Differences in Diffusion-Weighted Imaging and Resting-State Functional Connectivity Between Two Culturally Distinct Populations of Prairie Vole

Published:September 05, 2020DOI:



      We used the highly prosocial prairie vole to test the hypothesis that higher-order brain structure—microarchitecture and functional connectivity (FC)—would differ between males from populations with distinctly different levels of prosocial behavior. Specifically, we studied males from Illinois (IL), which display high levels of prosocial behavior, and first generation males from Kansas dams and IL males (KI), which display the lowest level of prosocial behavior and higher aggression. Behavioral differences between these males are associated with overexpression of estrogen receptor alpha in the medial amygdala and bed nucleus of the stria terminalis and neuropeptide expression in the paraventricular nucleus.


      We compared apparent diffusion coefficient, fractional anisotropy, and blood oxygen level–dependent resting-state FC between males.


      IL males displayed higher apparent diffusion coefficient in regions associated with prosocial behavior, including the bed nucleus of the stria terminalis, paraventricular nucleus, and anterior thalamic nuclei, while KI males showed higher apparent diffusion coefficient in the brainstem. KI males showed significantly higher fractional anisotropy than IL males in 26 brain regions, with the majority being in the brainstem reticular activating system. IL males showed more blood oxygen level–dependent resting-state FC between the bed nucleus of the stria terminalis, paraventricular nucleus, and medial amygdala along with other brain regions, including the hippocampus and areas associated with social and reward networks.


      Our results suggest that gray matter microarchitecture and FC may play a role the expression of prosocial behavior and that differences in other brain regions, especially the brainstem, could be involved. The differences between males suggests that this system represents a potentially valuable model system for studying emotional differences and vulnerability to stress and addiction.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


        • Mech S.
        • Dunlap A.
        • Hodges K.
        • Wolff J.
        Multi-male mating by paired and unpaired female prairie voles (Microtus ochrogaster).
        Behaviour. 2002; 139: 1147-1160
        • 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
        • Insel T.R.
        • Hulihan T.J.
        A gender-specific mechanism for pair bonding: Oxytocin and partner preference formation in monogamous voles.
        Behav Neurosci. 1995; 109: 782-789
        • Williams J.R.
        • Carter C.S.
        • Insel T.
        Partner preference development in female prairie voles is facilitated by mating or the central infusion of oxytocin.
        Ann N Y Acad Sci. 1992; 652: 487-489
        • Tickerhoof M.C.
        • Smith A.S.
        Vasopressinergic neurocircuitry regulating social attachment in a monogamous species.
        Front Endocrinol. 2017; 8: 265
        • Aragona B.J.
        • Liu Y.
        • Curtis J.T.
        • Stephan F.K.
        • Wang Z.
        A critical role for nucleus accumbens dopamine in partner-preference formation in male prairie voles.
        J Neurosci. 2003; 23: 3483-3490
        • Wang Z.
        • Yu G.
        • Cascio C.
        • Liu Y.
        • Gingrich B.
        • Insel T.R.
        Dopamine D2 receptor-mediated regulation of partner preferences in female prairie voles (Microtus ochrogaster): A mechanism for pair bonding?.
        Behav Neurosci. 1999; 113: 602-611
        • DeVries A.C.
        • DeVries M.B.
        • Taymans S.
        • Carter C.S.
        Modulation of pair bonding in female prairie voles (Microtus ochrogaster) by corticosterone.
        Proc Natl Acad Sci U S A. 1995; 92: 7744-7748
        • 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
        • Walum H.
        • Young L.J.
        The neural mechanisms and circuitry of the pair bond.
        Nat Rev Neurosci. 2018; 19: 643-654
        • Insel T.R.
        • Shapiro L.E.
        Oxytocin receptor distribution reflects social organization in monogamous and polygamous voles.
        Proc Natl Acad Sci U S A. 1992; 89: 5981-5985
        • Insel T.
        • Wang Z.
        • Ferris C.
        Patterns of brain vasopressin receptor distribution associated with social organization in microtine rodents.
        J Neurosci. 1994; 14: 5381-5392
        • 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
        • Smeltzer M.D.
        • Curtis J.T.
        • Aragona B.J.
        • Wang Z.
        Dopamine, oxytocin, and vasopressin receptor binding in the medial prefrontal cortex of monogamous and promiscuous voles.
        Neurosci Lett. 2006; 394: 146-151
        • Lim M.M.
        • Nair H.P.
        • Young L.J.
        Species and sex differences in brain distribution of corticotropin-releasing factor receptor subtypes 1 and 2 in monogamous and promiscuous vole species.
        J Comp Neurol. 2005; 487: 75-92
        • Getz L.L.
        • Carter C.S.
        • Gavish L.
        The mating system of the prairie vole, Microtus ochrogaster: Field and laboratory evidence for pair-bonding.
        Behav Ecol Sociobiol. 1981; 8: 189-194
        • Thomas J.A.
        • Birney E.C.
        Parental care and mating system of the prairie vole, Microtus ochrogaster.
        Behav Ecol Sociobiol. 1979; 5: 171-186
        • Roberts R.L.
        • Williams J.R.
        • Wang A.K.
        • Carter C.S.
        Cooperative breeding and monogamy in prairie voles: Influence of the sire and geographical variation.
        Anim Behav. 1998; 55: 1131-1140
        • 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
        • 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
        • Stetzik L.
        • Payne 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. 2018; 360: 94-102
        • 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
        • Cushing B.S.
        Estrogen receptor alpha distribution and expression in the social neural network of monogamous and polygynous Peromyscus.
        PLoS One. 2016; 11e0150373
        • 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
        • Stetzik L.
        • Ganshevsky D.
        • Lende M.N.
        • Roache L.E.
        • Musatov S.
        • Cushing B.S.
        Inhibiting ERα expression in the medial amygdala increases prosocial behavior in male meadow voles (Microtus pennsylvanicus).
        Behav Brain Res. 2018; 351: 42-48
        • Kramer K.M.
        • Carr M.S.
        • Schmidt J.V.
        • Cushing B.S.
        Parental regulation of central patterns of estrogen receptor α.
        Neuroscience. 2006; 142: 165-173
        • 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
        • Bellucci G.
        • Camilleri J.A.
        • Eickhoff S.B.
        • Krueger F.
        Neural signatures of prosocial behaviors.
        Neurosci Biobehav Rev. 2020; 118: 86-195
        • Ferris C.F.
        • Kulkarni P.
        • Toddes S.
        • Yee J.
        • Kenkel W.
        • Nedelman M.
        Studies on the Q175 knock-in model of Huntington’s disease using functional imaging in awake mice: Evidence of olfactory dysfunction.
        Front Neurol. 2014; 5: 94
        • Ferris C.F.
        • Nodinea S.
        • Pottalaa T.
        • Caia X.
        • Knoxa T.M.
        • Fofana F.H.
        • et al.
        Alterations in brain neurocircuitry following treatment with thechemotherapeutic agent paclitaxel in rats.
        Neurobiol Pain. 2019; 6: 100034
        • Kulkarni P.
        • Grant S.
        • Morrison T.R.
        • Cai X.
        • Iriah S.
        • Kristal B.S.
        • et al.
        Characterizing the human APOE epsilon 4 knock-in transgene in female and male rats with multimodal magnetic resonance imaging.
        Brain Res. 2020; 1747: 147030
        • 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
        • Benjamini Y.
        • Hochberg Y.
        Controlling the false discovery rate: A practical and powerful approach to multiple testing.
        J R Stat Soc Ser B Stat Methodol. 1995; 57: 289-300
        • Green J.G.
        • Hollander E.
        Autism and oxytocin: New developments in translational approaches to therapeutics.
        Neurotheraputics. 2010; 7: 250-257
        • Horie K.
        • Kiyoshi I.
        • Suzuki S.
        • Adachi S.
        • Yada S.
        • Hirayma 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
        • Hostetler C.M.
        • Anacker A.M.J.
        • Loftis J.M.
        • Ryabinin A.E.
        Social housing and alcohol drinking in male-female pairs of prairie voles (Microtus ochrogaster).
        Psychopharmacology (Berl). 2012; 224: 121-132
        • Zink C.F.
        • Meyer-Lindenberg A.
        Human neuroimaging of oxytocin and vasopressin in social cognition.
        Horm Behav. 2012; 61: 400-409
        • Noonan M.P.
        • Mars R.B.
        • Sallet J.
        • Dunbar R.I.M.
        • Fellows L.K.
        The structural and functional brain networks that support human social networks.
        Behav Brian Res. 2018; 355: 12-23
        • Yang C.
        • Xia M.
        • Han M.
        • Liang Y.
        Social support and resilience as mediators between stress and life satisfaction among people with substance use disorder in China.
        Front Psychiatry. 2018; 9: 436
        • Ersche K.D.
        • Menga C.
        • Ziauddeena H.
        • Stochla J.
        • Williamse G.B.
        • Bullmorea E.T.
        • Robbins T.W.
        Brain networks underlying vulnerability and resilience to drug addiction.
        Proc Nat Acad Sci U S A. 2020; 117: 15253-15261
        • Cushing B.S.
        • Kramer K.M.
        Microtines: A model system for studying the evolution and regulation of social monogamy.
        Acta Theriol Sinica. 2005; 25: 182-199
        • Kulkarni P.
        • Kenkel W.
        • Finklestein S.P.
        • Barchet T.M.
        • Ren J.
        • Davenport M.
        • et al.
        use of anisotropy, 3d segmented atlas, and computational analysis to identify gray matter subcortical lesions common to concussive injury from different sites on the cortex.
        PLoS One. 2015; 10e0125748
        • Young K.A.
        • Gobrogge K.L.
        • Liu Y.
        • Wang Z.
        The neurobiology of pair bonding: Insights from a socially monogamous rodent.
        Front Neuroendocrinol. 2010; 32: 53-69
        • 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
        • Wang Z.
        • Smith W.
        • Major D.E.
        • Vries G.J.D.
        Sex and species differences in the effects of cohabitation on vasopressin messenger RNA expression in the bed nucleus of the stria terminalis in prairie voles (Microtus ochrogaster) and meadow voles (Microtus pennsylvanicus).
        Brain Res. 1994; 650: 212-218
        • Numan M.
        • Insel T.R.
        Paternal behavior.
        in: The Neurobiology of Parental Behavior. Springer, New York2003
        • Ahern T.H.
        • Young L.J.
        The impact of early life family structure on adult social attachment, alloparental behavior, and the neuropeptide systems regulating affiliative behaviors in the monogamous prairie vole (Microtus ochrogaster).
        Front Behav Neurosci. 2009; 3: 17
        • Gobrogge K.L.
        • Jia X.
        • Liu Y.
        • Wang Z.
        Neurochemical mediation of affiliation and aggression associated with pair-bonding.
        Biol Psychiatry. 2017; 81: 231-242
        • Dupire A.
        • Kant P.
        • Mons N.
        • Marchand A.R.
        • Coutureau E.
        • Dalrymple-Alford J.
        • Wolff M.
        A role for anterior thalamic nuclei in affective cognition: interaction with environmental conditions.
        Hippocampus. 2013; 23: 392-404
        • Saper C.B.
        • Scammell T.E.
        • Lu J.
        Hypothalamic regulation of sleep and circadian rhythms.
        Nature. 2005; 437: 1257-1263
        • De Cicco V.
        • Fantozzi M.P.T.
        • Cataldo E.
        • Barresi M.
        • Bruschini L.
        • Faraguna U.
        • Manzoni D.
        Trigeminal, visceral and vestibular inputs may improve cognitive functions by acting through the locus coeruleus and the ascending reticular activating system: A new hypothesis.
        Front Neuroanat. 2017; 11: 130
        • 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
        • Ferguson J.N.
        • Aldag J.M.
        • Insel T.R.
        • Young L.J.
        Oxytocin in the medial amygdala is essential for social recognition in the mouse.
        J Neurosci. 2001; 21: 8278-8285
        • LeDoux J.E.
        Emotion circuits in the brain.
        Ann Rev Neurosci. 2000; 23: 155-184
        • 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
        • Kesner R.P.
        A behavioral analysis of dentate gyrus function.
        Prog Brain Res. 2007; 163: 567-576
        • Vazdarjanova A.
        • Guzowski J.F.
        Differences in hippocampal neuronal population responses to modifications of an environmental context: Evidence for distinct, yet complementary, functions of CA3 and CA1 ensembles.
        J Neurosci. 2004; 24: 6489-6496