{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:39:05Z","timestamp":1760236745868,"version":"build-2065373602"},"reference-count":47,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T00:00:00Z","timestamp":1640131200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["19-15-00026"],"award-info":[{"award-number":["19-15-00026"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Both aggressive and aggression-deprived (AD) species represent pathologic cases intensely addressed in psychiatry and substance abuse disciplines. Previously, we reported that AD mice displayed a higher aggressive behavior score than the aggressive group, implying the manifestation of a withdrawal effect. We employed an animal model of chronic social conflicts, curated in our lab for more than 30 years. In the study, we pursued the task of evaluating key events in the dorsal striatum transcriptome of aggression experienced mice and AD species compared to controls using RNA-Seq profiling. Aggressive species were subjected to repeated social conflict encounters (fights) with regular positive (winners) experience in the course of 20 consecutive days (A20 group). This led to a profoundly shifted transcriptome expression profile relative to the control group, outlined by more than 1000 differentially expressed genes (DEGs). RNA-Seq cluster analysis revealed that elevated cyclic AMP (cAMP) signaling cascade and associated genes comprising 170 differentially expressed genes (DEGs) in aggressive (A20) species were accompanied by a downturn in the majority of other metabolic\/signaling gene networks (839 DEGs) via the activation of transcriptional repressor DEGs. Fourteen days of a consecutive fighting deprivation period (AD group) featured the basic restoration of the normal (control) transcriptome expression profile yielding only 62 DEGs against the control. Notably, we observed a network of 12 coordinated DEG Transcription Factor (TF) activators from 62 DEGs in total that were distinctly altered in AD compared to control group, underlining the distinct transcription programs featuring AD group, partly retained from the aggressive encounters and not restored to normal in 14 days. We found circadian clock TFs among them, reported previously as a withdrawal effect factor. We conclude that the aggressive phenotype selection with positive reward effect (winning) manifests an addiction model featuring a distinct opioid-related withdrawal effect in AD group. Along with reporting profound transcriptome alteration in A20 group and gaining some insight on its specifics, we outline specific TF activator gene networks associated with transcriptional repression in affected species compared to controls, outlining Nr1d1 as a primary candidate, thus offering putative therapeutic targets in opioid-induced withdrawal treatment.<\/jats:p>","DOI":"10.3390\/genes13010021","type":"journal-article","created":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T02:01:19Z","timestamp":1640224879000},"page":"21","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Dorsal Striatum Transcriptome Profile Profound Shift in Repeated Aggression Mouse Model Converged to Networks of 12 Transcription Factors after Fighting Deprivation"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3077-9559","authenticated-orcid":false,"given":"Vladimir","family":"Babenko","sequence":"first","affiliation":[{"name":"FRC Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0942-8460","authenticated-orcid":false,"given":"Olga","family":"Redina","sequence":"additional","affiliation":[{"name":"FRC Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dmitry","family":"Smagin","sequence":"additional","affiliation":[{"name":"FRC Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irina","family":"Kovalenko","sequence":"additional","affiliation":[{"name":"FRC Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Galyamina","sequence":"additional","affiliation":[{"name":"FRC Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roman","family":"Babenko","sequence":"additional","affiliation":[{"name":"FRC Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia","family":"Kudryavtseva","sequence":"additional","affiliation":[{"name":"FRC Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia"},{"name":"Pavlov Institute of Physiology, Russian Academy of Sciences, 199034 Saint Petersburg, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,22]]},"reference":[{"doi-asserted-by":"crossref","unstructured":"Seto, M.C., Healey, L.V., and Ahmed, A.G. (2021). Legally Mandated, Formally Pressured, or Voluntary Anger Treatment: Associations with Treatment Recommendations, Refusal, and Completion. J. Interpers. Violence.","key":"ref_1","DOI":"10.1177\/08862605211050100"},{"unstructured":"O\u2019Neal, P.W. (2007). Straub tail, the deprivation effect and addiction to aggression. Motivation of Health Behavior, NOVA Science Publishers.","key":"ref_2"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.1016\/j.pnpbp.2010.10.013","article-title":"Modeling fighting deprivation effect in mouse repeated aggression paradigm","volume":"35","author":"Kudryavtseva","year":"2011","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"101403","DOI":"10.1016\/j.avb.2020.101403","article-title":"Positive fighting experience, addiction-like state, and relapse: Retrospective analysis of experimental studies","volume":"52","author":"Kudryavtseva","year":"2020","journal-title":"Aggress. Violent Behav."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3284","DOI":"10.4081\/ejh.2021.3284","article-title":"Striatal topographical organization: Bridging the gap between molecules, connectivity and behavior","volume":"65","author":"Basile","year":"2021","journal-title":"Eur. J. Histochem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5121","DOI":"10.1038\/s41467-021-25460-3","article-title":"Opposing roles for striatonigral and striatopallidal neurons in dorsolateral striatum in consolidating new instrumental actions","volume":"12","author":"Smith","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1038\/nn.4066","article-title":"The role of ventral striatal cAMP signaling in stress-induced behaviors","volume":"18","author":"Plattner","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.1074\/jbc.M116.752402","article-title":"Glutamate Counteracts Dopamine\/PKA Signaling via Dephosphorylation of DARPP-32 Ser-97 and Alteration of Its Cytonuclear Distribution","volume":"292","author":"Nishi","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"12838","DOI":"10.1038\/s41598-017-12811-8","article-title":"Establishment of a repeated social defeat stress model in female mice","volume":"7","author":"Takahashi","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7451","DOI":"10.1113\/JP274475","article-title":"Detection of phasic dopamine by D1 and D2 striatal medium spiny neurons","volume":"595","author":"Yapo","year":"2017","journal-title":"J. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s12868-020-00560-w","article-title":"Dopamine response gene pathways in dorsal striatum MSNs from a gene expression viewpoint: cAMP-mediated gene networks","volume":"21","author":"Babenko","year":"2020","journal-title":"BMC Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.neures.2019.02.007","article-title":"Adolescent psychosocial stress enhances sensitization to cocaine exposure in genetically vulnerable mice","volume":"151","author":"Hikida","year":"2020","journal-title":"Neurosci. Res."},{"key":"ref_13","first-page":"14","article-title":"Cannabinoid, melanocortin and opioid receptor expression on DRD1 and DRD2 subpopulations in rat striatum","volume":"8","author":"Ophuis","year":"2014","journal-title":"Front. Neuroanat."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7049","DOI":"10.1007\/s12035-017-0844-4","article-title":"Dynorphin and \u03ba-Opioid Receptor Dysregulation in the Dopaminergic Reward System of Human Alcoholics","volume":"55","author":"Bazov","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.neuropharm.2013.04.032","article-title":"Rapid, transient synaptic plasticity in addiction","volume":"76","author":"Gipson","year":"2014","journal-title":"Neuropharmacology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"110","DOI":"10.3389\/fnana.2014.00110","article-title":"The \u201caddicted\u201d spine","volume":"8","author":"Spiga","year":"2014","journal-title":"Front. Neuroanat."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1083\/jcb.201003008","article-title":"Actin in dendritic spines: Connecting dynamics to function","volume":"189","author":"Hotulainen","year":"2010","journal-title":"J. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1096\/fj.03-0612fje","article-title":"Morphine exposure and abstinence define specific stages of gene expression in the rat nucleus accumbens","volume":"18","author":"Spijker","year":"2004","journal-title":"FASEB J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.tins.2010.02.002","article-title":"The addicted synapse: Mechanisms of synaptic and structural plasticity in nucleus accumbens","volume":"33","author":"Russo","year":"2010","journal-title":"Trends Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1038\/nature12776","article-title":"Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways","volume":"504","author":"Chung","year":"2013","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.neubiorev.2020.10.015","article-title":"Opioid-induced structural and functional plasticity of medium-spiny neurons in the nucleus accumbens","volume":"120","author":"Thompson","year":"2021","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1146\/annurev.psych.54.101601.145237","article-title":"Addiction","volume":"54","author":"Robinson","year":"2003","journal-title":"Annu. Rev. Psychol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2705","DOI":"10.1038\/nprot.2014.156","article-title":"Repeated positive fighting experience in male inbred mice","volume":"9","author":"Kudryavtseva","year":"2014","journal-title":"Nat. Protoc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1002\/1098-2337(1991)17:5<285::AID-AB2480170505>3.0.CO;2-P","article-title":"The sensory contact model for the study of aggressive and submissive behaviors in male mice","volume":"17","author":"Kudryavtseva","year":"1991","journal-title":"Aggress. Behav."},{"unstructured":"(2021, April 24). The Allen Mouse Brain Atlas. Available online: http:\/\/mouse.brain-map.org\/static\/atlas.","key":"ref_25"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: A flexible trimmer for Illumina sequence data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"11.14.1","DOI":"10.1002\/0471250953.bi1114s51","article-title":"Mapping RNA-seq Reads with STAR","volume":"51","author":"Dobin","year":"2015","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/nbt.1621","article-title":"Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation","volume":"28","author":"Trapnell","year":"2010","journal-title":"Nat. Biotechnol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1046\/j.1600-079X.2003.00114.x","article-title":"Circadian rhythms of dopamine, glutamate and GABA in the striatum and nucleus accumbens of the awake rat: Modulation by light","volume":"36","author":"Prieto","year":"2004","journal-title":"J. Pineal Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1023\/A:1012235510600","article-title":"Behavioral Abnormalities of Zic1 and Zic2 Mutant Mice: Implications as Models for Human Neurological Disorders","volume":"31","author":"Ogura","year":"2001","journal-title":"Behav. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1002\/jcp.24326","article-title":"Systemic effects of Wnt signaling","volume":"228","author":"Maruotti","year":"2013","journal-title":"J. Cell. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"577758","DOI":"10.1016\/j.jneuroim.2021.577758","article-title":"The involvement of JAK\/STAT signaling pathway in the treatment of Parkinson\u2019s disease","volume":"361","author":"Lashgari","year":"2021","journal-title":"J. Neuroimmunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/S0896-6273(04)00048-0","article-title":"Identification of PSD-95 as a Regulator of Dopamine-Mediated Synaptic and Behavioral Plasticity","volume":"41","author":"Yao","year":"2004","journal-title":"Neuron"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2948","DOI":"10.1523\/JNEUROSCI.4424-08.2009","article-title":"PSD-95 Uncouples Dopamine-Glutamate Interaction in the D1\/PSD-95\/NMDA Receptor Complex","volume":"29","author":"Zhang","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"98","DOI":"10.3109\/01677063.2014.892486","article-title":"Motor impairments, striatal degeneration, and altered dopamine-glutamate interplay in mice lacking PSD-95","volume":"28","author":"Zhang","year":"2014","journal-title":"J. Neurogenet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.biopsych.2010.09.037","article-title":"Dysregulated postsynaptic density and endocytic zone in the amygdala of human heroin and cocaine abusers","volume":"69","author":"Fagergren","year":"2011","journal-title":"Biol. Psychiatry"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"11919","DOI":"10.18632\/aging.202896","article-title":"Bioinformatic analyses and experimental validation of the role of m6A RNA methylation regulators in progression and prognosis of adrenocortical carcinoma","volume":"13","author":"Xu","year":"2021","journal-title":"Aging"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1385\/JMN:11:1:57","article-title":"Glial Expression of the Proenkephalin Gene in Slice Cultures of the Subventricular Zone","volume":"11","author":"Just","year":"1998","journal-title":"J. Mol. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1038\/nrn2373","article-title":"Actin in action: The interplay between the actin cytoskeleton and synaptic efficacy","volume":"9","author":"Cingolani","year":"2008","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.neulet.2018.07.023","article-title":"Naloxone precipitated morphine withdrawal and clock genes expression in striatum: A comparative study in three different protocols for the development of morphine dependence","volume":"685","author":"Roy","year":"2018","journal-title":"Neurosci. Lett."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1111\/adb.12663","article-title":"The circadian gene, Per2, influences methamphetamine sensitization and reward through the dopaminergic system in the striatum of mice","volume":"24","author":"Kim","year":"2019","journal-title":"Addict. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/j.euroneuro.2010.03.006","article-title":"Development of morphine-induced tolerance and withdrawal: Involvement of the clock gene mPer2","volume":"20","author":"Schneider","year":"2010","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1111\/j.1601-183X.2012.00777.x","article-title":"Common transcriptional effects in the mouse striatum following chronic treatment with heroin and methamphetamine","volume":"11","author":"Piechota","year":"2012","journal-title":"Genes Brain Behav."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.bbrc.2021.04.053","article-title":"Increase of Cry 1 expression is a common phenomenon of the disturbed circadian clock in ischemic stroke and opioid addiction","volume":"558","author":"Roy","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"173105","DOI":"10.1016\/j.pbb.2021.173105","article-title":"Circadian rhythms and substance use disorders: A bidirectional relationship","volume":"201","author":"Tamura","year":"2021","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7929","DOI":"10.1007\/s12035-019-01650-5","article-title":"Opioid-Induced Hyperalgesia Is Associated with Dysregulation of Circadian Rhythm and Adaptive Immune Pathways in the Mouse Trigeminal Ganglia and Nucleus Accumbens","volume":"56","author":"Zhang","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1023\/A:1025774716976","article-title":"Aggression and the three opioid families (endorphins, enkephalins, and dynorphins) in mice","volume":"33","author":"Tordjman","year":"2003","journal-title":"Behav. Genet."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/1\/21\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:51:32Z","timestamp":1760169092000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/1\/21"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,22]]},"references-count":47,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["genes13010021"],"URL":"https:\/\/doi.org\/10.3390\/genes13010021","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2021,12,22]]}}}