Functional Connectivity Differences Between Two Culturally Distinct Prairie Vole Populations: Insights Into the Prosocial Network

Published:November 24, 2021DOI:



      The goal of this study was to elucidate the fundamental connectivity—resting-state connectivity—within and between nodes in the olfactory and prosocial (PS) cores, which permits the expression of social monogamy in males; and how differential connectivity accounts for differential expression of prosociality and aggression.


      Using resting-state functional magnetic resonance imaging, we integrated graph theory analysis to compare functional connectivity between two culturally/behaviorally distinct male prairie voles (Microtus ochrogaster).


      Illinois males display significantly higher levels of prosocial behavior and lower levels of aggression than KI (Kansas dam and Illinois sire) males, which are associated with differences in underlying neural mechanisms and brain microarchitecture. Shared connectivity 1) between the anterior hypothalamic area and the paraventricular nucleus and 2) between the medial preoptic area and bed nucleus of the stria terminalis and the nucleus accumbens core suggests essential relationships required for male prosocial behavior. In contrast, Illinois males displayed higher levels of global connectivity and PS intracore connectivity, a greater role for the bed nucleus of the stria terminalis and anterior hypothalamic area, which were degree connectivity hubs, and greater PS and olfactory intercore connectivity.


      These findings suggest that behavioral differences are associated with PS core degree of connectivity and postsignal induction. This transgenerational system may serve as powerful mental health and drug abuse translational model in future studies.


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        • Kleiman D.G.
        Monogamy in mammals.
        Q Rev Biol. 1977; 52: 39-69
        • Lukas D.
        • Clutton-Brock T.H.
        The evolution of social monogamy in mammals.
        Science. 2013; 341: 526-530
        • Young K.A.
        • Liu Y.
        • Wang Z.
        The neurobiology of social attachment: A comparative approach to behavioral, neuroanatomical, and neurochemical studies.
        Comp Biochem Physiol C Toxicol Pharmacol. 2008; 148: 401-410
        • Cushing B.S.
        • Wynne-Edwards K.E.
        Estrogen receptor-α distribution in male rodents is associated with social organization.
        J Comp Neurol. 2006; 494: 595-605
        • Yee J.R.
        • Kenkel W.M.
        • Kulkarni P.
        • Moore K.
        • Perkeybile A.M.
        • Toddes S.
        • et al.
        BOLD fMRI in awake prairie voles: A platform for translational social and affective neuroscience.
        Neuroimage. 2016; 138: 221-232
        • Ortiz J.J.
        • Portillo W.
        • Paredes R.G.
        • Young L.J.
        • Alcauter S.
        Resting state brain networks in the prairie vole.
        Sci Rep. 2018; 8: 1231
        • López-Gutiérrez M.F.
        • Gracia-Tabuenca Z.
        • Ortiz J.J.
        • Camacho F.J.
        • Young L.J.
        • Paredes R.G.
        • et al.
        Brain functional networks associated with social bonding in monogamous voles.
        Elife. 2021; 10e55081
        • Ortiz R.
        • Yee J.R.
        • Kulkarni P.P.
        • Solomon N.G.
        • Keane B.
        • Cai X.
        • et al.
        Differences in diffusion-weighted imaging and resting-state functional connectivity between two culturally distinct populations of prairie vole [published online ahead of print Sep 5].
        Biol Psychiatry Cogn Neurosci Neuroimaging. 2020;
        • Cushing B.S.
        • Martin J.O.
        • Young L.J.
        • Carter C.S.
        The effects of peptides on partner preference formation are predicted by habitat in prairie voles.
        Horm Behav. 2001; 39: 48-58
        • Cushing B.S.
        • Kramer K.M.
        Microtines: A model system for studying the evolution and regulation of social monogamy.
        Acta Theriol Sin. 2005; 25: 182-199
        • Cushing B.S.
        • Razzoli M.
        • Murphy A.Z.
        • Epperson P.M.
        • Le W.W.
        • Hoffman G.E.
        Intraspecific variation in estrogen receptor alpha and the expression of male sociosexual behavior in two populations of prairie voles.
        Brain Res. 2004; 1016: 247-254
        • Stetzik L.
        • Payne 3rd, R.E.
        • Roache L.E.
        • Ickes J.R.
        • Cushing B.S.
        Maternal and paternal origin differentially affect prosocial behavior and neural mechanisms in prairie voles.
        Behav Brain Res. 2019; 360: 94-102
        • Bellucci G.
        • Camilleri J.A.
        • Eickhoff S.B.
        • Krueger F.
        Neural signatures of prosocial behaviors.
        Neurosci Biobehav Rev. 2020; 118: 186-195
        • Wang F.
        • Kessels H.W.
        • Hu H.
        The mouse that roared: Neural mechanisms of social hierarchy.
        Trends Neurosci. 2014; 37: 674-682
        • Choleris E.
        • Clipperton-Allen A.E.
        • Phan A.
        • Kavaliers M.
        Neuroendocrinology of social information processing in rats and mice.
        Front Neuroendocrinol. 2009; 30: 442-459
        • Newman S.W.
        The medial extended amygdala in male reproductive behavior. A node in the mammalian social behavior network.
        Ann N Y Acad Sci. 1999; 877: 242-257
        • Bermond B.
        Effects of medial preoptic hypothalamus anterior lesions on three kinds of behavior in the rat: Intermale aggressive, male-sexual, and mouse-killing behavior.
        Aggr Behav. 1982; 8: 335-354
        • Ferris C.F.
        • Potegal M.
        Vasopressin receptor blockade in the anterior hypothalamus suppresses aggression in hamsters.
        Physiol Behav. 1988; 44: 235-239
        • Kirkpatrick B.
        • Williams J.R.
        • Slotnick B.M.
        • Carter C.S.
        Olfactory bulbectomy decreases social behavior in male prairie voles (M. ochrogaster).
        Physiol Behav. 1994; 55: 885-889
        • Dulac C.
        • Axel R.
        A novel family of genes encoding putative pheromone receptors in mammals.
        Cell. 1995; 83: 195-206
        • Swaney W.T.
        • Keverne E.B.
        The evolution of pheromonal communication.
        Behav Brain Res. 2009; 200: 239-247
        • Worsley K.J.
        Statistical analysis of activation images.
        in: Jezzard P. Matthews P.M. Smith S.M. Functional Magnetic Resonance Imaging: An Introduction to Methods. Oxford University Press, Oxford2001: 251-270
      1. Bastian M, Heymann S, Jacomy M (2009): Gephi: An open source software for exploring and manipulating networks. Presented at the International AAAI Conference on Weblogs and Social Media, May 17–20, San Jose, California.

        • Freeman L.C.
        Centrality in social networks conceptual clarification.
        Soc Netw. 1978; 1: 215-239
        • Bavelas A.
        Communication patterns in task-oriented groups.
        J Acoust Soc Am. 1950; 22: 725-730
        • Sporns O.
        • Honey C.J.
        • Kötter R.
        Identification and classification of hubs in brain networks.
        PLoS One. 2007; 2e1049
        • Rubinov M.
        • Sporns O.
        Complex network measures of brain connectivity: Uses and interpretations.
        Neuroimage. 2010; 52: 1059-1069
        • Koshimori Y.
        • Cho S.S.
        • Criaud M.
        • Christopher L.
        • Jacobs M.
        • Ghadery C.
        • et al.
        Disrupted nodal and hub organization account for brain network abnormalities in Parkinson’s disease.
        Front Aging Neurosci. 2016; 8: 259
        • Chen J.
        • Yang J.
        • Xiang Z.
        • Huang X.
        • Lu C.
        • Liu S.
        • et al.
        Graph theory analysis reveals premature ejaculation is a brain disorder with altered structural connectivity and depressive symptom: A DTI-based connectome study.
        Eur J Neurosci. 2021; 53: 1905-1921
        • Wang J.
        • Zuo X.
        • He Y.
        Graph-based network analysis of resting-state functional MRI.
        Front Syst Neurosci. 2010; 4: 16
        • Achard S.
        • Bullmore E.
        Efficiency and cost of economical brain functional networks.
        PLoS Comput Biol. 2007; 3: e17
        • Bassett D.S.
        • Bullmore E.
        • Verchinski B.A.
        • Mattay V.S.
        • Weinberger D.R.
        • Meyer-Lindenberg A.
        Hierarchical organization of human cortical networks in health and schizophrenia.
        J Neurosci. 2008; 28: 9239-9248
        • Supekar K.
        • Musen M.
        • Menon V.
        Development of large-scale functional brain networks in children.
        PLoS Biol. 2009; 7e1000157
        • Supekar K.
        • Menon V.
        • Rubin D.
        • Musen M.
        • Greicius M.D.
        Network analysis of intrinsic functional brain connectivity in Alzheimer’s disease.
        PLoS Comput Biol. 2008; 4e1000100
        • Wang J.
        • Zuo X.
        • Dai Z.
        • Xia M.
        • Zhao Z.
        • Zhao X.
        • et al.
        Disrupted functional brain connectome in individuals at risk for Alzheimer’s disease.
        Biol Psychiatry. 2013; 73: 472-481
        • Wang L.
        • Zhu C.
        • He Y.
        • Zang Y.
        • Cao Q.
        • Zhang H.
        • et al.
        Altered small-world brain functional networks in children with attention-deficit/hyperactivity disorder.
        Hum Brain Mapp. 2009; 30: 638-649
        • Chen Y.
        • Huang X.
        • Wu M.
        • Li K.
        • Hu X.
        • Jiang P.
        • et al.
        Disrupted brain functional networks in drug-naïve children with attention deficit hyperactivity disorder assessed using graph theory analysis.
        Hum Brain Mapp. 2019; 40: 4877-4887
        • Wang Y.
        • Tao F.
        • Zuo C.
        • Kanji M.
        • Hu M.
        • Wang D.
        Disrupted resting frontal–parietal attention network topology is associated with a clinical measure in children with attention-deficit/hyperactivity disorder.
        Front Psychiatry. 2019; 10: 300
        • Liu J.
        • Liang J.
        • Qin W.
        • Tian J.
        • Yuan K.
        • Bai L.
        • et al.
        Dysfunctional connectivity patterns in chronic heroin users: An fMRI study.
        Neurosci Lett. 2009; 460: 72-77
        • Hua K.
        • Wang T.
        • Li C.
        • Li S.
        • Ma X.
        • Li C.
        • et al.
        Abnormal degree centrality in chronic users of codeine-containing cough syrups: A resting-state functional magnetic resonance imaging study.
        NeuroImage Clin. 2018; 19: 775-781
        • Ieong H.F.
        • Yuan Z.
        Abnormal resting-state functional connectivity in the orbitofrontal cortex of heroin users and its relationship with anxiety: A pilot fNIRS study.
        Sci Rep. 2017; 7: 46522
        • Gaines M.S.
        • Fugate C.L.
        • Johnson M.L.
        • Johnson D.C.
        • Hisey J.R.
        • Quadagno D.M.
        Manipulation of aggressive behavior in male prairie voles (Microtus ochrogaster) implanted with testosterone in Silastic tubing.
        Can J Zool. 1985; 63: 2525-2528
        • Carter C.S.
        • Roberts R.L.
        The psychobiological basis of cooperative breeding in rodents.
        in: Solomon N.G. French J.A. Cooperative Breeding in Mammals. Cambridge University Press, Cambridge1997: 231-266
        • De Vries G.J.D.
        • Villalba C.
        Brain sexual dimorphism and sex differences in parental and other social behaviors.
        Ann N Y Acad Sci. 1997; 807: 273-286
        • Wang Z.
        • Hulihan T.J.
        • Insel T.R.
        Sexual and social experience is associated with different patterns of behavior and neural activation in male prairie voles.
        Brain Res. 1997; 767: 321-332
        • Kramer K.M.
        • Carr M.S.
        • Schmidt J.V.
        • Cushing B.S.
        Parental regulation of central patterns of estrogen receptor alpha.
        Neuroscience. 2006; 142: 165-173
        • Lei K.
        • Cushing B.S.
        • Musatov S.
        • Ogawa S.
        • Kramer K.M.
        Estrogen receptor-α in the bed nucleus of the stria terminalis regulates social affiliation in male prairie voles (Microtus ochrogaster).
        PLoS One. 2010; 5e8931
        • Cushing B.S.
        • Perry A.
        • Musatov S.
        • Ogawa S.
        • Papademetriou E.
        Estrogen receptors in the medial amygdala inhibit the expression of male prosocial behavior.
        J Neurosci. 2008; 28: 10399-10403
        • Lambert C.T.
        • Lichter J.B.
        • Perry A.N.
        • Castillo S.A.
        • Keane B.
        • Cushing B.S.
        • Solomon N.G.
        Medial amygdala ERα expression influences monogamous behaviour of male prairie voles in the field.
        Proc Biol Sci. 2021; 288: 20210318
        • Gobrogge K.L.
        • Wang Z.W.
        Chapter 6: Genetics of aggression in voles.
        Adv Genet. 2011; 75: 121-150
        • Gobrogge K.L.
        • Liu Y.
        • Jia X.
        • Wang Z.
        Anterior hypothalamic neural activation and neurochemical associations with aggression in pair-bonded male prairie voles.
        J Comp Neurol. 2007; 502: 1109-1122
        • Gobrogge K.L.
        • Liu Y.
        • Young L.J.
        • Wang Z.
        Anterior hypothalamic vasopressin regulates pair-bonding and drug-induced aggression in a monogamous rodent.
        Proc Natl Acad Sci U S A. 2009; 106: 19144-19149
        • Ache B.W.
        • Young J.M.
        Olfaction: Diverse species, conserved principles.
        Neuron. 2005; 48: 417-430
        • Corey EA
        • Ache BW
        Comparative olfactory transduction.
        in: Zufall F Munger SD Chemosensory Transduction. Elsevier, Amsterdam2016: 207-223
        • Kramer K.M.
        • Yamamoto Y.
        • Hoffman G.E.
        • Cushing B.S.
        Estrogen receptor α and vasopressin in the paraventricular nucleus of the hypothalamus in Peromyscus.
        Brain Res. 2005; 1032: 154-161
        • Roberts R.L.
        • Cushing B.S.
        • Carter C.S.
        Intraspecific variation in the induction of female sexual receptivity in prairie voles.
        Physiol Behav. 1998; 64: 209-212
        • Shipman M.L.
        • Green J.T.
        Cerebellum and cognition: Does the rodent cerebellum participate in cognitive functions?.
        Neurobiol Learn Mem. 2020; 170: 106996
        • Swihart R.K.
        • Slade N.A.
        Differences in home-range size between sexes of Microtus ochrogaster.
        J Mammal. 1989; 70: 816-820
        • Okhovat M.
        • Berrio A.
        • Wallace G.
        • Ophir A.G.
        • Phelps S.M.
        Sexual fidelity trade-offs promote regulatory variation in the prairie vole brain.
        Science. 2015; 350: 1371-1374
        • Grippo A.J.
        • Cushing B.S.
        • Carter C.S.
        Depression-like behavior and stressor-induced neuroendocrine activation in female prairie voles exposed to chronic social isolation.
        Psychosom Med. 2007; 69: 149-157
        • Horie K.
        • Inoue K.
        • Suzuki S.
        • Adachi S.
        • Yada S.
        • Hirayama T.
        • et al.
        Oxytocin receptor knockout prairie voles generated by CRISPR/Cas9 editing show reduced preference for social novelty and exaggerated repetitive behaviors.
        Horm Behav. 2019; 111: 60-69
        • Aragona B.J.
        • Detwiler J.M.
        • Wang Z.
        Amphetamine reward in the monogamous prairie vole.
        Neurosci Lett. 2007; 418: 190-194
        • Cushing B.S.
        • Mogekwu N.
        • Le W.W.
        • Hoffman G.E.
        • Carter C.S.
        Cohabitation induced Fos immunoreactivity in the monogamous prairie vole.
        Brain Res. 2003; 965: 203-211
        • Aragona B.J.
        • Liu Y.
        • Yu Y.J.
        • Curtis J.T.
        • Detwiler J.M.
        • Insel T.R.
        • Wang Z.
        Nucleus accumbens dopamine differentially mediates the formation and maintenance of monogamous pair bonds.
        Nat Neurosci. 2006; 9: 133-139
        • Kulkarni P.
        • Stolberg T.
        • Sullivanjr J.M.
        • Ferris C.F.
        Imaging evolutionarily conserved neural networks: Preferential activation of the olfactory system by food-related odor.
        Behav Brain Res. 2012; 230: 201-207