{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T03:12:02Z","timestamp":1792811522007,"version":"4.5.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,10,21]],"date-time":"2021-10-21T00:00:00Z","timestamp":1634774400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Behav. Neurosci."],"abstract":"<jats:p>Zona incerta (ZI), a largely inhibitory subthalamic region connected with many brain areas, has been suggested to serve as an integrative node for modulation of behaviors and physiological states, such as fear memory conditioning and aversion responses. It is, however, unclear whether ZI regulated the repeated social defeat stress (RSDS)-induced social conditioned place aversion (CPA) and post-traumatic stress disorder (PTSD)-like behaviors. In this study, the function of ZI was silenced via bilateral injection of tetanus toxin light chain (Tet-tox), a neurotoxin that completely blocks the evoked synaptic transmissions, expressing adeno-associated viruses (AAVs). We found ZI silencing: (1) significantly blocked the expression of RSDS-induced social CPA with no effect on the innate preference; (2) significantly enhanced the anxiety level in mice experienced RSDS with no effect on the locomotion activity; (3) altered the PTSD-associated behaviors, including the promotion of spatial cognitive impairment and the preventions of PPI deficit and social avoidance behavior. These effects were not observed on non-stressed mice. In summary, our results suggest the important role of ZI in modulating RSDS-induced social CPA and PTSD-like behaviors.<\/jats:p>","DOI":"10.3389\/fnbeh.2021.743484","type":"journal-article","created":{"date-parts":[[2021,10,21]],"date-time":"2021-10-21T05:45:57Z","timestamp":1634795157000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":27,"title":["Inactivation of Zona Incerta Blocks Social Conditioned Place Aversion and Modulates Post-traumatic Stress Disorder-Like Behaviors in Mice"],"prefix":"10.3389","volume":"15","author":[{"given":"Hong","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengbing","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,10,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/s0031-9384(01)00453-x","article-title":"Social status in mice: behavioral, endocrine and immune changes are context dependent.","volume":"73","author":"Bartolomucci","year":"2001","journal-title":"Physiol. Behav."},{"key":"B2","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1126\/science.1120972","article-title":"Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress.","volume":"311","author":"Berton","year":"2006","journal-title":"Science"},{"key":"B3","doi-asserted-by":"publisher","first-page":"5728","DOI":"10.1523\/jneurosci.2739-18.2019","article-title":"Anterior Cingulate Cortex to Ventral Hippocampus Circuit Mediates Contextual Fear Generalization.","volume":"39","author":"Bian","year":"2019","journal-title":"J. Neurosci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1016\/s0031-9384(01)00490-5","article-title":"Social defeat as a stressor in humans.","volume":"73","author":"Bj\u00f6rkqvist","year":"2001","journal-title":"Physiol. Behav."},{"key":"B5","doi-asserted-by":"publisher","first-page":"3394","DOI":"10.1007\/s12035-017-0586-3","article-title":"Molecular Adaptations to Social Defeat Stress and Induced Depression in Mice.","volume":"55","author":"Bondar","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1093\/ijnp\/pyx079","article-title":"Reversal of Stress-Induced Social Interaction Deficits by Buprenorphine.","volume":"21","author":"Browne","year":"2018","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.1038\/s41467-018-03581-6","article-title":"Inhibitory gain modulation of defense behaviors by zona incerta.","volume":"9","author":"Chou","year":"2018","journal-title":"Nat. Commun."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.24846","article-title":"Endogenous \u03bc-opioid receptor activity in the lateral and capsular subdivisions of the right central nucleus of the amygdala prevents chronic postoperative pain.","author":"Cooper","year":"2021","journal-title":"J. Neurosci. Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1124\/jpet.117.245704","article-title":"Monoacylglycerol Lipase Inhibitors Reverse Paclitaxel-Induced Nociceptive Behavior and Proinflammatory Markers in a Mouse Model of Chemotherapy-Induced Neuropathy.","volume":"366","author":"Curry","year":"2018","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B10","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1016\/j.bbi.2012.02.010","article-title":"Phenotypic effects of repeated psychosocial stress during adolescence in mice mutant for the schizophrenia risk gene neuregulin-1: a putative model of gene \u00d7 environment interaction.","volume":"26","author":"Desbonnet","year":"2012","journal-title":"Brain Behav. Immun."},{"key":"B11","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.tins.2015.12.002","article-title":"Warning! Dopaminergic Modulation of the Superior Colliculus.","volume":"39","author":"Essig","year":"2016","journal-title":"Trends Neurosci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1038\/s41593-020-0617-7","article-title":"Orexin signaling in GABAergic lateral habenula neurons modulates aggressive behavior in male mice.","volume":"23","author":"Flanigan","year":"2020","journal-title":"Nat. Neurosci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/s0091-3057(02)00795-5","article-title":"Social stress in tree shrews: effects on physiology, brain function, and behavior of subordinate individuals.","volume":"73","author":"Fuchs","year":"2002","journal-title":"Pharmacol. Biochem. Behav."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1183","DOI":"10.1038\/nprot.2011.361","article-title":"A standardized protocol for repeated social defeat stress in mice.","volume":"6","author":"Golden","year":"2011","journal-title":"Nat. Protoc."},{"key":"B15","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1038\/nature18601","article-title":"Basal forebrain projections to the lateral habenula modulate aggression reward.","volume":"534","author":"Golden","year":"2016","journal-title":"Nature"},{"key":"B16","doi-asserted-by":"publisher","first-page":"3081","DOI":"10.1111\/ejn.13099","article-title":"Effects of social defeat on dopamine neurons in the ventral tegmental area in male and female California mice.","volume":"42","author":"Greenberg","year":"2015","journal-title":"Eur. J. Neurosci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"8615","DOI":"10.1073\/pnas.1819218116","article-title":"Chronic psychosocial stress compromises the immune response and endochondral ossification during bone fracture healing via \u03b2-AR signaling.","volume":"116","author":"Haffner-Luntzer","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B18","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.neubiorev.2015.10.006","article-title":"Defeat stress in rodents: from behavior to molecules.","volume":"59","author":"Hammels","year":"2015","journal-title":"Neurosci. Biobehav. Rev."},{"key":"B19","doi-asserted-by":"publisher","first-page":"2020","DOI":"10.1523\/ENEURO.0390-19.2020","article-title":"Zona Incerta GABAergic Output Controls a Signaled Locomotor Action in the Midbrain Tegmentum.","volume":"7","author":"Hormigo","year":"2020","journal-title":"eNeuro"},{"key":"B20","doi-asserted-by":"publisher","first-page":"9130","DOI":"10.1523\/JNEUROSCI.1683-19.2019","article-title":"Activation of the Intrinsic Pain Inhibitory Circuit from the Midcingulate Cg2 to Zona Incerta Alleviates Neuropathic Pain.","volume":"39","author":"Hu","year":"2019","journal-title":"J. Neurosci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.pnpbp.2015.12.002","article-title":"Effect of chronic social defeat stress on behaviors and dopamine receptor in adult mice.","volume":"66","author":"Huang","year":"2016","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"B22","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1186\/s13041-019-0488-6","article-title":"Improvement of PTSD-like behavior by the forgetting effect of hippocampal neurogenesis enhancer memantine in a social defeat stress paradigm.","volume":"12","author":"Ishikawa","year":"2019","journal-title":"Mol. Brain"},{"key":"B23","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/j.bbi.2021.05.028","article-title":"Heat-sterilized Bifidobacterium breve prevents depression-like behavior and interleukin-1\u03b2 expression in mice exposed to chronic social defeat stress.","volume":"96","author":"Kosuge","year":"2021","journal-title":"Brain Behav. Immun."},{"key":"B24","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/0091-3057(91)90284-9","article-title":"Social model of depression in mice of C57BL\/6J strain.","volume":"38","author":"Kudryavtseva","year":"1991","journal-title":"Pharmacol. Biochem. Behav."},{"key":"B25","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1007\/s00210-018-1580-7","article-title":"Social behavior effects of diphenyl dimethyl bicarboxylate (DDB) in the sensory contact model.","volume":"392","author":"Mahfoz","year":"2019","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1016\/j.cell.2019.02.014","article-title":"Multi-sensory Gamma Stimulation Ameliorates Alzheimer\u2019s-Associated Pathology and Improves Cognition.","volume":"177","author":"Martorell","year":"2019","journal-title":"Cell"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1016\/j.biopsych.2020.12.030","article-title":"Nucleus Accumbens Medium Spiny Neuron Subtypes Differentially Regulate Stress-Associated Alterations in Sleep Architecture.","volume":"89","author":"McCullough","year":"2021","journal-title":"Biol. Psychiatry"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1752","DOI":"10.1038\/s41593-017-0010-3","article-title":"Social stress induces neurovascular pathology promoting depression.","volume":"20","author":"Menard","year":"2017","journal-title":"Nat. Neurosci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1594","DOI":"10.1038\/s41386-021-01033-2","article-title":"Striatal Shati\/Nat8l-BDNF pathways determine the sensitivity to social defeat stress in mice through epigenetic regulation.","volume":"46","author":"Miyanishi","year":"2021","journal-title":"Neuropsychopharmacology"},{"key":"B30","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.bbr.2008.08.029","article-title":"Anxiety increases the place conditioning induced by cocaine in rats.","volume":"197","author":"Pelloux","year":"2009","journal-title":"Behav. Brain Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1016\/j.tins.2016.04.004","article-title":"Neuroinflammation Regulates Cognitive Impairment in Socially Defeated Mice.","volume":"39","author":"Pfau","year":"2016","journal-title":"Trends Neurosci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"11000","DOI":"10.1038\/s41598-021-90521-y","article-title":"Stress-induced alterations of mesocortical and mesolimbic dopaminergic pathways.","volume":"11","author":"Quessy","year":"2021","journal-title":"Sci. Rep."},{"key":"B33","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1124\/jpet.119.259283","article-title":"Differential Roles of Accumbal GSK3\u03b2 in Cocaine versus Morphine-Induced Place Preference, U50,488H-Induced Place Aversion, and Object Memory.","volume":"371","author":"Shi","year":"2019","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B34","doi-asserted-by":"publisher","first-page":"R1799","DOI":"10.1152\/ajpregu.2001.280.6.R1799","article-title":"Social stress induces glucocorticoid resistance in macrophages.","volume":"280","author":"Stark","year":"2001","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1097\/aln.0000000000001756","article-title":"Hydrogen Peroxide Induces Muscle Nociception via Transient Receptor Potential Ankyrin 1 Receptors.","volume":"127","author":"Sugiyama","year":"2017","journal-title":"Anesthesiology"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1218","DOI":"10.1016\/j.neubiorev.2008.06.001","article-title":"Predator odor fear conditioning: current perspectives and new directions.","volume":"32","author":"Takahashi","year":"2008","journal-title":"Neurosci. Biobehav. Rev."},{"key":"B37","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1016\/j.biopsych.2020.10.015","article-title":"miR-218 in Adolescence Predicts and Mediates Vulnerability to Stress.","volume":"89","author":"Torres-Berr\u00edo","year":"2021","journal-title":"Biol. Psychiatry"},{"key":"B38","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1007\/s00441-013-1636-4","article-title":"Animal models of social avoidance and social fear.","volume":"354","author":"Toth","year":"2013","journal-title":"Cell Tissue Res."},{"key":"B39","doi-asserted-by":"publisher","first-page":"9072","DOI":"10.1073\/pnas.1820541116","article-title":"Modulation of fear generalization by the zona incerta.","volume":"116","author":"Venkataraman","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1658","DOI":"10.1038\/s41386-021-01006-5","article-title":"Incerto-thalamic modulation of fear via GABA and dopamine.","volume":"46","author":"Venkataraman","year":"2021","journal-title":"Neuropsychopharmacology"},{"key":"B41","doi-asserted-by":"publisher","first-page":"3857","DOI":"10.1523\/jneurosci.4333-12.2013","article-title":"Homer1 mediates acute stress-induced cognitive deficits in the dorsal hippocampus.","volume":"33","author":"Wagner","year":"2013","journal-title":"J. Neurosci."},{"key":"B42","doi-asserted-by":"publisher","first-page":"e42728","DOI":"10.7554\/eLife.42728","article-title":"A cross-modality enhancement of defensive flight via parvalbumin neurons in zona incerta.","volume":"8","author":"Wang","year":"2019","journal-title":"Elife"},{"key":"B43","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1016\/j.biopsych.2018.05.007","article-title":"AMPA Receptor Activation-Independent Antidepressant Actions of Ketamine Metabolite (S)-Norketamine.","volume":"84","author":"Yang","year":"2018","journal-title":"Biol. Psychiatry"},{"key":"B44","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1126\/science.aam7100","article-title":"Rapid binge-like eating and body weight gain driven by zona incerta GABA neuron activation.","volume":"356","author":"Zhang","year":"2017","journal-title":"Science"},{"key":"B45","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1038\/s41593-019-0404-5","article-title":"Zona incerta GABAergic neurons integrate prey-related sensory signals and induce an appetitive drive to promote hunting.","volume":"22","author":"Zhao","year":"2019","journal-title":"Nat. Neurosci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1515","DOI":"10.1038\/s41593-018-0248-4","article-title":"A central amygdala to zona incerta projection is required for acquisition and remote recall of conditioned fear memory.","volume":"21","author":"Zhou","year":"2018","journal-title":"Nat. Neurosci."}],"container-title":["Frontiers in Behavioral Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnbeh.2021.743484\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,21]],"date-time":"2021-10-21T05:45:58Z","timestamp":1634795158000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnbeh.2021.743484\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,21]]},"references-count":46,"alternative-id":["10.3389\/fnbeh.2021.743484"],"URL":"https:\/\/doi.org\/10.3389\/fnbeh.2021.743484","relation":{},"ISSN":["1662-5153"],"issn-type":[{"value":"1662-5153","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,21]]},"article-number":"743484"}}