[en] Although the participation of sex hormones and sex hormone-responsive neurons in aggressive behavior has been extensively studied, the role of other systems within the hypothalamus-pituitary-gonadal (HPG) axis remains elusive. Here we assessed how the gonadotropin-releasing hormone (GnRH) and kisspeptin systems are impacted by escalated aggression in male mice. We used a combination of social isolation and aggression training (IST) to exacerbate mice’s aggressive behavior. Next, low-aggressive (grouphoused, GH) and highly aggressive (IST) mice were compared regarding neuronal activity in the target populations and hormonal levels, using immunohistochemistry and ELISA, respectively. Finally, we used pharmacological and viral approaches to manipulate neuropeptide signaling and expression, subsequently evaluating its effects on behavior. IST mice exhibited enhanced aggressive behavior compared to GH controls, which was accompanied by elevated neuronal activity in GnRH neurons and arcuate nucleus kisspeptin neurons. Remarkably, IST mice presented an increased number of kisspeptin neurons in the anteroventral periventricular nucleus (AVPV). In addition, IST mice exhibited elevated levels of luteinizing hormone (LH) in serum. Accordingly, activation and blockade of GnRH receptors (GnRHR) exacerbated and reduced aggression, respectively. Surprisingly, kisspeptin had intricate effects on aggression, i.e., viral ablation of AVPV-kisspeptin neurons impaired the training-induced rise in aggressive behavior whereas kisspeptin itself strongly reduced aggression in IST mice. Our results indicate that IST enhances aggressive behavior in male mice by exacerbating HPG-axis activity. Particularly, increased GnRH neuron activity and GnRHR signaling were found to underlie aggression whereas the relationship with kisspeptin remains puzzling.
Disciplines :
Neurosciences & comportement
Auteur, co-auteur :
Oliveira, VEM; Universitätsmedizin der Johannes Gutenberg-Universität Mainz
Nelson RJ Trainor BC Neural mechanisms of aggression Nat Rev Neurosci 2007 8 536 46 1:CAS:528:DC%2BD2sXmslWjsrs%3D 17585306 10.1038/nrn2174
Lischinsky JE Lin D Neural mechanisms of aggression across species Nat Neurosci 2020 23 1317 28 1:CAS:528:DC%2BB3cXitVCrtbbP 33046890 10.1038/s41593-020-00715-2
Reidy DE Kearns MC DeGue S Lilienfeld SO Massetti G Kiehl KA Why psychopathy matters: implications for public health and violence prevention Aggress Violent Behav 2015 24 214 25 29593448 5868481 10.1016/j.avb.2015.05.018
Masis-Calvo M Schmidtner AK de Moura Oliveira VE Grossmann CP de Jong TR Neumann ID Animal models of social stress: the dark side of social interactions Stress 2018 5 41 432
Haller J. Preclinical models of conduct disorder—principles and pharmacologic perspectives. Neurosci Biobehav Rev. 2016. 2016. https://doi.org/10.1016/j.neubiorev.2016.05.032.
Freitag CM Konrad K Stadler C De Brito SA Popma A Herpertz SC et al. Conduct disorder in adolescent females: current state of research and study design of the FemNAT-CD consortium Eur Child Adolesc Psychiatry 2018 9 1077 93 10.1007/s00787-018-1172-6
Sandi C Haller J Stress and the social brain: behavioural effects and neurobiological mechanisms Nat Rev Neurosci 2015 16 290 304 1:CAS:528:DC%2BC2MXntFCiu78%3D 25891510 10.1038/nrn3918
Oliveira VE de M. Animal Models of Aggression. Handbook of Anger, Aggression, and Violence, Cham: Springer International Publishing; 2023. p. 1–24.
Kim HHS Jung JH Social isolation and psychological distress during the COVID-19 pandemic: a cross-national analysis Gerontologist 2021 61 103 13 33125065 10.1093/geront/gnaa168
Mojahed A, Brym S, Hense H, Grafe B, Helfferich C, Lindert J, et al. Rapid review on the associations of social and geographical isolation and intimate partner violence: implications for the ongoing COVID-19 pandemic. Front Psychiatry. 2021;12:1–14.
Sumner SA Mercy JA Dahlberg LL Hillis SD Klevens J Houry D Violence in the United States: status, challenges, and opportunities J Am Med Assoc. 2015 314 478 88 1:CAS:528:DC%2BC2MXhtlyktLnN 10.1001/jama.2015.8371
Oliveira VEM Lukas M Wolf HN Durante E Lorenz A Mayer AL et al. Oxytocin and vasopressin within the ventral and dorsal lateral septum modulate aggression in female rats Nat Commun 2021 12 2900 2021NatCo.12.2900O 1:CAS:528:DC%2BB3MXhtFaqtb%2FI 34006875 8131389 10.1038/s41467-021-23064-5
Oliveira VEM Neumann ID de Jong TR Post-weaning social isolation exacerbates aggression in both sexes and affects the vasopressin and oxytocin system in a sex-specific manner Neuropharmacology 2019 156 107504 1:CAS:528:DC%2BC1MXhvFSls7s%3D 30664846 10.1016/j.neuropharm.2019.01.019
Trainor BC Kyomen HH Marler CA Estrogenic encounters: How interactions between aromatase and the environment modulate aggression Front Neuroendocrinol 2006 27 170 9 1:CAS:528:DC%2BD28Xms1ensr0%3D 16376420 2080681 10.1016/j.yfrne.2005.11.001
Koolhaas JM Schuurman T Wiepkema PR The organization of intraspecific agonistic behaviour in the rat Prog Neurobiol 1980 15 247 68 1:STN:280:DyaL3M7gt1Siug%3D%3D 7005965 10.1016/0301-0082(80)90024-6
Albert DJ Dyson EM Walsh ML Cohabitation with a female activates testosterone-dependent social aggression in male rats independently of changes in serum testosterone concentration I 1988 44 735 40 1:CAS:528:DyaL1MXovV2jug%3D%3D
Oyegbile TO Marler CA Winning fights elevates testosterone levels in California mice and enhances future ability to win fights Horm Behav 2005 48 259 67 1:CAS:528:DC%2BD2MXosVCktro%3D 15979073 10.1016/j.yhbeh.2005.04.007
Sayegh JF, Kobor G, Lajtha A, Vadasz C. Effects of social isolation and the time of day on testosterone levels in plasma of C57BL/6By and BALB/cBy mice. Steroids. 1990;55:79–82.
Trainor BC Lin S Finy MS Rowland MR Nelson RJ Photoperiod reverses the effects of estrogens on male aggression via genomic and nongenomic pathways Proc Natl Acad Sci USA 2007 104 9840 5 2007PNAS.104.9840T 1:CAS:528:DC%2BD2sXmsFSmsbk%3D 17525148 1876655 10.1073/pnas.0701819104
Lee H Kim D-W Remedios R Anthony TE Chang A Madisen L et al. Scalable control of mounting and attack by Esr1+ neurons in the ventromedial hypothalamus Nature 2014 509 627 32 2014Natur.509.627L 1:CAS:528:DC%2BC2cXoslCrt78%3D 24739975 4098836 10.1038/nature13169
Yang CF Chiang MC Gray DC Prabhakaran M Alvarado M Juntti SA et al. Sexually dimorphic neurons in the ventromedial hypothalamus govern mating in both sexes and aggression in males Cell 2013 153 896 909 1:CAS:528:DC%2BC3sXnsFSksLg%3D 23663785 3767768 10.1016/j.cell.2013.04.017
Unger EK Burke KJ Fuller PM Unger EK Burke KJ Yang CF et al. Medial amygdalar aromatase neurons regulate aggression in both sexes report medial amygdalar aromatase neurons regulate aggression in both sexes Cell Rep. 2015 10 453 62 1:CAS:528:DC%2BC2MXhsVarsb4%3D 25620703 4349580 10.1016/j.celrep.2014.12.040
Trainor BC Greiwe KM Nelson RJ Individual differences in estrogen receptor α in select brain nuclei are associated with individual differences in aggression Horm Behav 2006 50 338 45 1:CAS:528:DC%2BD28Xms1Grsr4%3D 16753164 1950320 10.1016/j.yhbeh.2006.04.002
Delli V, Silva MSB, Prévot V, Chachlaki K The KiNG of reproduction: Kisspeptin/ nNOS interactions shaping hypothalamic GnRH release. Mol Cell Endocrinol. 2021;532:1–12.
Kaprara A Huhtaniemi IT The hypothalamus-pituitary-gonad axis: tales of mice and men Metabolism 2018 86 3 17 1:CAS:528:DC%2BC1cXhtFKkur8%3D 29223677 10.1016/j.metabol.2017.11.018
Rudolph LM, Bentley GE, Calandra RS, Paredes AH, Tesone M, Wu TJ, et al. Peripheral and central mechanisms involved in the hormonal control of male and female reproduction. J Neuroendocrinol. 2016;28:1–12.
Kingston DA Seto MC Ahmed AG Fedoroff P Firestone P Bradford JM The role of central and peripheral hormones in sexual and violent recidivism in sex offenders J Am Acad Psychiatry Law 2012 40 476 85 23233468
Veenema AH Torner L Blume A Beiderbeck DI Neumann ID Low inborn anxiety correlates with high intermale aggression: Link to ACTH response and neuronal activation of the hypothalamic paraventricular nucleus Horm Behav 2007 51 11 19 1:CAS:528:DC%2BD28Xht12mtrzE 16935287 10.1016/j.yhbeh.2006.07.004
Eleftheriou BE Church RL Effects of repeated exposure to aggressionand defeat on plasma and pituitary levels of luteinizing hormone Hin C57BL / 6J mice Gen Comp Endocrinol 1967 9 263 6 1:CAS:528:DyaF2sXltFGhs7s%3D 6069719 10.1016/0016-6480(67)90060-3
Penfold LM Norton T Asa CS Effects of GnRH agonists on testosterone and testosterone-stimulated parameters for contraception and aggression reduction in male lion-tailed Macaques (Macaca silenus) Zoo Biol 2021 40 541 50 1:CAS:528:DC%2BB3MXitFequrrF 34224162 10.1002/zoo.21635
Rydhmer L Lundström K Andersson K Immunocastration reduces aggressive and sexual behaviour in male pigs Animal 2010 4 965 72 1:CAS:528:DC%2BC3cXlsVOgt7Y%3D 22444270 10.1017/S175173111000011X
Van Der Weiden RMF, Helmerhorst FM, Eriksson T. Gonadotropin-releasing hormone agonist against severe aggression in autism. BMJ Case Rep. 2016;2016:1–3.
Wen S Götze IN Mai O Schauer C Leinders-Zufall T Boehm U Genetic identification of GnRH receptor neurons: a new model for studying neural circuits underlying reproductive physiology in the mouse brain Endocrinology 2011 152 1515 26 1:CAS:528:DC%2BC3MXkvVOkt70%3D 21303944 10.1210/en.2010-1208
Spergel DJ Neuropeptidergic modulation of GnRH neuronal activity and GnRH secretion controlling reproduction: insights from recent mouse studies Cell Tissue Res 2019 375 179 91 1:CAS:528:DC%2BC1cXhsVGjsb3M 30078104 10.1007/s00441-018-2893-z
Moore AM Coolen LM Lehman MN Kisspeptin/Neurokinin B/Dynorphin (KNDy) cells as integrators of diverse internal and external cues: evidence from viral-based monosynaptic tract-tracing in mice Sci Rep. 2019 9 26 28 10.1038/s41598-019-51201-0
Navarro VictorM Tena-Sempere M Kisspeptins and the neuroendocrine control of reproduction Front Biosci 2011 S3 267 75 10.2741/s150
Ruka KA Burger LL Moenter SM Regulation of arcuate neurons coexpressing kisspeptin, neurokinin b, and dynorphin by modulators of neurokinin 3 and k-opioid receptors in adult male mice Endocrinology 2013 154 2761 71 1:CAS:528:DC%2BC3sXhtF2nurbF 23744642 3713217 10.1210/en.2013-1268
Zelikowsky M Hui M Karigo T Choe A Yang B Blanco MR et al. The neuropeptide Tac2 controls a distributed brain state induced by chronic social isolation stress Cell 2018 173 1265 1279.e19 1:CAS:528:DC%2BC1cXpvVemurk%3D 29775595 5967263 10.1016/j.cell.2018.03.037
Koolhaas JM Coppens CM de Boer SF Buwalda B Meerlo P Timmermans PJ The resident-intruder paradigm: a standardized test for aggression, violence and social stress J Visualized Exp 2013 77 4367
Miczek KA Maxson SC Fish EW Faccidomo S Aggressive behavioral phenotypes in mice Behav Brain Res 2001 125 167 81 1:STN:280:DC%2BD3MrnsVCqug%3D%3D 11682108 10.1016/S0166-4328(01)00298-4
Blumstein DT, Evans CS, Daniel JC JWatcher 0.9: An Introductory User’s Guide. Animal Behaviour Laboratory, Macquarie University. 2000.
Oliveira VEM de Jong Trynke R Neumann ID Modelling sexual violence in male rats: the sexual aggression test (SxAT) Transl Psychiatry 2022 12 1 12
Oliveira VE de M, Bakker J. Neuroendocrine regulation of female aggression. Front Endocrinol (Lausanne). 2022;13.
Oliveira VEM Jong TR De Neumann ID Synthetic oxytocin and vasopressin act within the central amygdala to exacerbate aggression in female wistar rats Front Neurosci 2022 16 1 12 10.3389/fnins.2022.906617
Hellier V, Brock O, Candlish M, Desroziers E, Aoki M, Mayer C, et al. Female sexual behavior in mice is controlled by kisspeptin neurons. Nat Commun. 2018;9.
Faure MC, Corona R, de Bournonville C, Foidart J-M, Cornil CA. Role of membrane estrogen receptor alpha on the positive feedback of 1 estrogens on LH secretion 2 3. Biorxiv. 2023. 2023. https://doi.org/10.1101/2023.03.22.533736.
Steyn FJ Wan Y Clarkson J Veldhuis JD Herbison AE Chen C Development of a methodology for and assessment of pulsatile luteinizing hormone secretion in juvenile and adult male mice Endocrinology 2013 154 4939 45 1:CAS:528:DC%2BC3sXhvV2itL%2FL 24092638 5398599 10.1210/en.2013-1502
Haller J The neurobiology of abnormal manifestations of aggression-A review of hypothalamic mechanisms in cats, rodents, and humans Brain Res Bull 2013 93 97 109 2013amco.book...H 1:CAS:528:DC%2BC38Xhslaktb%2FN 23085544 10.1016/j.brainresbull.2012.10.003
Kagawa N Hirose S Fujimoto K Nomura C Fujita Y Honda A et al. Social rank-dependent expression of gonadotropin-releasing hormones and kisspeptin in the medaka brain Gen Comp Endocrinol 2017 249 48 54 1:CAS:528:DC%2BC2sXkt1WjsbY%3D 28279673 10.1016/j.ygcen.2017.03.001
Williamson CM Romeo RD Curley JP Dynamic changes in social dominance and mPOA GnRH expression in male mice following social opportunity Horm Behav 2017 87 80 88 1:CAS:528:DC%2BC28XhvVGqtLnN 27826060 10.1016/j.yhbeh.2016.11.001
Lin D Boyle MP Dollar P Lee H Lein ES Perona P et al. Functional identification of an aggression locus in the mouse hypothalamus Nature 2011 470 221 6 2011Natur.470.221L 1:CAS:528:DC%2BC3MXhslWrt74%3D 21307935 3075820 10.1038/nature09736
Yamaguchi T, Wei D, Song SC, Lim B, Tritsch NX, Lin D. Posterior amygdala regulates sexual and aggressive behaviors in male mice. Nat Neurosci. 2020. 2020. https://doi.org/10.1038/s41593-020-0675-x.
Lo B, Freeman AR, Singh B, Hanadari-Levy A, Berman J, Chaves A, et al. Effects of a gonadotropin-releasing hormone agonist on sex behavior in females of the southern giant pouched rat. Integr Comp Biol, 62, Oxford University Press; 2022. p. 613-24.
Bayerl DS Klampfl SM Bosch OJ More than reproduction: central gonadotropin-releasing hormone antagonism decreases maternal aggression in lactating rats J Neuroendocrinol 2019 31 1 8 10.1111/jne.12709
Tata B Mimouni NEH Barbotin AL Malone SA Loyens A Pigny P et al. Elevated prenatal anti-Müllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood Nat Med 2018 24 834 46 1:CAS:528:DC%2BC1cXpsFOltLY%3D 29760445 6098696 10.1038/s41591-018-0035-5
Stagkourakis S, Spigolon G, Liu G, Anderson DJ. Experience-dependent plasticity in an innate social behavior is mediated by hypothalamic LTP. 2020. 2020. https://doi.org/10.1073/pnas.2011782117/-/DCSupplemental.
Trainor BC Bird IM Marler CA Opposing hormonal mechanisms of aggression revealed through short-lived testosterone manipulations and multiple winning experiences Horm Behav 2004 45 115 21 1:CAS:528:DC%2BD2cXhvV2gs7w%3D 15019798 10.1016/j.yhbeh.2003.09.006
Nagae M, Uenoyama Y, Okamoto S, Tsuchida H, Ikegami K, Goto T. Direct evidence that KNDy neurons maintain gonadotropin pulses and folliculogenesis as the GnRH pulse generator. 2021;118:1–11.
James McQuillan H Han SY Cheong I Herbison AE GnRH pulse generator activity across the estrous cycle of female mice Endocrinology 2019 160 1480 91 31083714 10.1210/en.2019-00193
Tanaka K Osako Y Yuri K Juvenile social experience regulates central neuropeptides relevant to emotional and social behaviors Neuroscience 2010 166 1036 42 1:CAS:528:DC%2BC3cXivFGhtbs%3D 20096332 10.1016/j.neuroscience.2010.01.029
Brock O Bakker J The two kisspeptin neuronal populations are differentially organized and activated by estradiol in mice Endocrinology 2013 154 2739 49 1:CAS:528:DC%2BC3sXhtF2nurbL 23744640 10.1210/en.2013-1120
Szymanski L Bakker J Aromatase knockout mice show normal steroid-induced activation of gonadotrophin-releasing hormone neurones and luteinising hormone surges with a reduced population of kisspeptin neurones in the rostral hypothalamus J Neuroendocrinol 2012 24 1222 33 1:CAS:528:DC%2BC38Xht1Sktr7O 22577852 10.1111/j.1365-2826.2012.02334.x
Silva MSB Decoster L Trova S Mimouni NEH Delli V Chachlaki K et al. Female sexual behavior is disrupted in a preclinical mouse model of PCOS via an attenuated hypothalamic nitric oxide pathway Proc Natl Acad Sci USA 2022 119 1 12 10.1073/pnas.2203503119
Trainor BC Workman JL Jessen R Nelson RJ Impaired nitric oxide synthase signaling dissociates social investigation and aggression Behav Neurosci 2007 121 362 9 1:CAS:528:DC%2BD2sXltFKntbs%3D 17469926 2128042 10.1037/0735-7044.121.2.362
Demas GE Eliasson MJL Dawson TM Dawson VL Kriegsfeld LJ Nelson RJ et al. Inhibition of neuronal nitric oxide synthase increases aggressive behavior in mice Mol Med 1997 3 610 6 1:CAS:528:DyaK2sXntFCitrg%3D 9323712 2230093 10.1007/BF03401818
Nelson RJ Demais GE Huang PL Fishman MC Dawson VL Dawson TM et al. Behavioural abnormalities in male mice lacking neuronal nitric oxide synthase Nat Lett 1995 378 383 6 1995Natur.378.383N 1:CAS:528:DyaK2MXps1ams70%3D 10.1038/378383a0
Yang L Cui J Zeng L Lu W Targeting PSD95/nNOS by ZL006 alleviates social isolation-induced heightened attack behavior in mice Psychopharmacol (Berl) 2022 239 267 76 1:CAS:528:DC%2BB3MXit1OhsrjE 10.1007/s00213-021-06000-9
Stephens SBZ Di Giorgio NP Liaw RB Parra RA Yang JA Chahal N et al. Estradiol-dependent and -independent stimulation of KIss1 expression in the amygdala, BNST, and lateral septum of mice Endocrinology 2018 159 3389 402 1:CAS:528:DC%2BC1MXitlCgurfM 30107405 6112601 10.1210/en.2018-00583
Menon R, Süß T, Oliveira VEM, Neumann ID, Bludau A. Neurobiology of the lateral septum: regulation of social behavior. Trends Neurosci. 2022;45:27–40.
Wong LC Wang L D’Amour JA Yumita T Chen G Yamaguchi T et al. Effective modulation of male aggression through lateral septum to medial hypothalamus projection Curr Biol 2016 26 593 604 1:CAS:528:DC%2BC28XisFSrtLs%3D 26877081 4783202 10.1016/j.cub.2015.12.065
Newman EL Covington HE III Suh J Bicakci MB Ressler KJ Debold JF et al. Fighting females: neural and behavioral consequences of social defeat stress in female mice Biol Psychiatry 2019 86 657 68 31255250 6788975 10.1016/j.biopsych.2019.05.005
Ho HP Olsson M Westberg L Melke J Eriksson E The serotonin reuptake inhibitor fluoxetine reduces sex steroid-related aggression in female rats: an animal model of premenstrual irritability? Neuropsychopharmacology 2001 24 502 10 1:CAS:528:DC%2BD3MXitF2ks7c%3D 11282250 10.1016/S0893-133X(00)00219-0
