093/g3journal/jkaf033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 02/02/2025] [Indexed: 02/20/2025]
Abstract
Facultatively symbiotic corals provide important experimental models to explore the establishment, maintenance, and breakdown of the mutualism between corals and members of the algal family Symbiodiniaceae. Here, we report the de novo chromosome-scale genome assembly and annotation of the facultatively symbiotic, temperate coral Astrangia poculata. Though widespread segmental/tandem duplications of genomic regions were detected, we did not find strong evidence of a whole-genome duplication event. Comparison of the gene arrangement between As. poculata and the tropical coral Acropora millepora revealed considerable conserved colinearity despite ∼415 million years of divergence. Gene families related to sperm hyperactivation and innate immunity, including lectins, were found to contain more genes in Ac. millepora relative to As. poculata. Sperm hyperactivation in Ac. millepora is expected given the extreme requirements of gamete competition during mass spawning events in tropical corals, while lectins are important in the establishment of coral-algal symbiosis. By contrast, gene families involved in sleep promotion, feeding suppression, and circadian sleep/wake cycle processes were expanded in As. poculata. These expanded gene families may play a role in As. poculata's ability to enter a dormancy-like state (winter quiescence) to survive freezing temperatures at the northern edges of the species' range.
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Affiliation(s)
- Kathryn H Stankiewicz
- Department of Biology, The Pennsylvania State University, University Park, PA 16802, USA
- Institute for Systems Biology, Seattle, WA 98109, USA
| | - Nadège Guiglielmoni
- Department of Marine Biology, Université libre de Bruxelles (ULB), Brussels 1050, Belgium
| | - Sheila A Kitchen
- Department of Biology, The Pennsylvania State University, University Park, PA 16802, USA
- Department of Marine Biology, Texas A&M University at Galveston, Galveston, TX 77554, USA
| | - Jean-François Flot
- Department of Marine Biology, Université libre de Bruxelles (ULB), Brussels 1050, Belgium
- Interuniversity Institute of Bioinformatics in Brussels—(IB), Brussels 1050, Belgium
| | - Katie L Barott
- Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Sarah W Davies
- Department of Biology, Boston University, Boston, MA 02215, USA
| | - John R Finnerty
- Department of Biology, Boston University, Boston, MA 02215, USA
| | - Sean P Grace
- Department of Biology & Werth Center for Coastal and Marine Studies, Southern Connecticut State University, New Haven, CT 06515, USA
| | | | - Hollie M Putnam
- Department of Biological Sciences, University of Rhode Island, Kingston, RI 02881, USA
| | - Randi D Rotjan
- Department of Biology, Boston University, Boston, MA 02215, USA
| | - Koty H Sharp
- Department of Biology, Marine Biology, and Environmental Science, Roger Williams University, Bristol, RI 02809, USA
| | - Esther C Peters
- Department of Environmental Science and Policy, George Mason University, Fairfax, VA 22030, USA
| | - Iliana B Baums
- Department of Biology, The Pennsylvania State University, University Park, PA 16802, USA
- Helmholtz Institute for Functional Marine Biodiversity at the University of Oldenburg (HIFMB), Carl von Ossietzky Universität Oldenburg, Oldenburg 26129, Germany
- Alfred Wegener Institute, Helmholtz-Centre for Polar and Marine Research, Bremerhaven 27570, Germany
- Institute for Chemistry and Biology of the Marine Environment (ICBM), School of Mathematics and Science, Carl von Ossietzky Universität Oldenburg, Oldenburg 26129, Germany
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11
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Mariani S, Honisch C, Ruzza P, Tartaggia S. Unexpected Conversion of Tyrosine into a Coumaric Acid Residue at the N-Terminal Side of an Orexin Peptide Fragment Induced by UV Irradiation. Chemistry 2025; 31:e202500383. [PMID: 40019305 DOI: 10.1002/chem.202500383] [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: 01/29/2025] [Revised: 02/28/2025] [Accepted: 02/28/2025] [Indexed: 03/01/2025]
Abstract
The presence of reactive species exceeding the physiological self-defense mechanisms in cells and tissues, known as oxidative stress, usually leads to damage of DNA and proteins. In this work, we analyzed the impact of UV irradiation and radical species from different sources to the Tyr17-Leu33 segment of orexin A peptide, which is the minimal fragment with affinity for orexin 1 receptor. As a clear oxidation process, we detected the conversion of terminal Tyrosine residue into a mixture of E/Z coumaric acid derivatives. In fact, UV irradiation and nitrosyl radicals were found to selectively induce the deamination of tyrosine into the corresponding olefin derivative, which was confirmed by HPLC-MS and NMR investigations.
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Affiliation(s)
- Simone Mariani
- Institute of Biomolecular Chemistry, CNR National Research Council of Italy, Via Marzolo 1, 35131, Padova, Italy
| | - Claudia Honisch
- Institute of Biomolecular Chemistry, CNR National Research Council of Italy, Via Marzolo 1, 35131, Padova, Italy
| | - Paolo Ruzza
- Institute of Biomolecular Chemistry, CNR National Research Council of Italy, Via Marzolo 1, 35131, Padova, Italy
| | - Stefano Tartaggia
- Institute of Biomolecular Chemistry, CNR National Research Council of Italy, Via Marzolo 1, 35131, Padova, Italy
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12
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Imamura T, Kelz MB. Alluring Potential to Accelerate Emergence and Ameliorate Opioid-induced Respiratory Depression without Antagonizing Analgesia: Danavorexton Enters the Anesthetic Landscape. Anesthesiology 2025; 142:589-592. [PMID: 40067034 DOI: 10.1097/aln.0000000000005389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/01/2025]
Affiliation(s)
- Toshihiro Imamura
- Department of Medicine, Division of Sleep Medicine, Department of Anesthesiology and Critical Care, Chronobiology and Sleep Institute, and Center for Neuroscience of Unconsciousness and Reanimation Research Alliance, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania; Division of Pulmonary and Sleep Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Max B Kelz
- Department of Anesthesiology and Critical Care, Chronobiology and Sleep Institute, Center for Neuroscience of Unconsciousness and Reanimation Research Alliance, and Mahoney Institute of Neuroscience University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania
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13
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Rose L, Zahid AN, Piilgaard L, Egebjerg C, Sørensen FL, Andersen M, Radovanovic T, Tsopanidou A, Bastianini S, Berteotti C, Lo Martire V, Borsa M, Tisdale RK, Sun Y, Nedergaard M, Silvani A, Zoccoli G, Adamantidis A, Kilduff TS, Sakai N, Nishino S, Arthaud S, Peyron C, Fort P, Mørup M, Mignot E, Kornum BR. Probability estimation of narcolepsy type 1 in DTA mice using unlabeled EEG and EMG data. SLEEP ADVANCES : A JOURNAL OF THE SLEEP RESEARCH SOCIETY 2025; 6:zpaf025. [PMID: 40521226 PMCID: PMC12163710 DOI: 10.1093/sleepadvances/zpaf025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 04/05/2025] [Indexed: 06/18/2025]
Abstract
The manual evaluation of mouse sleep studies is labor-intensive and time-consuming. Although several approaches for automatic sleep stage classification have been proposed, no automatic pipeline for detecting a specific mouse phenotype has yet been developed. Here, we present a fully automated pipeline for estimating the probability of Narcolepsy Type 1 (NT1) in the hypocretin-tTA;TetO-Diphteria toxin A (DTA) mouse model using unlabeled electroencephalographic (EEG) and electromyographic (EMG) data. The pipeline is divided into three modules: (1) automatic sleep stage classification, (2) feature extraction, and (3) phenotype classification. We trained two automatic sleep stage classifiers, UsleepEEG and UsleepEMG, using data from 83 wild-type (WT) mice. We next computed features such as EEG spectral power bands, EMG root mean square, and bout metrics from 11 WT and 19 DTA mice. The features were used to train an L1-penalized logistic regression classifier in a Leave-One-Subject-Out approach, achieving an accuracy of 97%. Finally, we validated the pipeline in a held-out dataset of EEG/EMG recordings at four different timepoints during disease development in seven DTA mice, finding that the pipeline captured disease progression in all mice. While our pipeline generalizes well to data from other laboratories, it is sensitive to artifacts, which should be considered in its application. With this study, we present a pipeline that facilitates a fast assessment of NT1 probability in the DTA model and thus can accelerate large-scale evaluations of NT1 treatments.
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Affiliation(s)
- Laura Rose
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Alexander Neergaard Zahid
- Department of Applied Mathematics and Computer Science, Technical University of Denmark, Kgs. Lyngby, Denmark
| | - Louise Piilgaard
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Christine Egebjerg
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Frederikke Lynge Sørensen
- Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, University of Copenhagen, Copenhagen, Denmark
| | - Mie Andersen
- Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, University of Copenhagen, Copenhagen, Denmark
| | - Tessa Radovanovic
- Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, University of Copenhagen, Copenhagen, Denmark
| | - Anastasia Tsopanidou
- Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, University of Copenhagen, Copenhagen, Denmark
| | - Stefano Bastianini
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Chiara Berteotti
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Viviana Lo Martire
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Micaela Borsa
- Zentrum für Experimentelle Neurologie, Department of Neurology, University Hospital Bern, Bern, Switzerland
- Department of Biomedical Research, University of Bern, Bern, Switzerland
| | - Ryan K Tisdale
- Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA, USA
| | - Yu Sun
- Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA, USA
| | - Maiken Nedergaard
- Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, University of Copenhagen, Copenhagen, Denmark
| | - Alessandro Silvani
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Giovanna Zoccoli
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Antoine Adamantidis
- Zentrum für Experimentelle Neurologie, Department of Neurology, University Hospital Bern, Bern, Switzerland
- Department of Biomedical Research, University of Bern, Bern, Switzerland
| | - Thomas S Kilduff
- Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA, USA
| | - Noriaki Sakai
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Seiji Nishino
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Sébastien Arthaud
- Center for Neuroscience Research in Lyon (CRNL), SLEEP Team, Université de Lyon, Lyon, France
| | - Christelle Peyron
- Center for Neuroscience Research in Lyon (CRNL), SLEEP Team, Université de Lyon, Lyon, France
| | - Patrice Fort
- Center for Neuroscience Research in Lyon (CRNL), SLEEP Team, Université de Lyon, Lyon, France
| | - Morten Mørup
- Department of Applied Mathematics and Computer Science, Technical University of Denmark, Kgs. Lyngby, Denmark
| | - Emmanuel Mignot
- Center for Narcolepsy, Department of Psychiatry, Stanford University School of Medicine, Stanford, CA, USA
| | - Birgitte Rahbek Kornum
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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14
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Duske J, D'Souza N, Mayer D, Dieterich DC, Fendt M. Orexinergic modulation of chronic jet lag-induced deficits in mouse cognitive flexibility. Neuropsychopharmacology 2025; 50:762-771. [PMID: 39478089 PMCID: PMC11914050 DOI: 10.1038/s41386-024-02017-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 10/16/2024] [Accepted: 10/18/2024] [Indexed: 03/19/2025]
Abstract
Cognitive flexibility and working memory are important executive functions mediated by the prefrontal cortex and can be impaired by circadian rhythm disturbances such as chronic jet lag (CJL) or shift work. In the present study, we used mice to investigate whether (1) simulated CJL impairs cognitive flexibility, (2) the orexin system is involved in such impairment, and (3) nasal administration of orexin A is able to reverse CJL-induced deficits in cognitive flexibility and working memory. Mice were exposed to either standard light-dark conditions or simulated CJL consisting of series of advance time shifts. Experiment (1) investigated the effects of a mild CJL protocol on cognitive flexibility using the attentional set shifting task. Experiment (2) used a stronger CJL protocol and examined CJL effects on the orexin system utilizing c-Fos and orexin immunohistochemistry. Experiment (3) tested whether nasal orexin application can rescue CJL-induced deficits in cognitive flexibility and working memory, the latter by measuring spontaneous alternation in the Y-maze. The present data show that CJL (1) impairs cognitive flexibility and (2) reduces the activity of orexin neurons in the lateral hypothalamus. (3) Nasal administration of orexin A rescued CJL-induced deficits in working memory and cognitive flexibility. These findings suggest that executive function impairments by circadian rhythm disturbances such as CJL are caused by dysregulation of orexinergic input to the prefrontal cortex. Compensation of decreased orexinergic input by nasal administration of orexin A could be a potential therapy for CJL- or shift work-induced human deficits in executive functions.
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Affiliation(s)
- Julius Duske
- Institute for Pharmacology and Toxicology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany
| | - Nicole D'Souza
- Institute for Pharmacology and Toxicology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany
- Institute of Neurophysiology, Goethe University, Frankfurt, Germany
| | - Dana Mayer
- Institute for Pharmacology and Toxicology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany
| | - Daniela C Dieterich
- Institute for Pharmacology and Toxicology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany
- Center of Behavioural Brain Sciences, Otto-von-Guericke University, Magdeburg, Germany
| | - Markus Fendt
- Institute for Pharmacology and Toxicology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
- Center of Behavioural Brain Sciences, Otto-von-Guericke University, Magdeburg, Germany.
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15
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Bastianini S, Alvente S, Berteotti C, Lo Martire V, Matteoli G, Miglioranza E, Silvani A, Zoccoli G. Ageing-related modification of sleep and breathing in orexin-knockout narcoleptic mice. J Sleep Res 2025; 34:e14287. [PMID: 39032099 PMCID: PMC11911059 DOI: 10.1111/jsr.14287] [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: 12/05/2023] [Revised: 05/27/2024] [Accepted: 07/08/2024] [Indexed: 07/22/2024]
Abstract
Narcolepsy type-1 (NT1) is a lifelong sleep disease, characterised by impairment of the orexinergic system, with a typical onset during adolescence and young adulthood. Since the wake-sleep cycle physiologically changes with ageing, this study aims to compare sleep patterns between orexin-knockout (KO) and wild type (WT) control mice at different ages. Four groups of age-matched female KO and WT mice (16 weeks of age: 8 KO-YO and 9 WT-YO mice; 87 weeks of age: 13 KO-OLD and 12 WT-OLD mice) were implanted with electrodes for discriminating wakefulness, rapid-eye-movement sleep (REMS), and non-REMS (NREMS). Mice were recorded for 48 h in their home cages and for 7 more hours into a plethysmographic chamber to characterise their sleep-breathing pattern. Regardless of orexin deficiency, OLD mice spent less time awake and had fragmentation of this behavioural state showing more bouts of shorter length than YO mice. OLD mice also had more NREMS bouts and less frequent NREMS apneas than YO mice. Regardless of age, KO mice showed cataplexy-like episodes and shorter REMS latency than WT controls and had a faster breathing rate and an increased minute ventilation during REMS. KO mice also had more wakefulness, NREMS and REMS bouts, and a shorter mean length of wakefulness bouts than WT controls. Our experiment indicated that the lack of orexins as well as ageing importantly modulate the sleep and breathing phenotype in mice. The narcoleptic phenotype caused by orexin deficiency in female mice was substantially preserved with ageing.
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Affiliation(s)
- Stefano Bastianini
- Laboratory of Physiological Regulation in Sleeping Mice (PRISM), Department of Biomedical and Neuromotor SciencesAlma Mater Studiorum – University of BolognaBolognaItaly
| | - Sara Alvente
- Laboratory of Physiological Regulation in Sleeping Mice (PRISM), Department of Biomedical and Neuromotor SciencesAlma Mater Studiorum – University of BolognaBolognaItaly
| | - Chiara Berteotti
- Laboratory of Physiological Regulation in Sleeping Mice (PRISM), Department of Biomedical and Neuromotor SciencesAlma Mater Studiorum – University of BolognaBolognaItaly
| | - Viviana Lo Martire
- Laboratory of Physiological Regulation in Sleeping Mice (PRISM), Department of Biomedical and Neuromotor SciencesAlma Mater Studiorum – University of BolognaBolognaItaly
| | - Gabriele Matteoli
- Laboratory of Physiological Regulation in Sleeping Mice (PRISM), Department of Biomedical and Neuromotor SciencesAlma Mater Studiorum – University of BolognaBolognaItaly
| | - Elena Miglioranza
- Laboratory of Physiological Regulation in Sleeping Mice (PRISM), Department of Biomedical and Neuromotor SciencesAlma Mater Studiorum – University of BolognaBolognaItaly
| | - Alessandro Silvani
- Laboratory of Physiological Regulation in Sleeping Mice (PRISM), Department of Biomedical and Neuromotor SciencesAlma Mater Studiorum – University of BolognaBolognaItaly
| | - Giovanna Zoccoli
- Laboratory of Physiological Regulation in Sleeping Mice (PRISM), Department of Biomedical and Neuromotor SciencesAlma Mater Studiorum – University of BolognaBolognaItaly
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16
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Shinozawa T, Miyamoto K, Baker KS, Faber SC, Flores R, Uetrecht J, von Hehn C, Yukawa T, Tohyama K, Kadali H, von Grotthuss M, Sudo Y, Smith EN, Diogo D, Zhu AZX, Dragan Y, Cebers G, Wagoner MP. TAK-994 mechanistic investigation into drug-induced liver injury. Toxicol Sci 2025; 204:143-153. [PMID: 39786842 PMCID: PMC11939078 DOI: 10.1093/toxsci/kfaf003] [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] [Indexed: 01/12/2025] Open
Abstract
The frequency of drug-induced liver injury (DILI) in clinical trials remains a challenge for drug developers despite advances in human hepatotoxicity models and improvements in reducing liver-related attrition in preclinical species. TAK-994, an oral orexin receptor 2 agonist, was withdrawn from phase II clinical trials due to the appearance of severe DILI. Here, we investigate the likely mechanism of TAK-994 DILI in hepatic cell culture systems examined cytotoxicity, mitochondrial toxicity, impact on drug transporter proteins, and covalent binding. Hepatic liabilities were absent in rat and nonhuman primate safety studies, however, murine studies initiated during clinical trials revealed hepatic single-cell necrosis following cytochrome P450 induction at clinically relevant doses. Hepatic cell culture experiments uncovered wide margins to known mechanisms of intrinsic DILI, including cytotoxicity (>100× Cmax/IC50), mitochondrial toxicity (>100× Cmax/IC50), and bile salt efflux pump inhibition (>20× Css, avg/IC50). A potential covalent binding liability was uncovered with TAK-994 following hepatic metabolism consistent with idiosyncratic DILI and the delayed-onset clinical toxicity. Although idiosyncratic DILI is challenging to detect preclinically, reductions in total daily dose and covalent binding can reduce the covalent body binding burden and, subsequently, the clinical incidence of idiosyncratic DILI.
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Affiliation(s)
| | - Kazumasa Miyamoto
- Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan
| | - Kevin S Baker
- Takeda Development Center Americas, Inc, Cambridge, MA 02139, United States
| | - Samantha C Faber
- Takeda Development Center Americas, Inc, San Diego, CA 92121, United States
| | | | - Jack Uetrecht
- Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 3M2, Canada
| | - Christian von Hehn
- Takeda Development Center Americas, Inc, Cambridge, MA 02139, United States
| | - Tomoya Yukawa
- Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan
| | - Kimio Tohyama
- Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan
| | - Harisha Kadali
- Takeda Development Center Americas, Inc, Cambridge, MA 02139, United States
| | | | - Yusuke Sudo
- Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan
| | - Erin N Smith
- Takeda Development Center Americas, Inc, San Diego, CA 92121, United States
| | - Dorothée Diogo
- Takeda Development Center Americas, Inc, Cambridge, MA 02139, United States
| | - Andy Z X Zhu
- Takeda Development Center Americas, Inc, Cambridge, MA 02139, United States
| | - Yvonne Dragan
- Takeda Development Center Americas, Inc, Cambridge, MA 02139, United States
| | - Gvido Cebers
- Takeda Development Center Americas, Inc, Cambridge, MA 02139, United States
| | - Matthew P Wagoner
- Takeda Development Center Americas, Inc, Cambridge, MA 02139, United States
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17
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Chaki S. Orexin receptors: possible therapeutic targets for psychiatric disorders. Psychopharmacology (Berl) 2025:10.1007/s00213-025-06767-1. [PMID: 40153060 DOI: 10.1007/s00213-025-06767-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 02/24/2025] [Indexed: 03/30/2025]
Abstract
RATIONALE Orexins, comprising orexin-A and orexin-B, are neuropeptides with extensive projections throughout the central nervous system. They are implicated in a variety of physiological processes through their receptors, orexin type 1 (OX1) and orexin type 2 (OX2) receptors. Among the physiological functions of orexins, their role in sleep/wake regulation has garnered significant attention. Consequently, three orexin receptor antagonists that block both OX1 and OX2 receptors (dual orexin receptor antagonist; DORA) are available on the market for the treatment of insomnia. Additionally, another DORA, vornorexant, has been submitted for approval. OBJECTIVE Beyond sleep disorders, the orexin system is deeply implicated in the pathophysiology of several psychiatric disorders, including depression, anxiety, and substance use disorders. RESULTS Accumulating evidence indicates that orexin receptor antagonists improve behavioral abnormalities that mimic certain psychiatric disorders in animal models and are effective in treating these disorders or their symptoms in humans. Moreover, orexin receptor antagonists are expected not only to alleviate core symptoms of psychiatric disorders but also to improve sleep disturbances, which are often comorbid with these conditions. CONCLUSION Drug discovery and development targeting orexin receptors should provide novel therapeutic options for the treatment of psychiatric disorders.
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Affiliation(s)
- Shigeyuki Chaki
- Taisho Pharmaceutical Co., Ltd, Toshima-Ku, Tokyo, 170-8633, Japan.
- Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan.
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18
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Zhuang C, Yan H, Lu J, Zhou Y, Liu Y, Shi G, Li Y. Compensatory enhancement of orexinergic system functionality induced by amyloid-β protein: a neuroprotective response in Alzheimer's disease. Front Physiol 2025; 16:1529981. [PMID: 40196718 PMCID: PMC11973307 DOI: 10.3389/fphys.2025.1529981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 03/05/2025] [Indexed: 04/09/2025] Open
Abstract
Background Amyloid-β protein (Aβ) accumulation is a defining characteristic of Alzheimer's disease (AD), resulting in neurodegeneration and a decline in cognitive function. Given orexin's well-documented role in enhancing memory and cognition, this study investigates its potential to regulate Aβ-induced neurotoxicity, offering new perspectives into AD management. Methods This paper simulated Aβ accumulation in the hippocampus of AD patients by administering Aβ1-42 oligomers into the bilateral hippocampal dentate gyrus of ICR mice. Inflammatory cytokines (IL-6, TNF-α) and orexin-A levels were measured by ELISA. Additionally, the excitability of orexinergic neurons was assessed by IHC targeting c-Fos expression. These methodologies evaluated the Aβ-induced neuroinflammation, orexinergic system functionality, and dexamethasone's (Dex) effects on these processes. Results Injection of Aβ1-42 oligomer resulted in elevated levels of IL-6, TNF-α, and orexin-A in the hippocampus, as well as increased excitability of orexinergic neurons in the lateral hypothalamus (LH). Dex treatment reduced neuroinflammation, causing a reduction in orexin-A levels and the excitability of orexinergic neurons. Conclusion Aβ-induced neuroinflammation is accompanied by enhanced levels of orexin-A and orexinergic neuron excitability. These findings suggest that the enhanced functionality of the orexinergic system may become a compensatory neuroprotective mechanism to counteract neuroinflammation and enhance cognitive function.
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Affiliation(s)
- Chenyu Zhuang
- Medical College, Yangzhou University, Yangzhou, China
| | - Hengyu Yan
- Medical College, Yangzhou University, Yangzhou, China
| | - Jiayu Lu
- Medical College, Yangzhou University, Yangzhou, China
| | - Yifan Zhou
- Medical College, Yangzhou University, Yangzhou, China
| | - Yanqing Liu
- Medical College, Yangzhou University, Yangzhou, China
- The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou, China
| | - Guoshan Shi
- Department of Basic Medical Sciences, Guizhou University of Chinese Medicine, Guiyang, China
| | - Yan Li
- Medical College, Yangzhou University, Yangzhou, China
- The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou, China
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, Yangzhou, China
- Department of Traditional Chinese Medicine, Affiliated Hospital of Yangzhou University, Yangzhou, China
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19
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Berry EA, Huhulea EN, Ishibashi M, McGregor R, Siegel JM, Leonard CS. Chronic but not acute morphine exposure reversibly impairs spike generation and repetitive firing in a functionally distinct subpopulation of orexin neurons. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.20.644444. [PMID: 40196653 PMCID: PMC11974729 DOI: 10.1101/2025.03.20.644444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/09/2025]
Abstract
Orexin (hypocretin) neuropeptides regulate numerous essential functions including sleep/wake state stability and reward processing. Orexin synthesizing neurons respond to drug cues and undergo structural changes following persistent drug exposure. Post-mortem brains from opioid users, and opioid-treated rodents have orexin somata that become ~20 % smaller and ~50% more numerous and are postulated to promote hyper-motivation for drug-seeking though increased orexin release. Biophysical considerations suggest that decreased soma size should increase cellular excitability, however the impact of chronic opioids on firing ability, which drives peptide release, has not been explored. To test this, we assessed the intrinsic electrophysiological properties of orexin neurons by whole-cell recordings in slices from male orexin-EGFP mice treated by daily morphine or saline injections for two weeks. Paradoxically, we found that while daily morphine decreased average soma size, it impaired excitability in a subpopulation of orexin neurons identified by electrophysiological criteria as "H-type", while entirely sparing "D-type" neurons. This impairment was manifest by smaller, broader action potentials, variable firing and a downscaling of firing gain. These adaptations required more than a single morphine dose and recovered, along with soma size, after four weeks of passive withdrawal. Taken together, these observations indicate that daily opioid exposure differentially impacts H-type orexin neurons and predicts that the ability of these neurons to encode synaptic inputs into spike trains and to release neuropeptides becomes impaired in conjunction with opioid dependence.
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Affiliation(s)
| | - Ellen N. Huhulea
- Department of Physiology, New York Medical College, Valhalla, NY, USA
| | - Masaru Ishibashi
- Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Ronald McGregor
- Neuropsychiatric Institute, University of California, Los Angeles, CA and Veterans Administration, Greater Los Angeles Healthcare System, Los Angeles, CA, USA
| | - Jerome M. Siegel
- Neuropsychiatric Institute, University of California, Los Angeles, CA and Veterans Administration, Greater Los Angeles Healthcare System, Los Angeles, CA, USA
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20
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Wang W, Zhao L, He Z, Zhao Y, Jiang G, Gong C, Zhang Y, Yu J, Liang T, Guo L. Decoding Multifaceted Roles of Sleep-Related Genes as Molecular Bridges in Chronic Disease Pathogenesis. Int J Mol Sci 2025; 26:2872. [PMID: 40243466 PMCID: PMC11988575 DOI: 10.3390/ijms26072872] [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: 01/27/2025] [Revised: 03/01/2025] [Accepted: 03/19/2025] [Indexed: 04/18/2025] Open
Abstract
Sleep is a fundamental process essential for all organisms. Sleep deprivation can lead to significant detrimental effects, contributing to various physiological disorders and elevating the risk of several diseases. Investigating the relationship between sleep and human diseases offers valuable insights into the molecular mechanisms governing sleep regulation, potentially guiding the development of more effective treatments for sleep disorders and associated diseases. This study explored the roles of sleep-related genes in biological processes and their associations with chronic diseases, mainly including neurological, metabolic, cardiovascular diseases, and cancer. Additionally, an analysis on the sleep-related genes was also performed to understand the potential role in tumorigenesis. This review aims to enhance the understanding of the link between sleep-related genes and chronic diseases, contributing to the development of novel therapeutic approaches targeting sleep and circadian rhythm-related chronic diseases.
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Affiliation(s)
- Wenyuan Wang
- State Key Laboratory of Flexible Electronics (LoFE) & Institute of Advanced Materials (IAM), School of Chemistry and Life Sciences, Nanjing University of Posts & Telecommunications, Nanjing 210023, China; (W.W.); (L.Z.); (Z.H.); (Y.Z.); (C.G.); (Y.Z.)
| | - Linjie Zhao
- State Key Laboratory of Flexible Electronics (LoFE) & Institute of Advanced Materials (IAM), School of Chemistry and Life Sciences, Nanjing University of Posts & Telecommunications, Nanjing 210023, China; (W.W.); (L.Z.); (Z.H.); (Y.Z.); (C.G.); (Y.Z.)
| | - Zhiheng He
- State Key Laboratory of Flexible Electronics (LoFE) & Institute of Advanced Materials (IAM), School of Chemistry and Life Sciences, Nanjing University of Posts & Telecommunications, Nanjing 210023, China; (W.W.); (L.Z.); (Z.H.); (Y.Z.); (C.G.); (Y.Z.)
| | - Yang Zhao
- State Key Laboratory of Flexible Electronics (LoFE) & Institute of Advanced Materials (IAM), School of Chemistry and Life Sciences, Nanjing University of Posts & Telecommunications, Nanjing 210023, China; (W.W.); (L.Z.); (Z.H.); (Y.Z.); (C.G.); (Y.Z.)
| | - Guijie Jiang
- School of Life Science, Nanjing Normal University, Nanjing 210023, China;
| | - Chengjun Gong
- State Key Laboratory of Flexible Electronics (LoFE) & Institute of Advanced Materials (IAM), School of Chemistry and Life Sciences, Nanjing University of Posts & Telecommunications, Nanjing 210023, China; (W.W.); (L.Z.); (Z.H.); (Y.Z.); (C.G.); (Y.Z.)
| | - Yan Zhang
- State Key Laboratory of Flexible Electronics (LoFE) & Institute of Advanced Materials (IAM), School of Chemistry and Life Sciences, Nanjing University of Posts & Telecommunications, Nanjing 210023, China; (W.W.); (L.Z.); (Z.H.); (Y.Z.); (C.G.); (Y.Z.)
| | - Jiafeng Yu
- Shandong Provincial Key Laboratory of Biophysics, Institute of Biophysics, Dezhou University, Dezhou 253023, China;
| | - Tingming Liang
- School of Life Science, Nanjing Normal University, Nanjing 210023, China;
| | - Li Guo
- State Key Laboratory of Flexible Electronics (LoFE) & Institute of Advanced Materials (IAM), School of Chemistry and Life Sciences, Nanjing University of Posts & Telecommunications, Nanjing 210023, China; (W.W.); (L.Z.); (Z.H.); (Y.Z.); (C.G.); (Y.Z.)
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21
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Priebe T, Subkhangulova A, Toonen RF, Verhage M. Neuronal network inactivity potentiates neuropeptide release from mouse cortical neurons. eNeuro 2025; 12:ENEURO.0555-24.2024. [PMID: 40101959 PMCID: PMC11964291 DOI: 10.1523/eneuro.0555-24.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 12/20/2024] [Accepted: 12/24/2024] [Indexed: 03/20/2025] Open
Abstract
Neurons adapt to chronic activity changes by modifying synaptic properties, including neurotransmitter release. However, whether neuropeptide release via dense core vesicles (DCVs)-a distinct regulated secretory pathway-undergoes similar adaptation remains unclear. Here, we demonstrate that 24-hour action potential blockade leads to significant DCV accumulation in primary mouse cortical neurons of both sexes. Reactivation with action potential trains induced enhanced Ca2+-influx and 700% more DCV exocytosis compared to control neurons. Notably, total DCV cargo protein levels were unchanged, while mRNA levels of corresponding genes were reduced. Blocking neurotransmitter release with Tetanus toxin induced DCV accumulation, similar to that induced by network silencing with TTX. Hence, chronic network silencing triggers increased DCV accumulation due to reduced exocytosis during silencing. These accumulated DCVs can be released upon reactivation resulting in a massive potentiation of DCV exocytosis, possibly contributing to homeostatic mechanisms.Significance Statement This study addresses an unexplored area - how dense core vesicles (DCVs) exocytosis adapts to chronic changes in activity - and demonstrates accumulation of DCVs and a massive upregulation of DCV exocytosis in response to 24h inactivity. The potentiation of neuropeptide release might contribute to homeostatic regulation of neuronal networks in the brain.
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Affiliation(s)
- Theresa Priebe
- Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neurosciences Campus Amsterdam, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Aygul Subkhangulova
- Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neurosciences Campus Amsterdam, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Ruud F Toonen
- Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neurosciences Campus Amsterdam, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Matthijs Verhage
- Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neurosciences Campus Amsterdam, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands;
- Department of Human Genetics, Center for Neurogenomics and Cognitive Research, Neurosciences Campus Amsterdam, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands
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22
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Li N, Huang L, Zhang B, Zhu W, Dai W, Li S, Xu H. The mechanism of different orexin/hypocretin neuronal projections in wakefulness and sleep. Brain Res 2025; 1850:149408. [PMID: 39706239 DOI: 10.1016/j.brainres.2024.149408] [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: 06/30/2024] [Revised: 12/07/2024] [Accepted: 12/17/2024] [Indexed: 12/23/2024]
Abstract
Since the discovery of orexin/hypocretin, numerous studies have accumulated evidence demonstrating its key role in various aspects of neuromodulation, including addiction, motivation, and arousal. This paper focuses on the projection of orexin neurons to specific target brain regions through distinct neural pathways to regulate sleep and arousal. We provide a detailed discussion of the projection mechanisms of orexin neurons to downstream neurons, particularly emphasizing their activation of monoaminergic and cholinergic neurons associated with arousal. Additionally, we briefly explore the immune response and inflammatory factors linked to the loss of orexin neurons. Our findings underscore the significance of understanding specific neural projections in the generation and maintenance of arousal, which could guide advancements in neuroscience and lead to new therapeutic opportunities for treating insomnia or narcolepsy.
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Affiliation(s)
- Nanxi Li
- Geriatric Department, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - Lishan Huang
- Geriatric Department, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - Bin Zhang
- Geriatric Department, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - Wenwen Zhu
- Geriatric Department, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - Wenbin Dai
- Geriatric Department, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - Sen Li
- Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University.
| | - Houping Xu
- Geriatric Department, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China.
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23
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Kryger MH, Thomas RJ. The Past and Future of Sleep Medicine. Sleep Med Clin 2025; 20:1-17. [PMID: 39894590 DOI: 10.1016/j.jsmc.2024.10.012] [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] [Indexed: 02/04/2025]
Abstract
The past of sleep medicine is rich with seminal discoveries, from the recognition of clinical syndromes to measurement of sleep itself to classic and novel therapeutics. Advances in neurobiology have mapped a number of sleep circuits, described the central and peripheral circadian system, and identified the cause of narcolepsy with cataplexy. Sleep apnea endotypes and phenotypes now have established clinical relevance, though treatment implications are a work in progress. Artificial intelligence will continue to change sleep medicine in a number of domains from aiding scoring to health outcome predictions. There is a large gap between the known science and clinical translational.
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Affiliation(s)
- Meir H Kryger
- Yale University School of Medicine, 300 Cedar Street, New Haven, CT, USA
| | - Robert Joseph Thomas
- Harvard Medical School / Department of Medicine, Division of Pulmonary, Critical Care & Sleep Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.
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24
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Stapel B, Alvarenga ME, Kahl KG. Pharmacological and psychological approaches to insomnia treatment in cardiac patients: a narrative literature review. Front Psychiatry 2025; 16:1490585. [PMID: 40018681 PMCID: PMC11865029 DOI: 10.3389/fpsyt.2025.1490585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 01/24/2025] [Indexed: 03/01/2025] Open
Abstract
Sleep disorders are highly prevalent in the general population and are considered a major public health issue. Insomnia constitutes the most frequent sleep disorder in healthy individuals and has been shown to be even more frequent in patients with physical illnesses including cardiovascular diseases. Inadequate sleep quality and short sleep duration, independent of underlying causes, have been linked to the development and progression of cardiometabolic disorders. Additionally, insomnia has been found to be associated with adverse outcome measures, including daytime sleepiness, fatigue, decreased self-reported physical functioning, lower exercise capacity, poor health related quality of life, depressive symptoms, higher rates of hospitalization and increased mortality in patients with cardiovascular diseases. Against this background, comparatively little information is available in the literature regarding the treatment of chronic insomnia in cardiac patient populations. While guidelines for the general population suggest cognitive behavioral therapy for insomnia as a first-line treatment option and preliminary evidence suggests this treatment to be beneficial in cardiac patients with insomnia symptoms, it is often limited by availability and possibly the clinician's poor understanding of sleep issues in cardiac patients. Therefore, pharmacologic treatment remains an important option indicated by the high number of hypnotic drug prescriptions in the general population and in patients with cardiovascular disorders. In this narrative review of the literature, we summarize treatment options for chronic insomnia based on clinical guidelines for the general population and highlight necessary considerations for the treatment of patients with cardiovascular diseases.
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Affiliation(s)
- Britta Stapel
- Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany
| | - Marlies E. Alvarenga
- Institute of Health and Wellbeing, Federation University Australia and Victorian Heart Institute, Melbourne, VIC, Australia
| | - Kai G. Kahl
- Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany
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25
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Wu Y, Bhat NR, Liu M. Reduction of orexin-expressing neurons and a unique sleep phenotype in the Tg-SwDI mouse model of Alzheimer's disease. Front Aging Neurosci 2025; 17:1529769. [PMID: 39968126 PMCID: PMC11832706 DOI: 10.3389/fnagi.2025.1529769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Accepted: 01/20/2025] [Indexed: 02/20/2025] Open
Abstract
Sleep disturbances are common in Alzheimer's disease (AD) and AD-related dementia (ADRD). We performed a sleep study on Tg-SwDI mice, a cerebral amyloid angiopathy (CAA) model, and age-matched wild-type (WT) control mice. The results showed that at 12 months of age, the hemizygous Tg-SwDI mice spent significantly more time in non-rapid eye movement (NREM) sleep (44.6 ± 2.4% in Tg-SwDI versus 35.9 ± 2.5% in WT) and had a much shorter average length of wake bout during the dark (active) phase (148.5 ± 8.7 s in the Tg-SwDI versus 203.6 ± 13.0 s in WT). Histological analysis revealed stark decreases of orexin immunoreactive (orexin-IR) neuron number and soma size in these Tg-SwDI mice (cell number: 2187 ± 97.1 in Tg-SwDI versus 3318 ± 137.9 in WT. soma size: 109.1 ± 8.1 μm2 in Tg-SwDI versus 160.4 ± 6.6 μm2 in WT), while the number and size of melanin-concentrating hormone (MCH) immunoreactive (MCH-IR) neurons remained unchanged (cell number: 4256 ± 273.3 in Tg-SwDI versus 4494 ± 326.8 in WT. soma size: 220.1 ± 13.6 μm2 in Tg-SwDI versus 202.0 ± 7.8 μm2 in WT). The apoptotic cell death marker cleaved caspase-3 immunoreactive (Caspase-3-IR) percentage in orexin-IR neurons was significantly higher in Tg-SwDI mice than in WT controls. This selective loss of orexin-IR neurons could be associated with the abnormal sleep phenotype in these Tg-SwDI mice. Further studies are needed to determine the cause of the selective death of orexin-IR cells and relevant effects on cognition impairments in this mouse model of microvascular amyloidosis.
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Affiliation(s)
- Yan Wu
- Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, United States
| | - Narayan R. Bhat
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC, United States
| | - Meng Liu
- Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, United States
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26
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Yasugaki S, Okamura H, Kaneko A, Hayashi Y. Bidirectional relationship between sleep and depression. Neurosci Res 2025; 211:57-64. [PMID: 37116584 DOI: 10.1016/j.neures.2023.04.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 03/01/2023] [Accepted: 04/18/2023] [Indexed: 04/30/2023]
Abstract
Patients with depression almost inevitably exhibit abnormalities in sleep, such as shortened latency to enter rapid eye movement (REM) sleep and decrease in electroencephalogram delta power during non-REM sleep. Insufficient sleep can be stressful, and the accumulation of stress leads to the deterioration of mental health and contributes to the development of psychiatric disorders. Thus, it is likely that depression and sleep are bidirectionally related, i.e. development of depression contributes to sleep disturbances and vice versa. However, the relation between depression and sleep seems complicated. For example, acute sleep deprivation can paradoxically improve depressive symptoms. Thus, it is difficult to conclude whether sleep has beneficial or harmful effects in patients with depression. How antidepressants affect sleep in patients with depression might provide clues to understanding the effects of sleep, but caution is required considering that antidepressants have diverse effects other than sleep. Recent animal studies support the bidirectional relation between depression and sleep, and animal models of depression are expected to be beneficial for the identification of neuronal circuits that connect stress, sleep, and depression. This review provides a comprehensive overview regarding the current knowledge of the relationship between depression and sleep.
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Affiliation(s)
- Shinnosuke Yasugaki
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; Japan Society for the Promotion of Science (JSPS), Tokyo 102-0083, Japan
| | - Hibiki Okamura
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Japan Society for the Promotion of Science (JSPS), Tokyo 102-0083, Japan; Program in Humanics, School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Ami Kaneko
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Program in Humanics, School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Yu Hayashi
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
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27
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Hung CJ, Tsai CT, Rahaman SM, Yamanaka A, Seo W, Yokoyama T, Sakamoto M, Ono D. Neuropeptidergic Input from the Lateral Hypothalamus to the Suprachiasmatic Nucleus Alters the Circadian Period in Mice. J Neurosci 2025; 45:e0351242024. [PMID: 39622648 PMCID: PMC11756623 DOI: 10.1523/jneurosci.0351-24.2024] [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: 02/22/2024] [Revised: 10/09/2024] [Accepted: 11/19/2024] [Indexed: 01/24/2025] Open
Abstract
In mammals, the central circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus, which transmits circadian information to other brain regions and regulates the timing of sleep and wakefulness. Neurons in the lateral hypothalamus (LH), particularly those producing melanin-concentrating hormone (MCH) and orexin, are key regulators of sleep and wakefulness. Although the SCN receives nonphotic input from other brain regions, the mechanisms of functional input from the LH to the SCN remain poorly understood. Here, we show that orexin and MCH peptides influence the circadian period within the SCN of both sexes. When these neurons are ablated, the circadian behavioral rhythms are lengthened under constant darkness. Using anterograde and retrograde tracing, we found that orexin and MCH neurons project to the SCN. Furthermore, the application of these peptides to cultured SCN slices shortened circadian rhythms and reduced intracellular cAMP levels. Additionally, pharmacological reduction of intracellular cAMP levels similarly shortened the circadian period in SCN slices. These findings suggest that orexin and MCH peptides from the LH contribute to the modulation of the circadian period in the SCN.
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Affiliation(s)
- Chi Jung Hung
- Stress Recognition and Response, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan
| | - Chang-Ting Tsai
- Stress Recognition and Response, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan
| | - Sheikh Mizanur Rahaman
- Stress Recognition and Response, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan
| | - Akihiro Yamanaka
- Chinese Institute for Brain Research (CIBR), Beijing 102206, China
| | - Wooseok Seo
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Tatsushi Yokoyama
- Department of Brain Development and Regeneration, Graduate School of Biostudies, Kyoto University, Kyoto 606-8507, Japan
| | - Masayuki Sakamoto
- Department of Brain Development and Regeneration, Graduate School of Biostudies, Kyoto University, Kyoto 606-8507, Japan
| | - Daisuke Ono
- Stress Recognition and Response, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan
- Department of Neural Regulation, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
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28
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Yu J, Liu H, Gao R, Wang TV, Li C, Liu Y, Yang L, Xu Y, Cui Y, Jia C, Huang J, Chen PR, Rao Y. Calcineurin: An essential regulator of sleep revealed by biochemical, chemical biological, and genetic approaches. Cell Chem Biol 2025; 32:157-173.e7. [PMID: 39740665 DOI: 10.1016/j.chembiol.2024.12.003] [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: 07/09/2024] [Revised: 10/29/2024] [Accepted: 12/09/2024] [Indexed: 01/02/2025]
Abstract
Research into mechanisms underlying sleep traditionally relies on electrophysiology and genetics. Because sleep can only be measured on whole animals by behavioral observations and physical means, no sleep research was initiated by biochemical and chemical biological approaches. We used phosphorylation sites of kinases important for sleep as targets for biochemical and chemical biological approaches. Sleep was increased in mice carrying a threonine-to-alanine substitution at residue T469 of salt-inducible kinase 3 (SIK3). Our biochemical purification and photo-crosslinking revealed calcineurin (CaN) dephosphorylation, both in vitro and in vivo, of SIK3 at T469 and S551, but not T221. Knocking down CaN regulatory subunit reduced daily sleep by more than 5 h, exceeding all known mouse mutants. Our work uncovered a critical physiological role for CaN in sleep and pioneered biochemical purification and chemical biology as effective approaches to study sleep.
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Affiliation(s)
- Jianjun Yu
- Laboratory of Neurochemical Biology, Peking-Tsinghua Center for Life Sciences, Peking-Tsinghua-NIBS (PTN) Graduate Program, School of Life Sciences, Peking University, Beijing, China; Chinese Institute for Brain Research (CIBR), Beijing, China; Department of Chemical Biology, College of Chemistry and Chemical Engineering; School of Pharmaceutical Sciences, PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China; Chinese Institutes for Medical Research (CIMR), Beijing, China; Capital Medical University, Beijing, China
| | - Huijie Liu
- Laboratory of Neurochemical Biology, Peking-Tsinghua Center for Life Sciences, Peking-Tsinghua-NIBS (PTN) Graduate Program, School of Life Sciences, Peking University, Beijing, China; Chinese Institute for Brain Research (CIBR), Beijing, China; Department of Chemical Biology, College of Chemistry and Chemical Engineering; School of Pharmaceutical Sciences, PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China; Chinese Institutes for Medical Research (CIMR), Beijing, China; Capital Medical University, Beijing, China
| | - Rui Gao
- Laboratory of Neurochemical Biology, Peking-Tsinghua Center for Life Sciences, Peking-Tsinghua-NIBS (PTN) Graduate Program, School of Life Sciences, Peking University, Beijing, China; Chinese Institute for Brain Research (CIBR), Beijing, China; Department of Chemical Biology, College of Chemistry and Chemical Engineering; School of Pharmaceutical Sciences, PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China
| | - Tao V Wang
- Laboratory of Neurochemical Biology, Peking-Tsinghua Center for Life Sciences, Peking-Tsinghua-NIBS (PTN) Graduate Program, School of Life Sciences, Peking University, Beijing, China; Chinese Institute for Brain Research (CIBR), Beijing, China; Department of Chemical Biology, College of Chemistry and Chemical Engineering; School of Pharmaceutical Sciences, PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China; Chinese Institutes for Medical Research (CIMR), Beijing, China; Capital Medical University, Beijing, China
| | - Chenggang Li
- Laboratory of Neurochemical Biology, Peking-Tsinghua Center for Life Sciences, Peking-Tsinghua-NIBS (PTN) Graduate Program, School of Life Sciences, Peking University, Beijing, China; Chinese Institute for Brain Research (CIBR), Beijing, China; Department of Chemical Biology, College of Chemistry and Chemical Engineering; School of Pharmaceutical Sciences, PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China; Chinese Institutes for Medical Research (CIMR), Beijing, China; Capital Medical University, Beijing, China
| | - Yuxiang Liu
- Laboratory of Neurochemical Biology, Peking-Tsinghua Center for Life Sciences, Peking-Tsinghua-NIBS (PTN) Graduate Program, School of Life Sciences, Peking University, Beijing, China; Chinese Institute for Brain Research (CIBR), Beijing, China; Department of Chemical Biology, College of Chemistry and Chemical Engineering; School of Pharmaceutical Sciences, PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China; Chinese Institutes for Medical Research (CIMR), Beijing, China; Capital Medical University, Beijing, China
| | - Lu Yang
- Laboratory of Neurochemical Biology, Peking-Tsinghua Center for Life Sciences, Peking-Tsinghua-NIBS (PTN) Graduate Program, School of Life Sciences, Peking University, Beijing, China; Chinese Institute for Brain Research (CIBR), Beijing, China; Department of Chemical Biology, College of Chemistry and Chemical Engineering; School of Pharmaceutical Sciences, PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China; Chinese Institutes for Medical Research (CIMR), Beijing, China; Capital Medical University, Beijing, China
| | - Ying Xu
- National Center for Protein Sciences Phoenix, Beijing, China
| | - Yunfeng Cui
- Chinese Institutes for Medical Research (CIMR), Beijing, China; Capital Medical University, Beijing, China
| | - Chenxi Jia
- National Center for Protein Sciences Phoenix, Beijing, China
| | - Juan Huang
- Laboratory of Neurochemical Biology, Peking-Tsinghua Center for Life Sciences, Peking-Tsinghua-NIBS (PTN) Graduate Program, School of Life Sciences, Peking University, Beijing, China; Chinese Institute for Brain Research (CIBR), Beijing, China; Department of Chemical Biology, College of Chemistry and Chemical Engineering; School of Pharmaceutical Sciences, PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China
| | - Peng R Chen
- Laboratory of Neurochemical Biology, Peking-Tsinghua Center for Life Sciences, Peking-Tsinghua-NIBS (PTN) Graduate Program, School of Life Sciences, Peking University, Beijing, China; Chinese Institute for Brain Research (CIBR), Beijing, China; Department of Chemical Biology, College of Chemistry and Chemical Engineering; School of Pharmaceutical Sciences, PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China
| | - Yi Rao
- Laboratory of Neurochemical Biology, Peking-Tsinghua Center for Life Sciences, Peking-Tsinghua-NIBS (PTN) Graduate Program, School of Life Sciences, Peking University, Beijing, China; Chinese Institute for Brain Research (CIBR), Beijing, China; Department of Chemical Biology, College of Chemistry and Chemical Engineering; School of Pharmaceutical Sciences, PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China; Chinese Institutes for Medical Research (CIMR), Beijing, China; Capital Medical University, Beijing, China.
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29
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Naganuma F, Girgin B, Agu ABS, Hirano K, Nakamura T, Yanai K, Vetrivelan R, Mochizuki T, Yanagisawa M, Yoshikawa T. Pharmacological inhibition of histamine N-methyltransferase extends wakefulness and suppresses cataplexy in a mouse model of narcolepsy. Sleep 2025; 48:zsae244. [PMID: 39441998 DOI: 10.1093/sleep/zsae244] [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: 06/22/2024] [Revised: 09/13/2024] [Indexed: 10/25/2024] Open
Abstract
Histamine, a neurotransmitter, plays a predominant role in maintaining wakefulness. Furthermore, our previous studies showed that histamine N-methyltransferase (HNMT), a histamine-metabolizing enzyme, is important for regulating brain histamine concentration. However, the effects of pharmacological HNMT inhibition on mouse behavior, including the sleep-wake cycle and cataplexy, in a mouse model of narcolepsy have not yet been investigated. In the present study, we investigated the effects of metoprine, an HNMT inhibitor with high blood-brain barrier permeability, in wild-type (WT) and orexin-deficient (OxKO) narcoleptic mice. Metoprine increased brain histamine concentration in a time- and dose-dependent manner without affecting peripheral histamine concentrations. Behavioral tests showed that metoprine increased locomotor activity in both novel and familiar environments, but did not alter anxiety-like behavior. Sleep analysis showed that metoprine increased wakefulness and decreased non-rapid eye movement (NREM) sleep through the activation of the histamine H1 receptor (H1R) in WT mice. In contrast, the reduction of rapid eye movement (REM) sleep by metoprine occurred independent of H1R. In OxKO mice, metoprine was found to prolong wakefulness and robustly suppress cataplexy. In addition, metoprine has a greater therapeutic effect on cataplexy than pitolisant, which induces histamine release in the brain and has been approved for patients with narcolepsy. These data demonstrate that HNMT inhibition has a strong effect on wakefulness, demonstrating therapeutic potential against cataplexy in narcolepsy.
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Affiliation(s)
- Fumito Naganuma
- Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Hokkaido, Japan
- Department of Pharmacology, Tohoku University Graduate School of Medicine, Miyagi, Japan
- Division of Pharmacology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Miyagi, Japan
| | - Birkan Girgin
- Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Hokkaido, Japan
| | - Anne Bernadette S Agu
- Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Hokkaido, Japan
| | - Kyosuke Hirano
- Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Hokkaido, Japan
| | - Tadaho Nakamura
- Division of Pharmacology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Miyagi, Japan
- Division of Bioregulatory Pharmacology, Department of Pharmacology, Iwate Medical University, Iwate, Japan
| | - Kazuhiko Yanai
- Cyclotron and Radioisotope Center, Tohoku University, Miyagi, Japan
| | - Ramalingam Vetrivelan
- Department of Neurology, Beth Israel Deaconess Medical Center and Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA
| | - Takatoshi Mochizuki
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Ibaraki, Japan
| | - Masashi Yanagisawa
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Ibaraki, Japan
| | - Takeo Yoshikawa
- Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Hokkaido, Japan
- Department of Pharmacology, Tohoku University Graduate School of Medicine, Miyagi, Japan
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30
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Luo PX, Trainor BC. Hypocretin modulation of behavioral coping strategies for social stress. Neuroscience 2025; 564:126-134. [PMID: 39547335 DOI: 10.1016/j.neuroscience.2024.11.031] [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: 08/21/2024] [Revised: 10/30/2024] [Accepted: 11/11/2024] [Indexed: 11/17/2024]
Abstract
Best known for promoting wakefulness and arousal, the neuropeptide hypocretin (Hcrt) also plays an important role in mediating stress responses, including social stress. However, central and systemic manipulation of the Hcrt system has produced diverse behavioral outcomes in animal models. In this review, we first focus on studies where similar manipulations of the Hcrt system led to divergent coping behaviors. We hypothesize that Hcrt differentially facilitates active and passive coping behaviors in response to social stress by acting in different brain regions and on different cell types. We then focus on region and cell type-specific effects of Hcrt in the ventral pallidum, lateral habenula, ventral tegmental area, nucleus accumbens, amygdala, and bed nucleus of the stria terminalis. Overall, the evidence suggests that rather than enhancing or inhibiting behavioral responses to social stress, Hcrt may signal the heightened arousal associated with stressful contexts. The resulting behavioral effects depend on which circuits Hcrt release occurs in and which receptor types are activated. Further study is needed to determine how and why circuit specific activation of Hcrt neurons occurs.
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Affiliation(s)
- Pei X Luo
- Department of Psychology, University of California - Davis, Davis, CA 95616, USA
| | - Brian C Trainor
- Department of Psychology, University of California - Davis, Davis, CA 95616, USA.
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31
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Yang W, Shi J, Li C, Yang J, Yu J, Huang J, Rao Y. Calcium/calmodulin-dependent protein kinase II α and β differentially regulate mammalian sleep. Commun Biol 2025; 8:11. [PMID: 39757286 DOI: 10.1038/s42003-024-07449-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 12/30/2024] [Indexed: 01/07/2025] Open
Abstract
While sleep is important, our understanding of its molecular mechanisms is limited. Over the last two decades, protein kinases including Ca2+/calmodulin-dependent protein kinase II (CaMKII) α and β have been implicated in sleep regulation. Of all the known mouse genetic mutants, the biggest changes in sleep is reported to be observed in adult mice with sgRNAs for Camk2b injected into their embryos: sleep is reduced by approximately 120 min (mins) over 24 h (hrs). We have reexamined the sleep phenotype in mice with either Camk2a or Camk2b gene knocked-out by conventional gene targetting. While the basal sleep is reduced in Camk2a knockout mice, it remains unaltered in Camk2b mutants. Knockout of either Camk2a or Camk2b reduces sleep rebound after deprivation, indicating their roles in sleep homeostasis. These results indicate the involvement of CaMKIIα in both basal sleep and sleep homeostasis while CaMKIIβ is mainly required physiologically for sleep homeostasis, serving as a stimulus for rigorous studies in the future.
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Affiliation(s)
- Weiwen Yang
- Chinese Institute of Brain Research, Beijing (CIBR), and Chinese Institutes for Medical Research, Beijing (CIMR), Capital Medical University, Beijing, China
- Laboratory of Neurochemical Biology, Peking-Tsinghua-NIBS (PTN) Graduate Program, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, PKU-IDG/McGovern Institute for Brain Research, School of Life Sciences; Department of Chemical Biology, College of Chemistry and Chemical Engineering; School of Pharmaceutical Sciences at the Health Sciences Center, Peking University, Beijing, China
| | - Jingyi Shi
- Laboratory of Neurochemical Biology, Peking-Tsinghua-NIBS (PTN) Graduate Program, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, PKU-IDG/McGovern Institute for Brain Research, School of Life Sciences; Department of Chemical Biology, College of Chemistry and Chemical Engineering; School of Pharmaceutical Sciences at the Health Sciences Center, Peking University, Beijing, China
| | - Chenggang Li
- Chinese Institute of Brain Research, Beijing (CIBR), and Chinese Institutes for Medical Research, Beijing (CIMR), Capital Medical University, Beijing, China
- Laboratory of Neurochemical Biology, Peking-Tsinghua-NIBS (PTN) Graduate Program, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, PKU-IDG/McGovern Institute for Brain Research, School of Life Sciences; Department of Chemical Biology, College of Chemistry and Chemical Engineering; School of Pharmaceutical Sciences at the Health Sciences Center, Peking University, Beijing, China
| | - Jingqun Yang
- Chinese Institute of Brain Research, Beijing (CIBR), and Chinese Institutes for Medical Research, Beijing (CIMR), Capital Medical University, Beijing, China
| | - Jianjun Yu
- Chinese Institute of Brain Research, Beijing (CIBR), and Chinese Institutes for Medical Research, Beijing (CIMR), Capital Medical University, Beijing, China
- Laboratory of Neurochemical Biology, Peking-Tsinghua-NIBS (PTN) Graduate Program, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, PKU-IDG/McGovern Institute for Brain Research, School of Life Sciences; Department of Chemical Biology, College of Chemistry and Chemical Engineering; School of Pharmaceutical Sciences at the Health Sciences Center, Peking University, Beijing, China
| | - Juan Huang
- Chinese Institute of Brain Research, Beijing (CIBR), and Chinese Institutes for Medical Research, Beijing (CIMR), Capital Medical University, Beijing, China
- Laboratory of Neurochemical Biology, Peking-Tsinghua-NIBS (PTN) Graduate Program, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, PKU-IDG/McGovern Institute for Brain Research, School of Life Sciences; Department of Chemical Biology, College of Chemistry and Chemical Engineering; School of Pharmaceutical Sciences at the Health Sciences Center, Peking University, Beijing, China
| | - Yi Rao
- Chinese Institute of Brain Research, Beijing (CIBR), and Chinese Institutes for Medical Research, Beijing (CIMR), Capital Medical University, Beijing, China.
- Laboratory of Neurochemical Biology, Peking-Tsinghua-NIBS (PTN) Graduate Program, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, PKU-IDG/McGovern Institute for Brain Research, School of Life Sciences; Department of Chemical Biology, College of Chemistry and Chemical Engineering; School of Pharmaceutical Sciences at the Health Sciences Center, Peking University, Beijing, China.
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32
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Park HJ, Rhie SJ, Jeong W, Kim KR, Rheu KM, Lee BJ, Shim I. GABALAGEN Alleviates Stress-Induced Sleep Disorders in Rats. Biomedicines 2024; 12:2905. [PMID: 39767811 PMCID: PMC11672954 DOI: 10.3390/biomedicines12122905] [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: 11/04/2024] [Revised: 12/11/2024] [Accepted: 12/13/2024] [Indexed: 01/11/2025] Open
Abstract
(1) Background: Gamma-aminobutyric acid (GABA) is an amino acid and the primary inhibitory neurotransmitter in the brain. GABA has been shown to reduce stress and promote sleep. GABALAGEN (GBL) is the product of fermented fish collagen by Lactobacillus brevis BJ20 and Lactobacillus plantarum BJ21, naturally enriched with GABA through the fermentation process and characterized by low molecular weight. (2) Methods: The present study evaluated the GABAA affinity of GBL through receptor binding assay. The sedative effects of GBL were investigated through electroencephalography (EEG) analysis in an animal model of electro foot shock (EFS) stress-induced sleep disorder, and then we examined the expression of orexin and the GABAA receptor in the brain region using immunohistochemistry and an enzyme-linked immunosorbent assay (ELISA). (3) Results: We found that on the binding assay, GBL displayed high affinity to the GABAA receptor. Also, after treatment with GBL, the percentage of the total time in rapid eye movement (REM) and non-rapid eye movement (NREM) sleep was significantly and dose-dependently increased in EFS-induced rats. Consistent with behavioral results, the GBL-treated groups showed that the expression of GABAA receptor immune-positive cells in the VLPO was markedly and dose-dependently increased. Also, the GBL-treated groups showed that the expression of the orexin-A level in LH was significantly decreased. (4) Conclusions: GBL showed efficacy and potential to be used as an anti-stress therapy to treat sleep deprivation through the stimulation of GABAA receptors and the consequent inhibition of orexin activity.
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Affiliation(s)
- Hyun-Jung Park
- Department of Food Science and Biotechnology, Kyonggi University, Suwon 16227, Republic of Korea;
| | - Sung Ja Rhie
- Department of Beauty Design, Halla University, Wonju 26404, Republic of Korea;
| | - Woojin Jeong
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (W.J.); (K.-R.K.)
| | - Kyu-Ri Kim
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (W.J.); (K.-R.K.)
| | - Kyoung-Min Rheu
- Marine Bioprocess Co., Ltd., Busan 47281, Republic of Korea; (K.-M.R.); (B.-J.L.)
| | - Bae-Jin Lee
- Marine Bioprocess Co., Ltd., Busan 47281, Republic of Korea; (K.-M.R.); (B.-J.L.)
| | - Insop Shim
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (W.J.); (K.-R.K.)
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Jászberényi M, Thurzó B, Jayakumar AR, Schally AV. The Aggravating Role of Failing Neuropeptide Networks in the Development of Sporadic Alzheimer's Disease. Int J Mol Sci 2024; 25:13086. [PMID: 39684795 DOI: 10.3390/ijms252313086] [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: 10/12/2024] [Revised: 11/27/2024] [Accepted: 12/02/2024] [Indexed: 12/18/2024] Open
Abstract
Alzheimer's disease imposes an increasing burden on aging Western societies. The disorder most frequently appears in its sporadic form, which can be caused by environmental and polygenic factors or monogenic conditions of incomplete penetrance. According to the authors, in the majority of cases, Alzheimer's disease represents an aggravated form of the natural aging of the central nervous system. It can be characterized by the decreased elimination of amyloid β1-42 and the concomitant accumulation of degradation-resistant amyloid plaques. In the present paper, the dysfunction of neuropeptide regulators, which contributes to the pathophysiologic acceleration of senile dementia, is reviewed. However, in the present review, exclusively those neuropeptides or neuropeptide families are scrutinized, and the authors' investigations into their physiologic and pathophysiologic activities have made significant contributions to the literature. Therefore, the pathophysiologic role of orexins, neuromedins, RFamides, corticotrope-releasing hormone family, growth hormone-releasing hormone, gonadotropin-releasing hormone, ghrelin, apelin, and natriuretic peptides are discussed in detail. Finally, the therapeutic potential of neuropeptide antagonists and agonists in the inhibition of disease progression is discussed here.
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Affiliation(s)
- Miklós Jászberényi
- Department of Pathophysiology, University of Szeged, P.O. Box 427, H-6701 Szeged, Hungary
| | - Balázs Thurzó
- Department of Pathophysiology, University of Szeged, P.O. Box 427, H-6701 Szeged, Hungary
- Emergency Patient Care Unit, Albert Szent-Györgyi Health Centre, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary
| | - Arumugam R Jayakumar
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Andrew V Schally
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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Vringer M, Zhou J, Gool JK, Bijlenga D, Lammers GJ, Fronczek R, Schinkelshoek MS. Recent insights into the pathophysiology of narcolepsy type 1. Sleep Med Rev 2024; 78:101993. [PMID: 39241492 DOI: 10.1016/j.smrv.2024.101993] [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: 12/22/2023] [Revised: 08/12/2024] [Accepted: 08/13/2024] [Indexed: 09/09/2024]
Abstract
Narcolepsy type 1 (NT1) is a sleep-wake disorder in which people typically experience excessive daytime sleepiness, cataplexy and other sleep-wake disturbances impairing daily life activities. NT1 symptoms are due to hypocretin deficiency. The cause for the observed hypocretin deficiency remains unclear, even though the most likely hypothesis is that this is due to an auto-immune process. The search for autoantibodies and autoreactive T-cells has not yet produced conclusive evidence for or against the auto-immune hypothesis. Other mechanisms, such as reduced corticotrophin-releasing hormone production in the paraventricular nucleus have recently been suggested. There is no reversive treatment, and the therapeutic approach is symptomatic. Early diagnosis and appropriate NT1 treatment is essential, especially in children to prevent impaired cognitive, emotional and social development. Hypocretin receptor agonists have been designed to replace the attenuated hypocretin signalling. Pre-clinical and clinical trials have shown encouraging initial results. A better understanding of NT1 pathophysiology may contribute to faster diagnosis or treatments, which may cure or prevent it.
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Affiliation(s)
- Marieke Vringer
- Stichting Epilepsie Instellingen Nederland (SEIN), Sleep-Wake center, Heemstede, the Netherlands; Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Jingru Zhou
- Stichting Epilepsie Instellingen Nederland (SEIN), Sleep-Wake center, Heemstede, the Netherlands; Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Jari K Gool
- Stichting Epilepsie Instellingen Nederland (SEIN), Sleep-Wake center, Heemstede, the Netherlands; Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands; Department of Anatomy & Neurosciences, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; Compulsivity, Impulsivity and Attention, Amsterdam Neuroscience, Amsterdam, the Netherlands
| | - Denise Bijlenga
- Stichting Epilepsie Instellingen Nederland (SEIN), Sleep-Wake center, Heemstede, the Netherlands; Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Gert Jan Lammers
- Stichting Epilepsie Instellingen Nederland (SEIN), Sleep-Wake center, Heemstede, the Netherlands; Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Rolf Fronczek
- Stichting Epilepsie Instellingen Nederland (SEIN), Sleep-Wake center, Heemstede, the Netherlands; Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Mink S Schinkelshoek
- Stichting Epilepsie Instellingen Nederland (SEIN), Sleep-Wake center, Heemstede, the Netherlands; Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands.
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Amin AM, Hassan A, Khlidj Y, Mansour A, Esawy A, Mohamed RG, Mansour A, Abbas A. Efficacy and safety of sodium oxybate treatment in adults with narcolepsy and cataplexy: a systematic review and meta-analysis. Sleep Breath 2024; 29:12. [PMID: 39601985 DOI: 10.1007/s11325-024-03163-5] [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: 07/05/2024] [Revised: 11/08/2024] [Accepted: 11/15/2024] [Indexed: 11/29/2024]
Abstract
BACKGROUND AND PURPOSE Narcolepsy is a chronic illness characterized by excessive daytime sleepiness and cataplexy. Recently, sodium oxybate (SXB) has been the only effective drug in treating multiple symptoms of narcolepsy. Our study aims to assess the effectiveness and safety of SXB in treating narcolepsy. METHOD We searched four databases for eligible studies. Our primary outcome was to investigate the effectiveness of SXB through symptom improvement. For the secondary outcome, we assess its safety through the reported adverse events. RESULT Five RCTs were included. The SXB group had significantly improved weekly cataplexy attacks better than the placebo (MD = -5.04, 95% CI [-6.35, -3.72], P < 0.00001), also the improvement in the Maintenance of Wakefulness Test, and ESS was better in the SXB group with (MD = 4.66, 95% CI: [2.24, 7.07], p = 0.0002), (MD = -1.93, 95% CI: [-2.73, -1.13], p < 0.00001) respectively. CGI-I was observed to be significantly better in the SXB group with (RR = 2.15, 95% CI: [1.69, 2.73], p < 0.00001). The weekly cataplexy attack was significantly improved by the doses (4.5, 6, and 9 gm) in comparison with the placebo, with the 9-gm dose having the most beneficial effect. The improvements were significant only in SXB 9 gm in ESS and 6 and 9 gm in CGI-I. CONCLUSION SXB is an effective pharmacological treatment for the management of narcoleptic patients with cataplexy with an acceptable safety profile. Further studies with a large scale are needed to investigate and prove the efficacy and tolerability of SXB.
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Affiliation(s)
- Ahmed Mostafa Amin
- Faculty of Medicine, Al-Azhar University, Cairo, Egypt.
- Medical Research Group of Egypt (MRGE), Negida Academy, Arlington, MA, USA.
| | - Ahmed Hassan
- Department of Cardiology, Suez Medical Complex, Ministry of Health and Population, Suez, Egypt
- Medical Research Group of Egypt (MRGE), Negida Academy, Arlington, MA, USA
| | - Yehya Khlidj
- Faculty of Medicine, University of Algiers 1, Algiers, Algeria
- Medical Research Group of Egypt (MRGE), Negida Academy, Arlington, MA, USA
| | - Ahmed Mansour
- Faculty of Medicine, Al-Azhar University, Cairo, Egypt
- Medical Research Group of Egypt (MRGE), Negida Academy, Arlington, MA, USA
| | - Ahmed Esawy
- Mansoura Manchester Program for Medical Education, Faculty of Medicine, Mansoura University, Mansoura, Egypt
- Medical Research Group of Egypt (MRGE), Negida Academy, Arlington, MA, USA
| | - Rashad G Mohamed
- Mansoura Manchester Program for Medical Education, Faculty of Medicine, Mansoura University, Mansoura, Egypt
- Medical Research Group of Egypt (MRGE), Negida Academy, Arlington, MA, USA
| | - Anas Mansour
- Faculty of Medicine, Al-Azhar University, Cairo, Egypt
- Medical Research Group of Egypt (MRGE), Negida Academy, Arlington, MA, USA
| | - Abdallah Abbas
- Faculty of Medicine, Al-Azhar University, Damietta, Egypt
- Medical Research Group of Egypt (MRGE), Negida Academy, Arlington, MA, USA
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Pandi-Perumal SR, Saravanan KM, Paul S, Chidambaram SB. Harnessing Simple Animal Models to Decode Sleep Mysteries. Mol Biotechnol 2024:10.1007/s12033-024-01318-z. [PMID: 39579174 DOI: 10.1007/s12033-024-01318-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 10/28/2024] [Indexed: 11/25/2024]
Abstract
Whether it involves human subjects or non-human animals, basic, translational, or clinical sleep research poses significant ethical challenges for researchers and ethical committees alike. Sleep research greatly benefits from using diverse animal models, each offering unique insights into sleep control mechanisms. The fruit fly (Drosophila melanogaster) is a superior genetic model due to its quick generation period, large progenies, and rich genetic tools. Its well-characterized genome and ability to respond to hypnotics and stimulants make it an effective tool for studying sleep genetics and physiological foundations. The nematode (Caenorhabditis elegans) has a simpler neural organization and transparent body, allowing researchers to explore molecular underpinnings of sleep control. Vertebrate models, like zebrafish (Danio rerio), provide insights into circadian rhythm regulation, memory consolidation, and drug effects on sleep. Invertebrate models, like California sea hare (Aplysia californica) and Upside-down jellyfish (Cassiopea xamachana), have simpler nervous systems and behave similarly to humans, allowing for the examination of sleep principles without logistical and ethical challenges. Combining vertebrate and invertebrate animal models offers a comprehensive approach to studying sleep, improving our understanding of sleep regulation and potentially leading to new drug discovery processes for sleep disorders and related illnesses.
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Affiliation(s)
- Seithikurippu R Pandi-Perumal
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, 570015, Karnataka, India
- Centre for Research and Development, Chandigarh University, Mohali, 140413, Punjab, India
- Division of Research and Development, Lovely Professional University, Phagwara, 144411, Punjab, India
| | | | - Sayan Paul
- Department of Biochemistry & Molecular Biology, The University of Texas Medical Branch at Galveston, Galveston, TX, 77555, USA
| | - Saravana Babu Chidambaram
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, 570015, Karnataka, India.
- Centre for Experimental Pharmacology and Toxicology, Central Animal Facility, JSS Academy of Higher Education & Research, Mysuru, 570015, Karnataka, India.
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Tavares MR, Dos Santos WO, Furigo IC, List EO, Kopchick JJ, Donato J. Growth Hormone Receptor in Lateral Hypothalamic Neurons Is Required for Increased Food-Seeking Behavior during Food Restriction in Male Mice. J Neurosci 2024; 44:e1761232024. [PMID: 39358046 PMCID: PMC11580784 DOI: 10.1523/jneurosci.1761-23.2024] [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: 09/18/2023] [Revised: 09/20/2024] [Accepted: 09/26/2024] [Indexed: 10/04/2024] Open
Abstract
Growth hormone (GH) action in the brain regulates neuroendocrine axes, energy and glucose homeostasis, and several neurological functions. The lateral hypothalamic area (LHA) contains numerous neurons that respond to a systemic GH injection by expressing the phosphorylated STAT5, a GH receptor (GHR) signaling marker. However, the potential role of GHR signaling in the LHA is unknown. In this study, we demonstrated that ∼70% of orexin- and leptin receptor (LepR)-expressing neurons in the LHA are responsive to GH. Male mice carrying inactivation of the Ghr gene in the LHA were generated via bilateral injections of an adeno-associated virus. In ad libitum-fed mice, GHR ablation in LHA neurons did not significantly change energy and glucose homeostasis. Subsequently, mice were subjected to 5 d of 40% food restriction. Food restriction decreased body weight, energy expenditure, and carbohydrate oxidation. These effects were similarly observed in control and LHAΔGHR mice. While food-deprived control mice progressively increased ambulatory/exploratory activity and food-seeking behavior, LHAΔGHR mice did not show hyperactivity induced by food restriction. GHR ablation in the LHA reduced the percentage of orexin neurons expressing c-Fos during food restriction. Additionally, an acute GH injection increased the expression of c-Fos in LHAORX neurons. Inactivation of Ghr in LepR-expressing cells did not prevent hyperactivity in food-deprived mice, whereas whole-brain Ghr knock-out mice showed reduced ambulatory activity during food restriction. Our findings indicate that GHR signaling in the LHA regulates the activity of orexin neurons and is necessary to increase food-seeking behavior in food-deprived male mice.
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Affiliation(s)
- Mariana R Tavares
- Department of Physiology and Biophysics, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo 05508-000, Sao Paulo, Brazil
| | - Willian O Dos Santos
- Department of Physiology and Biophysics, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo 05508-000, Sao Paulo, Brazil
| | - Isadora C Furigo
- Department of Physiology and Biophysics, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo 05508-000, Sao Paulo, Brazil
- Centre for Health and Life Sciences, Coventry University, Coventry CV1 2DS, Warwickshire, United Kingdom
| | - Edward O List
- Edison Biotechnology Institute and Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701
| | - John J Kopchick
- Edison Biotechnology Institute and Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701
| | - Jose Donato
- Department of Physiology and Biophysics, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo 05508-000, Sao Paulo, Brazil
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38
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Grenot M, Roman A, Villalba M, Morel AL, Fort P, Arthaud S, Libourel PA, Peyron C. Major alteration of motor control during rapid eye movements sleep in mice models of sleep disorders. Sleep 2024; 47:zsae178. [PMID: 39121093 DOI: 10.1093/sleep/zsae178] [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: 02/06/2024] [Revised: 07/16/2024] [Indexed: 08/11/2024] Open
Abstract
Alteration of motor control during rapid eye movements (REM) sleep has been extensively described in sleep disorders, in particular in isolated REM sleep behavior disorder (iRBD) and narcolepsy type 1 (NT1). NT1 is caused by the loss of orexin/hypocretin (ORX) neurons. Unlike in iRBD, the RBD comorbid symptoms of NT1 are not associated with alpha-synucleinopathies. To determine whether the chronic absence of ORX neuropeptides is sufficient to induce RBD symptoms, we analyzed during REM sleep the EMG signal of the prepro-hypocretin knockout mice (ORX-/-), a recognized mouse model of NT1. Then, we evaluated the severity of motor alterations by comparing the EMG data of ORX-/- mice to those of mice with a targeted suppression of the sublaterodorsal glutamatergic neurotransmission, a recognized rodent model of iRBD. We found a significant alteration of tonic and phasic components of EMG during REM sleep in ORX-/- mice, with more phasic events and more REM sleep episodes without atonia compared to the control wild-type mice. However, these phasic events were fewer, shorter, and less complex in ORX-/- mice compared to the RBD-like ORX-/- mice. We thus show that ORX deficiency, as seen in NT1, is sufficient to impair muscle atonia during REM sleep with a moderate severity of alteration as compared to isolated RBD mice. As described in NT1 patients, we report a major interindividual variability in the severity and frequency of RBD symptoms in ORX-deficient mice.
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Affiliation(s)
- Maxime Grenot
- Université Claude Bernard Lyon 1
- CNRS, INSERM, Centre de Recherche en Neurosciences de Lyon CRNL UMR5292, U1028, SLEEP team, Bron, France
| | - Alexis Roman
- Université Claude Bernard Lyon 1
- CNRS, INSERM, Centre de Recherche en Neurosciences de Lyon CRNL UMR5292, U1028, SLEEP team, Bron, France
| | - Manon Villalba
- Université Claude Bernard Lyon 1
- CNRS, INSERM, Centre de Recherche en Neurosciences de Lyon CRNL UMR5292, U1028, SLEEP team, Bron, France
| | - Anne-Laure Morel
- Université Claude Bernard Lyon 1
- CNRS, INSERM, Centre de Recherche en Neurosciences de Lyon CRNL UMR5292, U1028, SLEEP team, Bron, France
| | - Patrice Fort
- Université Claude Bernard Lyon 1
- CNRS, INSERM, Centre de Recherche en Neurosciences de Lyon CRNL UMR5292, U1028, SLEEP team, Bron, France
| | - Sébastien Arthaud
- Université Claude Bernard Lyon 1
- CNRS, INSERM, Centre de Recherche en Neurosciences de Lyon CRNL UMR5292, U1028, SLEEP team, Bron, France
| | - Paul-Antoine Libourel
- Université Claude Bernard Lyon 1
- CNRS, INSERM, Centre de Recherche en Neurosciences de Lyon CRNL UMR5292, U1028, SLEEP team, Bron, France
| | - Christelle Peyron
- Université Claude Bernard Lyon 1
- CNRS, INSERM, Centre de Recherche en Neurosciences de Lyon CRNL UMR5292, U1028, SLEEP team, Bron, France
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Flores-Ramirez FJ, Illenberger JM, Martin-Fardon R. Interaction between corticotropin-releasing factor, orexin, and dynorphin in the infralimbic cortex may mediate exacerbated alcohol-seeking behavior. Neurobiol Stress 2024; 33:100695. [PMID: 39640001 PMCID: PMC11617300 DOI: 10.1016/j.ynstr.2024.100695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 10/28/2024] [Accepted: 11/18/2024] [Indexed: 12/07/2024] Open
Abstract
A major challenge for the treatment of alcohol use disorder (AUD) is relapse to alcohol use, even after protracted periods of self-imposed abstinence. Stress significantly contributes to the chronic relapsing nature of AUD, given its long-lasting ability to elicit intense craving and precipitate relapse. As individuals transition to alcohol dependence, compensatory allostatic mechanisms result in insults to hypothalamic-pituitary-adrenal axis function, mediated by corticotropin-releasing factor (CRF), which is subsequently hypothesized to alter brain reward pathways, influence affect, elicit craving, and ultimately perpetuate problematic drinking and relapse vulnerability. Orexin (OX; also called hypocretin) plays a well-established role in regulating diverse physiological processes, including stress, and has been shown to interact with CRF. Interestingly, most hypothalamic cells that express Ox mRNA also express Pdyn mRNA. Both dynorphin and OX are located in the same synaptic vesicles, and they are co-released. The infralimbic cortex (IL) of the medial prefrontal cortex (mPFC) has emerged as being directly involved in the compulsive nature of alcohol consumption during dependence. The IL is a CRF-rich region that receives OX projections from the hypothalamus and where OX receptor mRNA has been detected. Although not thoroughly understood, anatomical and behavioral pharmacology data suggest that CRF, OX, and dynorphin may interact, particularly in the IL, and that functional interactions between these three systems in the IL may be critical for the etiology and pervasiveness of compulsive alcohol seeking in dependent subjects that may render them vulnerable to relapse. The present review presents evidence of the role of the IL in AUD and discusses functional interactions between CRF, OX, and dynorphin in this structure and how they are related to exacerbated alcohol drinking and seeking.
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Affiliation(s)
- Francisco J. Flores-Ramirez
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
- Department of Psychology, California State University, San Marcos, CA, USA
| | | | - Rémi Martin-Fardon
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
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Xiang X, Wang F, Chen C, Guan Z, Zhou W. Orexinergic projections to substantia innominata mediate arousal and analgesia. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.29.620973. [PMID: 39554139 PMCID: PMC11565723 DOI: 10.1101/2024.10.29.620973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
Understanding neural circuits involved in anesthesia is crucial for improving its safety and efficacy. Hypothalamic orexin neurons (LHA OX ), projecting broadly, are essential in regulating arousal and pain. However, the precise targets remain unclear. Here we investigated the orexin projections to the substantia innominata (SI). Combining optogenetics, fiber photometry, and EEG/EMG allowed us to manipulate orexin activities, while simultaneously recording local ligand release and global cortical activities during anesthesia. Brain slice electrophysiology revealed the synaptic connections in the SI, while RNAscope was employed to examine the distribution of orexin receptors and downstream neuronal types. Presynaptic vesicles were identified in the orexin terminals in the SI, where 49.16% of cells expressed OX2R and 6.8% expressed OX1R. Orexin release in the SI was reversibly suppressed by isoflurane. Optogenetic activation of the LHA OX →SI circuit significantly increased orexin release and promoted arousal from various anesthesia stages, including reanimation during 0.75% isoflurane (p < 0.0001), prolongation of 3% isoflurane induction (p = 0.0033), and acceleration of emergence from 2% isoflurane (p < 0.0001). Furthermore, activating this circuit induced analgesia to both thermal (p = 0.0074) and inflammatory (p = 0.0127) pain. Patch-clamp recordings revealed that optogenetic activation of orexin terminals in the SI elicited excitatory postsynaptic currents, which were blocked by the OX2R antagonist. SI contains more GABAergic (28.17%) and glutamatergic (11.96%) neurons than cholinergic neurons (4.13%), all of which expressed OX2R. Thus, LHA OX neurons innervate SI neurons to regulate both arousal and pain predominantly through OX2R.
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Kashiwagi M, Beck G, Kanuka M, Arai Y, Tanaka K, Tatsuzawa C, Koga Y, Saito YC, Takagi M, Oishi Y, Sakaguchi M, Baba K, Ikuno M, Yamakado H, Takahashi R, Yanagisawa M, Murayama S, Sakurai T, Sakai K, Nakagawa Y, Watanabe M, Mochizuki H, Hayashi Y. A pontine-medullary loop crucial for REM sleep and its deficit in Parkinson's disease. Cell 2024; 187:6272-6289.e21. [PMID: 39303715 DOI: 10.1016/j.cell.2024.08.046] [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: 03/01/2023] [Revised: 03/22/2024] [Accepted: 08/21/2024] [Indexed: 09/22/2024]
Abstract
Identifying the properties of the rapid eye movement (REM) sleep circuitry and its relation to diseases has been challenging due to the neuronal heterogeneity of the brainstem. Here, we show in mice that neurons in the pontine sublaterodorsal tegmentum (SubLDT) that express corticotropin-releasing hormone-binding protein (Crhbp+ neurons) and project to the medulla promote REM sleep. Within the medullary area receiving projections from Crhbp+ neurons, neurons expressing nitric oxide synthase 1 (Nos1+ neurons) project to the SubLDT and promote REM sleep, suggesting a positively interacting loop between the pons and the medulla operating as a core REM sleep circuit. Nos1+ neurons also project to areas that control wide forebrain activity. Ablating Crhbp+ neurons reduces sleep and impairs REM sleep atonia. In Parkinson's disease patients with REM sleep behavior disorders, CRHBP-immunoreactive neurons are largely reduced and contain pathologic α-synuclein, providing insight into the mechanisms underlying the sleep deficits characterizing this disease.
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Affiliation(s)
- Mitsuaki Kashiwagi
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Goichi Beck
- Department of Neurology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Mika Kanuka
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Yoshifumi Arai
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Kaeko Tanaka
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Chika Tatsuzawa
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Yumiko Koga
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Yuki C Saito
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Marina Takagi
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Yo Oishi
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Masanori Sakaguchi
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Kousuke Baba
- Department of Neurology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Masashi Ikuno
- Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto 605-8507, Japan
| | - Hodaka Yamakado
- Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto 605-8507, Japan
| | - Ryosuke Takahashi
- Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto 605-8507, Japan
| | - Masashi Yanagisawa
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Japan Life Science Center for Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Shigeo Murayama
- Department of Neurology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; Brain Bank for Neurodevelopmental, Neurological and Psychiatric Disorders, Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita, Osaka 565-0871, Japan; Department of Neurology and Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Institute for Geriatrics and Gerontology, Itabashi-Ku, Tokyo 173-0015, Japan
| | - Takeshi Sakurai
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Kazuya Sakai
- Integrative Physiology of the Brain Arousal System, Lyon Neuroscience Research Center, INSERM U1028-CNRS UMR5292, School of Medicine, Claude Bernard University Lyon 1, 69373 Lyon, France
| | - Yoshimi Nakagawa
- Division of Complex Biosystem Research Institute of Natural Medicine, University of Toyama, Toyama, Toyama 930-0194, Japan
| | - Masahiko Watanabe
- Department of Anatomy, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan
| | - Hideki Mochizuki
- Department of Neurology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Yu Hayashi
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
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Naganuma F, Khanday M, Bandaru SS, Hasan W, Hirano K, Yoshikawa T, Vetrivelan R. Regulation of wakefulness by neurotensin neurons in the lateral hypothalamus. Exp Neurol 2024; 383:115035. [PMID: 39481513 DOI: 10.1016/j.expneurol.2024.115035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 10/04/2024] [Accepted: 10/27/2024] [Indexed: 11/02/2024]
Abstract
The lateral hypothalamic region (LH) has been identified as a key region for arousal regulation, yet the specific cell types and underlying mechanisms are not fully understood. While neurons expressing orexins (OX) are considered the primary wake-promoting population in the LH, their loss does not reduce daily wake levels, suggesting the presence of additional wake-promoting populations. In this regard, we recently discovered that a non-OX cell group in the LH, marked by the expression of neurotensin (Nts), could powerfully drive wakefulness. Activation of these NtsLH neurons elicits rapid arousal from non-rapid eye movement (NREM) sleep and produces uninterrupted wakefulness for several hours in mice. However, it remains unknown if these neurons are necessary for spontaneous wakefulness and what their precise role is in the initiation and maintenance of this state. To address these questions, we first examined the activity dynamics of the NtsLH population across sleep-wake behavior using fiber photometry. We find that NtsLH neurons are more active during wakefulness, and their activity increases concurrently with, but does not precede, wake-onset. We then selectively destroyed the NtsLH neurons using a diphtheria-toxin-based conditional ablation method, which significantly reduced wake amounts and mean duration of wake bouts and increased the EEG delta power during wakefulness. These findings demonstrate a crucial role for NtsLH neurons in maintaining normal arousal levels, and their loss may be associated with chronic sleepiness in mice.
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Affiliation(s)
- Fumito Naganuma
- Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, United States of America; Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Mudasir Khanday
- Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, United States of America; Division of Sleep Medicine, Harvard Medical School, Boston, MA, United States of America
| | - Sathyajit Sai Bandaru
- Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, United States of America
| | - Whidul Hasan
- Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, United States of America; Division of Sleep Medicine, Harvard Medical School, Boston, MA, United States of America
| | - Kyosuke Hirano
- Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Takeo Yoshikawa
- Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Ramalingam Vetrivelan
- Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, United States of America; Division of Sleep Medicine, Harvard Medical School, Boston, MA, United States of America.
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Grujic N, Polania R, Burdakov D. Neurobehavioral meaning of pupil size. Neuron 2024; 112:3381-3395. [PMID: 38925124 DOI: 10.1016/j.neuron.2024.05.029] [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: 11/24/2023] [Revised: 03/22/2024] [Accepted: 05/31/2024] [Indexed: 06/28/2024]
Abstract
Pupil size is a widely used metric of brain state. It is one of the few signals originating from the brain that can be readily monitored with low-cost devices in basic science, clinical, and home settings. It is, therefore, important to investigate and generate well-defined theories related to specific interpretations of this metric. What exactly does it tell us about the brain? Pupils constrict in response to light and dilate during darkness, but the brain also controls pupil size irrespective of luminosity. Pupil size fluctuations resulting from ongoing "brain states" are used as a metric of arousal, but what is pupil-linked arousal and how should it be interpreted in neural, cognitive, and computational terms? Here, we discuss some recent findings related to these issues. We identify open questions and propose how to answer them through a combination of well-defined tasks, neurocomputational models, and neurophysiological probing of the interconnected loops of causes and consequences of pupil size.
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Affiliation(s)
- Nikola Grujic
- Neurobehavioural Dynamics Lab, ETH Zürich, Department of Health Sciences and Technology, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland.
| | - Rafael Polania
- Decision Neuroscience Lab, ETH Zürich, Department of Health Sciences and Technology, Winterthurstrasse 190, 8057 Zürich, Switzerland
| | - Denis Burdakov
- Neurobehavioural Dynamics Lab, ETH Zürich, Department of Health Sciences and Technology, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland.
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Hitrec T, Del Vecchio F, Alberti L, Luppi M, Martelli D, Occhinegro A, Piscitiello E, Taddei L, Tupone D, Amici R, Cerri M. Activation of orexin-A (hypocretin-1) receptors in the Raphe Pallidus at different ambient temperatures in the rat: effects on thermoregulation, cardiovascular control, sleep, and feeding behavior. Front Neurosci 2024; 18:1458437. [PMID: 39429700 PMCID: PMC11486763 DOI: 10.3389/fnins.2024.1458437] [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: 07/02/2024] [Accepted: 09/18/2024] [Indexed: 10/22/2024] Open
Abstract
The Raphe Pallidus (RPa) is a brainstem nucleus containing sympathetic premotor neurons that control thermogenesis and modulate cardiovascular function. It receives inputs from various hypothalamic areas, including the Lateral Hypothalamus (LH), a heterogeneous region intricately involved in several autonomic and behavioral functions. A key subpopulation of neurons in the LH expresses orexin/hypocretin, a neuropeptide which is crucially involved in the regulation of the wake-sleep states and feeding behavior. The RPa receives orexinergic projections from the LH and orexinergic signalling in the RPa has been shown to enhance thermogenesis in the anaesthetized rat, but only in the presence of an already existing thermogenic drive, without significantly affecting cardiovascular function. The present work was aimed at exploring the effects on thermoregulation and autonomic function and the possible role in the modulation of the wake-sleep states and feeding behavior of orexin injection in the RPa in the free-behaving rat. In order to assess the influence of an already present thermogenic drive on orexinergic signalling in the RPa, animals were studied at three different ambient temperatures (Ta, 10°C, 24°C, and 32°C). We found that orexin injection into the RPa variably affected the wake-sleep states, autonomic functions, motor activity, and feeding behavior, at the different Tas. In particular, in the first post-injection hour, we observed an increase in wakefulness, which was large at Ta 24°C and Ta 10°C and rather mild at Ta 32°C. Deep brain temperature was increased by orexin injection at Ta 10°C, but not at either Ta 24°C or Ta 32°C. Moreover, an increase in mean arterial blood pressure occurred at Ta 24°C, which was probably masked by the high baseline levels at Ta 10°C and was completely absent at Ta 32°C. Finally, an enhancement in feeding behavior was observed at Ta 24°C and 10°C only. In accordance with what observed in anaesthetized rats, orexinergic signalling in the RPa seems to be ineffective in the absence of any thermogenic drive. Moreover, the effects observed on the wake-sleep states and feeding behavior introduce the RPa as a novel player in the central neural network promoting wakefulness and feeding.
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Affiliation(s)
- Timna Hitrec
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Flavia Del Vecchio
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Luca Alberti
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Marco Luppi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Davide Martelli
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Alessandra Occhinegro
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Emiliana Piscitiello
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Ludovico Taddei
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Domenico Tupone
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
- Department of Neurological Surgery, Oregon Health and Science University, Portland, OR, United States
| | - Roberto Amici
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Matteo Cerri
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
- Italian Institute of Technology (IIT), Genova, Italy
- National Institute of Nuclear Physics of Bologna, Bologna, Italy
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Giatti S, Cioffi L, Diviccaro S, Piazza R, Melcangi RC. Analysis of the finasteride treatment and its withdrawal in the rat hypothalamus and hippocampus at whole-transcriptome level. J Endocrinol Invest 2024; 47:2565-2574. [PMID: 38493246 PMCID: PMC11393021 DOI: 10.1007/s40618-024-02345-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 02/18/2024] [Indexed: 03/18/2024]
Abstract
PURPOSE As reported in patients treated for androgenetic alopecia with finasteride (i.e., a blocker of the enzyme 5 alpha-reductase) and in an animal model, side effects affecting sexual, psychiatric, neurological, and physical domains, may occur during the treatment and persist with drug suspension. The etiopathogenesis of these side effects has been poorly explored. Therefore, we performed a genome-wide analysis of finasteride effects in the brain of adult male rat. METHODS Animals were treated (i.e., for 20 days) with finasteride (1mg/rat/day). 24 h after the last treatment and 1 month after drug suspension, RNA sequencing analysis was performed in hypothalamus and hippocampus. Data were analyzed by differential expression analysis and Gene-Set Enrichment Analyses (GSEA). RESULTS Data obtained after finasteride treatment showed that 186 genes (i.e., 171 up- and 15 downregulated) and 19 (i.e., 17 up- and 2 downregulated) were differentially expressed in the hypothalamus and hippocampus, respectively. Differential expression analysis at the drug withdrawal failed to identify dysregulated genes. Several gene-sets were enriched in these brain areas at both time points. CONCLUSION Some of the genes reported to be differentially expressed (i.e., TTR, DIO2, CLDN1, CLDN2, SLC4A5, KCNE2, CROT, HCRT, MARCKSL1, VGF, IRF2BPL) and GSEA, suggest a potential link with specific side effects previously observed in patients and in the animal model, such as depression, anxiety, disturbance in memory and attention, and sleep disturbance. These data may provide an important background for future experiments aimed at confirming the pathological role of these genes.
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Affiliation(s)
- S Giatti
- Dipartimento di Scienze Farmacologiche e Biomolecolari "Rodolfo Paoletti", Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy
| | - L Cioffi
- Dipartimento di Scienze Farmacologiche e Biomolecolari "Rodolfo Paoletti", Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy
| | - S Diviccaro
- Dipartimento di Scienze Farmacologiche e Biomolecolari "Rodolfo Paoletti", Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy
| | - R Piazza
- Dipartimento di Medicina e Chirurgia, Università di Milano-Bicocca, Milan, Italy
| | - R C Melcangi
- Dipartimento di Scienze Farmacologiche e Biomolecolari "Rodolfo Paoletti", Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy.
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Mori K, Kimura M, Usami E. Short-Term Efficacy and Safety of Suvorexant and Lemborexant: A Retrospective Study. Cureus 2024; 16:e71049. [PMID: 39512953 PMCID: PMC11541064 DOI: 10.7759/cureus.71049] [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] [Accepted: 10/07/2024] [Indexed: 11/15/2024] Open
Abstract
PURPOSE Given the risks of long-term benzodiazepine use, safer alternatives like orexin receptor antagonists (ORAs) are needed for insomnia treatment. This study aims to compare suvorexant and lemborexant, focusing on early-stage sleep duration as an efficacy measure and fall incidence as a safety measure. METHODS We included patients admitted to our hospital between April 1, 2022 and December 31, 2022, who were newly prescribed suvorexant or lemborexant, excluding patients taking other concomitant sleep medications or antipsychotics. Primary and secondary endpoints were sleep duration during the first three days after taking the medications and the incidence of falls, respectively. RESULTS We analyzed data from 48 and 57 patients taking suvorexant and lemborexant, respectively. When compared with that in the pre-treatment period, sleep duration was significantly longer on days 2 and 3 in the suvorexant group, and on all three days in the lemborexant group. On day 1 of drug administration, the lemborexant group had a significantly longer sleep duration than the suvorexant group (5.10 ± 1.84 vs. 5.93 ± 1.90 h, respectively; P = 0.017). Zero (0.0%) and three (5.3%) falls occurred in the suvorexant and lemborexant groups, respectively (P = 0.248). CONCLUSIONS Lemborexant exerted a potent inhibitory effect on orexin 2 receptors, which could explain the longer sleep duration experienced by patients taking this drug on the first day of treatment.
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Affiliation(s)
- Koki Mori
- Pharmacy, Ogaki Municipal Hospital, Ogaki, JPN
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Sahoo P, Sarkar D, Sharma S, Verma A, Naik SK, Prashar V, Parkash J, Singh SK. Knockdown of type 2 orexin receptor in adult mouse testis potentiates testosterone production and germ cell proliferation. Mol Cell Endocrinol 2024; 592:112312. [PMID: 38866320 DOI: 10.1016/j.mce.2024.112312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 06/06/2024] [Accepted: 06/08/2024] [Indexed: 06/14/2024]
Abstract
Orexins (OXs) are neuropeptides which regulate various physiological processes. OXs exist in two different forms, mainly orexin A (OXA) and orexin B (OXB) and their effects are mediated via OX1R and OX2R. Presence of OXB and OX2R in mouse testis is also reported. However, the role of OXB/OX2R in the male gonad remains unexplored. Herein we investigated the role of OXB/OX2R system in testicular physiology under in vivo and ex vivo conditions. Adult mice were given a single dose of bilateral intratesticular injection of siRNA targeting OX2R and were sacrificed 96 h post-injection. OX2R-knockdown potentiated serum and intratesticular testosterone levels with up-regulation in the expressions of major steroidogenic proteins. Germ cell proliferation also increased in siRNA-treated mice. Results of the ex vivo experiment also supported the findings of the in vivo study. In conclusion, OX2R may regulate testosterone production and thereby control the fine-tuning between steroidogenesis and germ cell dynamics.
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Affiliation(s)
- Pratikshya Sahoo
- Department of Zoology, School of Basic Sciences, Central University of Punjab, VPO-Ghudda, Bathinda, 151401, India
| | - Debarshi Sarkar
- Department of Zoology, School of Basic Sciences, Central University of Punjab, VPO-Ghudda, Bathinda, 151401, India.
| | - Shubhangi Sharma
- Department of Zoology, School of Basic Sciences, Central University of Punjab, VPO-Ghudda, Bathinda, 151401, India
| | - Arpit Verma
- Department of Zoology, School of Basic Sciences, Central University of Punjab, VPO-Ghudda, Bathinda, 151401, India
| | - Suraj Kumar Naik
- Department of Zoology, School of Basic Sciences, Central University of Punjab, VPO-Ghudda, Bathinda, 151401, India
| | - Vikash Prashar
- Department of Zoology, School of Basic Sciences, Central University of Punjab, VPO-Ghudda, Bathinda, 151401, India
| | - Jyoti Parkash
- Department of Zoology, School of Basic Sciences, Central University of Punjab, VPO-Ghudda, Bathinda, 151401, India
| | - Shio Kumar Singh
- Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi-221005, India
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48
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Bjorness TE, Greene RW. Orexin-mediated motivated arousal and reward seeking. Peptides 2024; 180:171280. [PMID: 39159833 DOI: 10.1016/j.peptides.2024.171280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Revised: 08/03/2024] [Accepted: 08/05/2024] [Indexed: 08/21/2024]
Abstract
The neuromodulator orexin has been identified as a key factor for motivated arousal including recent evidence that sleep deprivation-induced enhancement of reward behavior is modulated by orexin. While orexin is not necessary for either reward or arousal behavior, orexin neurons' broad projections, ability to sense the internal state of the animal, and high plasticity of signaling in response to natural rewards and drugs of abuse may underlie heightened drug seeking, particularly in a subset of highly motivated reward seekers. As such, orexin receptor antagonists have gained deserved attention for putative use in addiction treatments. Ongoing and future clinical trials are expected to identify individuals most likely to benefit from orexin receptor antagonist treatment to promote abstinence, such as those with concurrent sleep disorders or high craving, while attention to methodological considerations will aid interpretation of the numerous preclinical studies investigating disparate aspects of the role of orexin in reward and arousal.
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Affiliation(s)
- Theresa E Bjorness
- Research Service, VA North Texas Health Care System, Dallas, TX 75126, USA; Departments of Psychiatry University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA.
| | - Robert W Greene
- Departments of Psychiatry University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA; Department of Neuroscience, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA; International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba 305-8577, Japan
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49
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Rahimi S, Joyce L, Fenzl T, Drexel M. Crosstalk between the subiculum and sleep-wake regulation: A review. J Sleep Res 2024; 33:e14134. [PMID: 38196146 DOI: 10.1111/jsr.14134] [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: 09/25/2023] [Revised: 12/07/2023] [Accepted: 12/09/2023] [Indexed: 01/11/2024]
Abstract
The circuitry underlying the initiation, maintenance, and coordination of wakefulness, rapid eye movement sleep, and non-rapid eye movement sleep is not thoroughly understood. Sleep is thought to arise due to decreased activity in the ascending reticular arousal system, which originates in the brainstem and awakens the thalamus and cortex during wakefulness. Despite the conventional association of sleep-wake states with hippocampal rhythms, the mutual influence of the hippocampal formation in regulating vigilance states has been largely neglected. Here, we focus on the subiculum, the main output region of the hippocampal formation. The subiculum, particulary the ventral part, sends extensive monosynaptic projections to crucial regions implicated in sleep-wake regulation, including the thalamus, lateral hypothalamus, tuberomammillary nucleus, basal forebrain, ventrolateral preoptic nucleus, ventrolateral tegmental area, and suprachiasmatic nucleus. Additionally, second-order projections from the subiculum are received by the laterodorsal tegmental nucleus, locus coeruleus, and median raphe nucleus, suggesting the potential involvement of the subiculum in the regulation of the sleep-wake cycle. We also discuss alterations in the subiculum observed in individuals with sleep disorders and in sleep-deprived mice, underscoring the significance of investigating neuronal communication between the subiculum and pathways promoting both sleep and wakefulness.
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Affiliation(s)
- Sadegh Rahimi
- Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
| | - Leesa Joyce
- Clinic of Anesthesiology and Intensive Care, School of Medicine, Technical University of Munich, München, Germany
| | - Thomas Fenzl
- Clinic of Anesthesiology and Intensive Care, School of Medicine, Technical University of Munich, München, Germany
| | - Meinrad Drexel
- Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
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50
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Armstrong RC, Sullivan GM, Perl DP, Rosarda JD, Radomski KL. White matter damage and degeneration in traumatic brain injury. Trends Neurosci 2024; 47:677-692. [PMID: 39127568 DOI: 10.1016/j.tins.2024.07.003] [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: 04/18/2024] [Revised: 06/17/2024] [Accepted: 07/19/2024] [Indexed: 08/12/2024]
Abstract
Traumatic brain injury (TBI) is a complex condition that can resolve over time but all too often leads to persistent symptoms, and the risk of poor patient outcomes increases with aging. TBI damages neurons and long axons within white matter tracts that are critical for communication between brain regions; this causes slowed information processing and neuronal circuit dysfunction. This review focuses on white matter injury after TBI and the multifactorial processes that underlie white matter damage, potential for recovery, and progression of degeneration. A multiscale perspective across clinical and preclinical advances is presented to encourage interdisciplinary insights from whole-brain neuroimaging of white matter tracts down to cellular and molecular responses of axons, myelin, and glial cells within white matter tissue.
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Affiliation(s)
- Regina C Armstrong
- Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA; Military Traumatic Brain Injury Initiative (MTBI(2)), Bethesda, MD, USA.
| | - Genevieve M Sullivan
- Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA; Military Traumatic Brain Injury Initiative (MTBI(2)), Bethesda, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA
| | - Daniel P Perl
- Pathology, School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA; Department of Defense - Uniformed Services University Brain Tissue Repository, Bethesda, MD, USA
| | - Jessica D Rosarda
- Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Kryslaine L Radomski
- Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
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