Academic Journal
Προβολή σε EDS
Συνδεδεμένο Πλήρες Κείμενο

Circuit Mechanisms Underlying the Contribution of Leptin Receptor-Expressing Neurons in the Nucleus Tractus Solitarius to Ventilatory Homeostasis.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος: Circuit Mechanisms Underlying the Contribution of Leptin Receptor-Expressing Neurons in the Nucleus Tractus Solitarius to Ventilatory Homeostasis.
Συγγραφείς: Hao Y; Department of Neurobiology, Hebei Medical University, Shijiazhuang, 050017, China.; Experimental Center for Teaching, Hebei Medical University, Shijiazhuang, 050017, China., Zhu M; Department of Neurobiology, Hebei Medical University, Shijiazhuang, 050017, China.; Department of Laboratory Diagnostics, Hebei Medical University, Shijiazhuang, 050017, China., Yu H; Department of Neurobiology, Hebei Medical University, Shijiazhuang, 050017, China., Zhang X; Department of Neurobiology, Hebei Medical University, Shijiazhuang, 050017, China., Shi Y; Department of Neurobiology, Hebei Medical University, Shijiazhuang, 050017, China., Sun L; Department of Neurobiology, Hebei Medical University, Shijiazhuang, 050017, China., Hao Y; Department of Neurobiology, Hebei Medical University, Shijiazhuang, 050017, China., Huang Y; Department of Neurobiology, Hebei Medical University, Shijiazhuang, 050017, China., Yu L; Department of Neurobiology, Hebei Medical University, Shijiazhuang, 050017, China., Wang S; Department of Neurobiology, Hebei Medical University, Shijiazhuang, 050017, China.; Hebei Key Laboratory of Brain Science and Brain-Inspired Intelligence, Shijiazhuang, 050017, China.; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, 050017, China., Zhao D; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Joint International Research Laboratory of Respiratory Health, Guangdong Basic Research Center of Excellence for Respiratory Medicine, Sleep Medicine Center, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510162, China. rieast@163.com., Yuan F; Department of Neurobiology, Hebei Medical University, Shijiazhuang, 050017, China. yuanfang@hebmu.edu.cn.; Hebei Key Laboratory of Brain Science and Brain-Inspired Intelligence, Shijiazhuang, 050017, China. yuanfang@hebmu.edu.cn.; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, 050017, China. yuanfang@hebmu.edu.cn.
Πηγή: Neuroscience bulletin [Neurosci Bull] 2026 Oct; Vol. 42 (10), pp. 2199-2218. Date of Electronic Publication: 2026 Apr 06.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Springer Singapore Country of Publication: Singapore NLM ID: 101256850 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1995-8218 (Electronic) Linking ISSN: 19958218 NLM ISO Abbreviation: Neurosci Bull Subsets: MEDLINE
Imprint Name(s): Publication: Singapore : Springer Singapore
Original Publication: Beijing, China : Science Press, 2005-
Ιατρικοί όροι (MeSH): Solitary Nucleus*/metabolism , Neurons*/metabolism , Receptors, Leptin*/metabolism , Receptors, Leptin*/genetics , Homeostasis*/physiology , Sleep Apnea Syndromes*/physiopathology , Sleep Apnea Syndromes*/metabolism , Respiration*, Leptin/metabolism ; Neural Pathways/metabolism ; Animals ; Mice, Inbred C57BL ; Male ; Mice
Περίληψη: Sleep apnea syndrome (SAS) is a prevalent disorder characterized by recurrent respiratory pauses during sleep; however, the neural mechanisms governing respiratory stability remain poorly understood. In this study, we identify the ratio of sigh expiratory volume to eupneic expiratory volume as a potential predictor of post-sigh apnea in susceptible C57BL/6J mice. We demonstrate that leptin signaling within the nucleus tractus solitarius (NTS) is critical for maintaining respiratory drive and suppressing apnea. Chemogenetic activation of Leptin receptor b-expressing NTS (NTSLepRb) neurons significantly reduced apnea incidence, whereas their ablation exacerbated respiratory dysfunction. Moreover, NTSLepRb neurons mediate these effects through anatomically and functionally segregated projections to the dorsomedial hypothalamus and the lateral parabrachial nucleus. These findings define a specific leptin-mediated brainstem circuit that stabilizes respiratory output, providing new mechanistic insights and potential therapeutic targets for sleep-disordered breathing.
(© 2026. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences.)
Competing Interests: Conflict of interest: The authors declare that there are no conflicts of interest.
References: Benjafield AV, Ayas NT, Eastwood PR, Heinzer R, Ip MSM, Morrell MJ. Estimation of the global prevalence and burden of obstructive sleep apnoea: A literature-based analysis. Lancet Respir Med 2019, 7: 687–698. (PMID: 31300334700776310.1016/S2213-2600(19)30198-5)
Alvente S, Matteoli G, Miglioranza E, Zoccoli G, Bastianini S. How to study sleep apneas in mouse models of human pathology. J Neurosci Methods 2023, 395: 109923. (PMID: 3745989710.1016/j.jneumeth.2023.109923)
Chen J, Lin M, Shi N, Shen J, Weng X, Pang F, et al. Altered cortical information interaction during respiratory events in children with obstructive sleep apnea-hypopnea syndrome. Neurosci Bull 2024, 40: 1458–1470. (PMID: 10.1007/s12264-024-01197-z3855836511422393)
Faria A, Allen AH, Fox N, Ayas N, Laher I. The public health burden of obstructive sleep apnea. Sleep Sci 2021, 14: 257–265. (PMID: 351862048848533)
Seravalle G, Grassi G. Sleep apnea and hypertension. High Blood Press Cardiovasc Prev 2022, 29: 23–31. (PMID: 10.1007/s40292-021-00484-434739711)
Henning RJ, Anderson WM. Sleep apnea is a common and dangerous cardiovascular risk factor. Curr Probl Cardiol 2025, 50: 102838. (PMID: 3924206210.1016/j.cpcardiol.2024.102838)
Kumari S, Chaudhary SC, Sawlani KK, Gupta KK, Usman K, Reddy HD, et al. Obstructive sleep apnea in metabolic syndrome. Ann Afr Med 2024, 23: 710–716. (PMID: 392791781155647410.4103/aam.aam_24_24)
Andrisani G, Andrisani G. Sleep apnea pathophysiology. Sleep Breath 2023, 27: 2111–2122. (PMID: 10.1007/s11325-023-02783-73697641310656321)
Roberts EG, Raphelson JR, Orr JE, LaBuzetta JN, Malhotra A. The pathogenesis of central and complex sleep apnea. Curr Neurol Neurosci Rep 2022, 22: 405–412. (PMID: 10.1007/s11910-022-01199-2355880429239939)
Cleary CM, James S, Maher BJ, Mulkey DK. Disordered breathing in a Pitt-Hopkins syndrome model involves Phox2b-expressing parafacial neurons and aberrant Nav1.8 expression. Nat Commun 2021, 12: 5962. (PMID: 10.1038/s41467-021-26263-2346458238514575)
Li P, Yackle K. Sighing. Curr Biol 2017, 27: R88–R89. (PMID: 2817176110.1016/j.cub.2016.09.006)
Severs LJ, Vlemincx E, Ramirez JM. The psychophysiology of the sigh: I: The sigh from the physiological perspective. Biol Psychol 2022, 170: 108313. (PMID: 35288214920485410.1016/j.biopsycho.2022.108313)
Baldwin DN, Suki B, Pillow JJ, Roiha HL, Minocchieri S, Frey U. Effect of sighs on breathing memory and dynamics in healthy infants. J Appl Physiol 2004, 97: 1830–1839. (PMID: 1520829310.1152/japplphysiol.00298.2004)
Qureshi M, Khalil M, Kwiatkowski K, Alvaro RE. Morphology of sighs and their role in the control of breathing in preterm infants, term infants and adults. Neonatology 2009, 96: 43–49. (PMID: 1920440910.1159/000201738)
Ramirez JM, Garcia AJ, Anderson TM, Koschnitzky JE, Peng YJ, Kumar GK, et al. Central and peripheral factors contributing to obstructive sleep apneas. Respir Physiol Neurobiol 2013, 189: 344–353. (PMID: 23770311390143710.1016/j.resp.2013.06.004)
Stettner GM, Zanella S, Huppke P, Gärtner J, Hilaire G, Dutschmann M. Spontaneous central apneas occur in the C57BL/6J mouse strain. Respir Physiol Neurobiol 2008, 160: 21–27. (PMID: 1786919110.1016/j.resp.2007.07.011)
Han F, Subramanian S, Dick TE, Dreshaj IA, Strohl KP. Ventilatory behavior after hypoxia in C57BL/6J and A/J mice. J Appl Physiol 2001, 91: 1962–1970. (PMID: 1164133110.1152/jappl.2001.91.5.1962)
Li P, Janczewski WA, Yackle K, Kam K, Pagliardini S, Krasnow MA, et al. The peptidergic control circuit for sighing. Nature 2016, 530: 293–297. (PMID: 10.1038/nature16964268554254852886)
Deng T, Jing X, Shao L, Wang Y, Fu C, Yu H, et al. A molecularly defined medullary network for control of respiratory homeostasis. Adv Sci 2025, 12: 2412822. (PMID: 10.1002/advs.202412822)
Cui Y, Bondarenko E, Thörn Perez C, Chiu DN, Feldman JL. Sigh generation in preBötzinger complex. Elife 2025, 13: RP100192. (PMID: 405530991218713110.7554/eLife.100192.3)
Yao Y, Chen J, Li X, Chen ZF, Li P. A carotid body-brainstem neural circuit mediates sighing in hypoxia. Curr Biol 2023, 33: 827-837.e4. (PMID: 367500921033729010.1016/j.cub.2023.01.019)
Moya EA, Go A, Kim CB, Fu Z, Simonson TS, Powell FL. Neuronal HIF-1α in the nucleus tractus solitarius contributes to ventilatory acclimatization to hypoxia. J Physiol 2020, 598: 2021–2034. (PMID: 32026480723000610.1113/JP279331)
Do J, Chang Z, Sekerková G, McCrimmon DR, Martina M. A leptin-mediated neural mechanism linking breathing to metabolism. Cell Rep 2020, 33: 108358. (PMID: 3317613910.1016/j.celrep.2020.108358)
Tsirigotaki A, Dansercoer A, Verschueren KHG, Marković I, Pollmann C, Hafer M, et al. Mechanism of receptor assembly via the pleiotropic adipokine Leptin. Nat Struct Mol Biol 2023, 30: 551–563. (PMID: 10.1038/s41594-023-00941-936959263)
Gauda EB, Conde S, Bassi M, Zoccal DB, Almeida Colombari DS, Colombari E, et al. Leptin: Master regulator of biological functions that affects breathing. Compr Physiol 2020, 10: 1047–1083. (PMID: 3294168810.1002/j.2040-4603.2020.tb00137.x)
Pho H, Hernandez AB, Arias RS, Leitner EB, Van Kooten S, Kirkness JP, et al. The effect of leptin replacement on sleep-disordered breathing in the leptin-deficient ob/ob mouse. J Appl Physiol 2016, 120: 78–86. (PMID: 2647286710.1152/japplphysiol.00494.2015)
Philbrick KA, Wong CP, Branscum AJ, Turner RT, Iwaniec UT. Leptin stimulates bone formation in ob/ob mice at doses having minimal impact on energy metabolism. J Endocrinol 2017, 232: 461–474. (PMID: 28057869528812510.1530/JOE-16-0484)
Bassi M, Furuya WI, Zoccal DB, Menani JV, Colombari DSA, Mulkey DK, et al. Facilitation of breathing by leptin effects in the central nervous system. J Physiol 2016, 594: 1617–1625. (PMID: 2609574810.1113/JP270308)
Kumar NN, Velic A, Soliz J, Shi Y, Li K, Wang S, et al. Regulation of breathing by CO<sub>2</sub> requires the proton-activated receptor GPR4 in retrotrapezoid nucleus neurons. Science 2015, 348: 1255–1260. (PMID: 26068853517122910.1126/science.aaa0922)
Nakamura A, Fukuda Y, Kuwaki T. Sleep apnea and effect of chemostimulation on breathing instability in mice. J Appl Physiol 2003, 94: 525–532. (PMID: 1243386710.1152/japplphysiol.00226.2002)
Toledo C, Díaz-Jara E, Diaz HS, Schwarz KG, Pereyra KV, Las Heras A, et al. Medullary astrocytes mediate irregular breathing patterns generation in chronic heart failure through purinergic P2X7 receptor signalling. EBioMedicine 2022, 80: 104044. (PMID: 35533501909763210.1016/j.ebiom.2022.104044)
Yamauchi M, Ocak H, Dostal J, Jacono FJ, Loparo KA, Strohl KP. Post-sigh breathing behavior and spontaneous pauses in the C57BL/6J (B6) mouse. Respir Physiol Neurobiol 2008, 162: 117–125. (PMID: 18565803369896910.1016/j.resp.2008.05.003)
Han F, Subramanian S, Price ER, Nadeau J, Strohl KP. Periodic breathing in the mouse. J Appl Physiol 2002, 92: 1133–1140. (PMID: 1184205010.1152/japplphysiol.00785.2001)
Younes M. Measurement of the CO<sub>2</sub> apneic threshold. Am J Respir Crit Care Med 2003, 167: 472–473. (PMID: 1255463110.1164/ajrccm.167.3.297)
Nguyen CD, Dakin C, Yuill M, Crozier S, Wilson S. The effect of sigh on cardiorespiratory synchronization in healthy sleeping infants. Sleep 2012, 35: 1643–1650. (PMID: 23204607349035710.5665/sleep.2236)
Goheen J, Anderson JAE, Zhang J, Northoff G. From lung to brain: Respiration modulates neural and mental activity. Neurosci Bull 2023, 39: 1577–1590. (PMID: 10.1007/s12264-023-01070-53728501710533478)
Eckert DJ, Malhotra A, Jordan AS. Mechanisms of apnea. Prog Cardiovasc Dis 2009, 51: 313–323. (PMID: 19110133342774810.1016/j.pcad.2008.02.003)
Heinzer RC, Stanchina ML, Malhotra A, Jordan AS, Patel SR, Lo YL, et al. Effect of increased lung volume on sleep disordered breathing in patients with sleep apnoea. Thorax 2006, 61: 435–439. (PMID: 16490766211119910.1136/thx.2005.052084)
Baertsch NA, Baker TL. Reduced respiratory neural activity elicits a long-lasting decrease in the CO<sub>2</sub> threshold for apnea in anesthetized rats. Exp Neurol 2017, 287: 235–242. (PMID: 2747451210.1016/j.expneurol.2016.07.020)
Zong S, Du P, Li H, Wang M, Xiao H. Advances in animal models of obstructive sleep apnea. Front Med 2023, 10: 988752. (PMID: 10.3389/fmed.2023.988752)
Ramirez JM. The integrative role of the sigh in psychology, physiology, pathology, and neurobiology. The Central Nervous System Control of Respiration. Amsterdam: Elsevier, 2014: 91–129.
Amorim MR, Wang X, Aung O, Bevans-Fonti S, Anokye-Danso F, Ribeiro C, et al. Leptin signaling in the dorsomedial hypothalamus couples breathing and metabolism in obesity. Cell Rep 2023, 42: 113512. (PMID: 380391291080428610.1016/j.celrep.2023.113512)
Amorim MR, Williams NR, Aung O, Ruiz MA, Anokye-Danso F, de Deus JL, et al. Targeting melanocortin 4 receptor to treat sleep-disordered breathing in mice. J Clin Invest 2025, 135: e177823. (PMID: 402328481216579610.1172/JCI177823)
Inyushkin AN, Inyushkina EM, Merkulova NA. Respiratory responses to microinjections of leptin into the solitary tract nucleus. Neurosci Behav Physiol 2009, 39: 231–240. (PMID: 1923480110.1007/s11055-009-9124-8)
Chang Z, Ballou E, Jiao W, McKenna KE, Morrison SF, McCrimmon DR. Systemic leptin produces a long-lasting increase in respiratory motor output in rats. Front Physio 2013, 4: 16. (PMID: 10.3389/fphys.2013.00016)
Ciriello J, Caverson MM. Carotid chemoreceptor afferent projections to leptin receptor containing neurons in nucleus of the solitary tract. Peptides 2014, 58: 30–35. (PMID: 2490562110.1016/j.peptides.2014.05.014)
Del Negro CA, Funk GD, Feldman JL. Breathing matters. Nat Rev Neurosci 2018, 19: 351–367. (PMID: 10.1038/s41583-018-0003-6297401756636643)
Aychman MM, Goldman DL, Kaplan JS. Cannabidiol’s neuroprotective properties and potential treatment of traumatic brain injuries. Front Neurol 2023, 14: 1087011. (PMID: 36816569993204810.3389/fneur.2023.1087011)
Chen Y, Xiao L, Qiu J. Neuronomodulation of excitable neurons. Neurosci Bull 2024, 40: 103–112. (PMID: 10.1007/s12264-023-01095-w37584858)
Severs LJ, Bush NE, Quina LA, Hidalgo-Andrade S, Burgraff NJ, Dashevskiy T, et al. Purinergic signaling mediates neuroglial interactions to modulate sighs. Nat Commun 2023, 14: 5300. (PMID: 10.1038/s41467-023-40812-x3765290310471608)
Pho H, Berger S, Freire C, Kim LJ, Shin MK, Streeter SR, et al. Leptin receptor expression in the dorsomedial hypothalamus stimulates breathing during NREM sleep in db/db mice. Sleep 2021, 44: zsab046. (PMID: 33624805819356410.1093/sleep/zsab046)
Hao Y, Wei Z, Wang S, An P, Huang Y, Yu L, et al. Inhibition of SOCS3 signaling in the nucleus tractus solitarii and retrotrapezoid nucleus alleviates hypoventilation in diet-induced obese male mice. Brain Res 2024, 1822: 148608. (PMID: 3777864810.1016/j.brainres.2023.148608)
Sun L, Zhu M, Wang M, Hao Y, Hao Y, Jing X, et al. Whole-brain monosynaptic inputs and outputs of leptin receptor b neurons of the nucleus tractus solitarii in mice. Brain Res Bull 2023, 201: 110693. (PMID: 3734882210.1016/j.brainresbull.2023.110693)
Yu H, Shi L, Chen J, Jun S, Hao Y, Wang S, et al. A neural circuit mechanism controlling breathing by leptin in the nucleus tractus solitarii. Neurosci Bull 2022, 38: 149–165. (PMID: 10.1007/s12264-021-00742-434212297)
Georgescu T, Lyons D, Doslikova B, Garcia AP, Marston O, Burke LK, et al. Neurochemical characterization of brainstem pro-opiomelanocortin cells. Endocrinology 2020, 161: bqaa032. (PMID: 32166324710287310.1210/endocr/bqaa032)
Li YC, Zhang FC, Li D, Weng RX, Yu Y, Gao R, et al. Distinct circuits and molecular targets of the paraventricular hypothalamus decode visceral and somatic pain. Neuron 2024, 112: 3734-3749.e5. (PMID: 3932640710.1016/j.neuron.2024.08.024)
Huda R, Pollema-Mays SL, Chang Z, Alheid GF, McCrimmon DR, Martina M. Acid-sensing ion channels contribute to chemosensitivity of breathing-related neurons of the nucleus of the solitary tract. J Physiol 2012, 590: 4761–4775. (PMID: 22890703348703510.1113/jphysiol.2012.232470)
Fu C, Xue J, Wang R, Chen J, Ma L, Liu Y, et al. Chemosensitive Phox2b-expressing neurons are crucial for hypercapnic ventilatory response in the nucleus tractus solitarius. J Physiol 2017, 595: 4973–4989. (PMID: 28488367550988210.1113/JP274437)
Arthurs JW, Bowen AJ, Palmiter RD, Baertsch NA. Parabrachial tachykinin1-expressing neurons involved in state-dependent breathing control. Nat Commun 2023, 14: 963. (PMID: 10.1038/s41467-023-36603-z368106019944916)
Chen J, Gannot N, Li X, Zhu R, Zhang C, Li P. Control of emotion and wakefulness by neurotensinergic neurons in the parabrachial nucleus. Neurosci Bull 2023, 39: 589–601. (PMID: 10.1007/s12264-022-00994-836522525)
Kaur S, Lynch N, Sela Y, Lima JD, Thomas RC, Bandaru SS, et al. Lateral parabrachial FoxP2 neurons regulate respiratory responses to hypercapnia. Nat Commun 2024, 15: 4475. (PMID: 10.1038/s41467-024-48773-53879656811128025)
Contributed Indexing: Keywords: Leptin; Neural circuit; Nucleus tractus solitarius; Sleep apnea
Substance Nomenclature: 0 (Receptors, Leptin)
0 (Leptin)
Entry Date(s): Date Created: 20260406 Date Completed: 20261006 Latest Revision: 20261009
Update Code: 20261009
PubMed Central ID: PMC13642890
DOI: 10.1007/s12264-026-01614-5
PMID: 41942684
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1995-8218
DOI:10.1007/s12264-026-01614-5