Sex differences in the regulation of social and anxiety-related behaviors: insights from vasopressin and oxytocin brain systems

Current Opinion in Neurobiology

Volumn 49, Issue , 2018, Pages 132-140

  Bredewold, Remco ^a   Veenema, Alexa H ^a  

^a MICHIGAN STATE UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

OXYTOCIN; VASOPRESSIN; VASOPRESSIN DERIVATIVE;

AGE; ANTISOCIAL PERSONALITY DISORDER; ANXIETY; BRAIN DEPTH STIMULATION; BRAIN FUNCTION; BRAIN REGION; ELECTROENCEPHALOGRAM; EMOTIONAL DISORDER; EXPERIMENTAL BEHAVIORAL TEST; HUMAN; NERVE CELL NETWORK; NONHUMAN; PREPUBERTY; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; SEX DIFFERENCE; SIGNAL TRANSDUCTION; SOCIAL BEHAVIOR; SOCIAL RECOGNITION TEST; ANIMAL; BRAIN; FEMALE; MALE; METABOLISM; PATHOLOGY; SEXUAL CHARACTERISTICS;

ANIMALS; ANXIETY; BRAIN; FEMALE; HUMANS; MALE; OXYTOCIN; SEX CHARACTERISTICS; SOCIAL BEHAVIOR; VASOPRESSINS;

EID: 85042776446     PISSN: 09594388     EISSN: 18736882     Source Type: Journal    
DOI: 10.1016/j.conb.2018.02.011     Document Type: Review

References (64)

1. Fields, R.D., NIH policy: mandate goes too far. Nature, 510, 2014, 340.
2. McCullough, L.D., McCarthy, M.M., de Vries, G.J., NIH policy: status quo is also costly. Nature, 510, 2014, 340.
3. Clayton, J.A., Studying both sexes: a guiding principle for biomedicine. FASEB J 30 (2016), 519–524.
4. Eliot, L., Richardson, S.S., Sex in context: limitations of animal studies for addressing human sex gender neurobehavioral health disparities. J Neurosci 36 (2016), 11823–11830.
5. Shansky, R.M., Woolley, C.S., Considering sex as a biological variable will be valuable for neuroscience research. J Neurosci 36 (2016), 11817–11822.
6. Taborsky, M., Hofmann, H.A., Beery, A.K., Blumstein, D.T., Hayes, L.D., Lacey, E.A., Martins, E.P., Phelps, S.M., Solomon, N.G., Rubenstein, D.R., Taxon matters: promoting integrative studies of social behavior: NESCent Working Group on integrative models of vertebrate sociality: evolution, mechanisms, and emergent properties. Trends Neurosci 38 (2015), 189–191.
7. Donaldson, Z.R., We're the same…but different: addressing academic divides in the study of brain and behavior. Front Behav Neurosci, 21, 2010, 4 pii: 41.
8. Hofmann, H.A., Renn, S.C., Rubenstein, D.R., Introduction to symposium: new frontiers in the integrative study of animal behavior: nothing in neuroscience makes sense except in the light of behavior. Integr Comp Biol 56 (2016), 1192–1196.
9. Beery, A.K., Zucker, I., Sex bias in neuroscience and biomedical research. Neurosci Biobehav Rev 35 (2011), 565–572 The authors performed a large analysis of sex bias in biomedical research and found biases toward male animals in eight of the 10 fields with the highest male-to-female ratios in neuroscience (5.5:1), pharmacology (5:1), and physiology (3.7:1).
10. Bangasser, D.A., Wicks, B., Sex-specific mechanisms for responding to stress. J Neurosci Res 95 (2017), 75–82.
11. Palanza, P., Parmigiani, S., How does sex matter? Behavior, stress and animal models of neurobehavioral disorders. Neurosci Biobehav Rev 76:Pt A (2017), 134–143 Excellent review emphasizing that males and females use different social strategies and that this is associated with marked differences in which males and females respond to social challenges. The authors argue that data obtained in males are often irrelevant for inferring psychopathology and efficacy of pharmacological treatments for females, and that female animal modeling should use an ethological approach and center around female reproduction given the higher parental investment and reproductive burden in females compared to males.
12. Sheehan, T.P., Chambers, R.A., Russell, D.S., Regulation of affect by the lateral septum: implications for neuropsychiatry. Brain Res Brain Res Rev 46 (2004), 71–117 Comprehensive review on the lateral septum highlighting its central role in mood and motivation through extensive connections with the mesocorticolimbic dopamine system, hippocampus, and hypothalamus, among others.
13. De Vries, G.J., Buijs, R.M., The origin of the vasopressinergic and oxytocinergic innervation of the rat brain with special reference to the lateral septum. Brain Res 273 (1983), 307–317.
14. Caffé A.R., van Leeuwen, F.W., Luiten, P.G., Vasopressin cells in the medial amygdala of the rat project to the lateral septum and ventral hippocampus. J Comp Neurol 261 (1987), 237–252.
15. De Vries, G.J., Buijs, R.M., Swaab, D.F., Ontogeny of the vasopressinergic neurons of the suprachiasmatic nucleus and their extrahypothalamic projections in the rat brain — presence of a sex difference in the lateral septum. Brain Res 218 (1981), 67–78 This study in rats is the first to report the existence of a sex difference in vasopressin fiber density in the brain. The finding was somewhat serendipitous; rats were separated by sex when the authors found a ‘disturbingly large variability’. Since these first findings, homologous sex differences have been found in many different species, in mammals as well as other vertebrates.
16. DiBenedictis, B.T., Nussbaum, E.R., Cheung, H.K., Veenema, A.H., Quantitative mapping reveals age and sex differences in vasopressin, but not oxytocin, immunoreactivity in the rat social behavior neural network. J Comp Neurol 525 (2017), 2549–2570.
17. Veenema, A.H., Bredewold, R., De Vries, G.J., Vasopressin regulates social recognition in juvenile and adult rats of both sexes, but in sex- and age-specific ways. Horm Behav 61 (2012), 50–56.
18. Smith, C.J.W., Poehlmann, M.L., Li, S., Ratnaseelan, A.M., Bredewold, R., Veenema, A.H., Age and sex differences in oxytocin and vasopressin V1a receptor binding densities in the rat brain: focus on the social decision-making network. Brain Struct Funct 222 (2017), 981–1006.
19. Dantzer, R., Koob, G.F., Bluthé R.M., Le Moal, M., Septal vasopressin modulates social memory in male rats. Brain Res 457 (1988), 143–147.
20. Engelmann, M., Landgraf, R., Microdialysis administration of vasopressin into the septum improves social recognition in Brattleboro rats. Physiol Behav 55 (1994), 145–149.
21. Wang, Z., Ferris, C.F., De Vries, G.J., Role of septal vasopressin innervation in paternal behavior in prairie voles (Microtus ochrogaster). Proc Natl Acad Sci U S A 91 (1994), 400–404.
22. Landgraf, R., Gerstberger, R., Montkowski, A., Probst, J.C., Wotjak, C.J., Holsboer, F., Engelmann, M., V1 vasopressin receptor antisense oligodeoxynucleotide into septum reduces vasopressin binding, social discrimination abilities, and anxiety-related behavior in rats. J Neurosci 15 (1995), 4250–4258.
23. Landgraf, R., Frank, E., Aldag, J.M., Neumann, I.D., Sharer, C.A., Ren, X., Terwilliger, E.F., Niwa, M., Wigger, A., Young, L.J., Viral vector-mediated gene transfer of the vole V1a vasopressin receptor in the rat septum: improved social discrimination and active social behaviour. Eur J Neurosci 18 (2003), 403–411.
24. Bielsky, I.F., Hu, S.B., Ren, X., Terwilliger, E.F., Young, L.J., The V1a vasopressin receptor is necessary and sufficient for normal social recognition: a gene replacement study. Neuron 47 (2005), 503–513.
25. Beiderbeck, D.I., Neumann, I.D., Veenema, A.H., Differences in intermale aggression are accompanied by opposite vasopressin release patterns within the septum in rats bred for low and high anxiety. Eur J Neurosci 26 (2007), 3597–3605.
26. Veenema, A.H., Beiderbeck, D.I., Lukas, M., Neumann, I.D., Distinct correlations of vasopressin release within the lateral septum and the bed nucleus of the stria terminalis with the display of intermale aggression. Horm Behav 58 (2010), 273–281.
27. Veenema, A.H., Bredewold, R., De Vries, G.J., Sex-specific modulation of juvenile social play by vasopressin. Psychoneuroendocrinology 38 (2013), 2554–2561 Demonstration that vasopressin regulates social play in opposite ways in male and female juvenile rats as shown by V1aR antagonist application intracerebroventricularly and locally in the lateral septum.
28. Bredewold, R., Smith, C.J., Dumais, K.M., Veenema, A.H., Sex-specific modulation of juvenile social play behavior by vasopressin and oxytocin depends on social context. Front Behav Neurosci, 8, 2014, 216.
29. Trezza, V., Baarendse, P.J., Vanderschuren, L.J., The pleasures of play: pharmacological insights into social reward mechanisms. Trends Pharmacol Sci 31 (2010), 463–469.
30. Smith, C.J., Wilkins, K.B., Mogavero, J.N., Veenema, A.H., Social novelty investigation in the juvenile rat: modulation by the μ-opioid system. J Neuroendocrinol 27 (2015), 752–764.
31. Liebsch, G., Wotjak, C.T., Landgraf, R., Engelmann, M., Septal vasopressin modulates anxiety-related behaviour in rats. Neurosci Lett 217 (1996), 101–104.
32. Everts, H.G., Koolhaas, J.M., Differential modulation of lateral septal vasopressin receptor blockade in spatial learning, social recognition, and anxiety-related behaviors in rats. Behav Brain Res 99 (1999), 7–16.
33. Manning, M., Stoev, S., Chini, B., Durroux, T., Mouillac, B., Guillon, G., Peptide and non-peptide agonists and antagonists for the vasopressin and oxytocin V1a, V1b, V2 and OT receptors: research tools and potential therapeutic agents. Prog Brain Res 170 (2008), 473–512.
34. Bredewold, R., Schiavo, J.K., van der Hart, M., Verreij, M., Veenema, A.H., Dynamic changes in extracellular release of GABA and glutamate in the lateral septum during social play behavior in juvenile rats: implications for sex-specific regulation of social play behavior. Neuroscience 307 (2015), 117–127.
35. Risold, P.Y., Swanson, L.W., Connections of the rat lateral septal complex. Brain Res Brain Res Rev 24 (1997), 115–195.
36. Dumais, K.M., Veenema, A.H., Vasopressin and oxytocin receptor systems in the brain: sex differences and sex-specific regulation of social behavior. Front Neuroendocrinol 40 (2016), 1–23 First comprehensive review on sex differences in vasopressin and oxytocin systems and in their regulation of social behavior.
37. Dumais, K.M., Veenema, A.H., Presence and absence of sex differences in structure and function of the brain oxytocin system: implications for understanding social behavior. Shansky, R., Johnson, J., (eds.) Sex Differences in the Central Nervous System, 2016, Academic Press, 247–295.
38. Reppucci, C.J., Gergely, C.K., Veenema, A.H., Activation patterns of vasopressinergic and oxytocinergic brain regions following social play exposure in juvenile male and female rats. J Neuroendocrinol, 2018, 10.1111/jne.12582 [Epub ahead of print].
39. Dumais, K.M., Alonso, A.G., Immormino, M.A., Bredewold, R., Veenema, A.H., Involvement of the oxytocin system in the bed nucleus of the stria terminalis in the sex-specific regulation of social recognition. Psychoneuroendocrinology 64 (2016), 79–88 First study to compare extracellular OXT release in male and female rodents showing that baseline OXT release in the posterior BNST is similar between the sexes, but that males show higher BNST-OXT release than females when exposed to social stimuli.
40. Bale, T.L., Dorsa, D.M., Sex differences in and effects of estrogen on oxytocin receptor messenger ribonucleic acid expression in the ventromedial hypothalamus. Endocrinology 136 (1995), 27–32.
41. Dumais, K.M., Bredewold, R., Mayer, T.E., Veenema, A.H., Sex differences in oxytocin receptor binding in forebrain regions: correlations with social interest in brain region- and sex-specific ways. Horm Behav 64 (2013), 693–701.
42. 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 394 (2006), 146–151.
43. Ebner, N.C., Chen, H., Porges, E., Lin, T., Fischer, H., Feifel, D., Cohen, R.A., Oxytocin's effect on resting-state functional connectivity varies by age and sex. Psychoneuroendocrinology 69 (2016), 50–59.
44. Domes, G., Heinrichs, M., Glascher, J., Muchel, C., Braus, D.F., Herpertz, S.C., Oxytocin attenuates amygdala responses to emotional faces regardless of valence. Biol Psychiatry 62 (2007), 1187–1190.
45. Domes, G., Lischke, A., Berger, C., Grossmann, A., Hauenstein, K., Heinrichs, M., Herpertz, S.C., Effects of intranasal oxytocin on emotional face processing in women. Psychoneuroendocrinology 35 (2010), 83–93 First study in women studying the effects of intranasal oxytocin on social emotional stimuli and demonstrating that intranasal OXT increased fear-induced amygdala BOLD activation in women, an effect opposite to men.
46. Kirsch, P., Esslinger, C., Chen, Q., Mier, D., Lis, S., Siddhanti, S., Gruppe, H., Mattay, V.S., Gallhofer, B., Meyer-Lindenberg, A., Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci 25 (2005), 11489–11493.
47. Lischke, A., Gamer, M., Berger, C., Grossmann, A., Hauenstein, K., Heinrichs, M., Herpertz, S.C., Domes, G., Oxytocin increases amygdala reactivity to threatening scenes in females. Psychoneuroendocrinology 37 (2012), 1431–1438.
48. Rilling, J.K., DeMarco, A.C., Hackett, P.D., Thompson, R., Ditzen, B., Patel, R., Pagnoni, G., Effects of intranasal oxytocin and vasopressin on cooperative behavior and associated brain activity in men. Psychoneuroendocrinology 37 (2012), 447–461.
49. Rilling, J.K., DeMarco, A.C., Hackett, P.D., Chen, X., Gautam, P., Stair, S., Haroon, E., Thompson, R., Ditzen, B., Patel, R., Pagnoni, G., Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction. Psychoneuroendocrinology 39 (2014), 237–248 First study to investigate the effect of intranasal oxytocin on brain function in human males and females within the same paradigm and showing sex-specific activation patterns in the nucleus accumbens, central amygdala, and insular cortex during cooperation.
50. Dumais, K.M., Kulkarni, P.P., Ferris, C.F., Veenema, A.H., Sex differences in neural activation following different routes of oxytocin administration in awake adult rats. Psychoneuroendocrinology 81 (2017), 52–62 First study to investigate the effects of central and peripheral application of oxytocin on brain activation in male and female rats using fMRI showing overall activation in more brain regions in males than in females and sex differences in activation in the nucleus accumbens, central amygdala, and insular cortex.
51. Nakajima, M., Görlich, A., Heintz, N., Oxytocin modulates female sociosexual behavior through a specific class of prefrontal cortical interneurons. Cell 159 (2014), 295–305.
52. Li, K., Nakajima, M., Ibañez-Tallon, I., Heintz, N., A cortical circuit for sexually dimorphic oxytocin-dependent anxiety behaviors. Cell 167 (2016), 60–72 This study in mice revealed a potential mechanism by which the OTR in the mPFC regulates anxiety-related behavior in sex-specific ways. Despite the absence of a sex difference in the expression level of mPFC-OTR or in the response of mPFC-OTR neurons, sex differences in gene expression of mPFC-OTR interneurons and sex differences in the strength of inhibition of layer 2/3 and layer 5 pyramidal mPFC neurons by mPFC-OTR interneurons were found. These sex differences may contribute to a distinct OTR-mediated neural network in males versus females that, in turn, may underlie the observed sex differences in anxiety-related behavior.
53. Sabihi, S., Durosko, N.E., Dong, S.M., Leuner, B., Oxytocin in the prelimbic medial prefrontal cortex reduces anxiety-like behavior in female and male rats. Psychoneuroendocrinology 45 (2014), 31–42.
54. Sabihi, S., Dong, S.M., Maurer, S.D., Post, C., Leuner, B., Oxytocin in the medial prefrontal cortex attenuates anxiety: anatomical and receptor specificity and mechanism of action. Neuropharmacology 125 (2017), 1–12.
55. Sabihi, S., Dong, S.M., Durosko, N.E., Leuner, B., Oxytocin in the medial prefrontal cortex regulates maternal care, maternal aggression and anxiety during the postpartum period. Front Behav Neurosci, 8, 2014, 258.
56. Baran, N.M., Tomaszycki, M.L., Adkins-Regan, E., Early life manipulations of the nonapeptide system alter pair maintenance behaviors and neural activity in adult male zebra finches. Front Behav Neurosci, 10, 2016, 58.
57. Goldsby, J.A., Wolstenholme, J.T., Rissman, E.F., Multi- and transgenerational consequences of bisphenol a on sexually dimorphic cell populations in mouse brain. Endocrinology 158 (2017), 21–30.
58. Taylor, P.V., Veenema, A.H., Paul, M.J., Bredewold, R., Isaacs, S., de Vries, G.J., Sexually dimorphic effects of a prenatal immune challenge on social play and vasopressin expression in juvenile rats. Biol Sex Differ, 3, 2012, 15.
59. Veenema, A.H., Bredewold, R., Neumann, I.D., Opposite effects of maternal separation on intermale and maternal aggression in C57BL/6 mice: link to hypothalamic vasopressin and oxytocin immunoreactivity. Psychoneuroendocrinology 32 (2007), 437–450.
60. Meyer-Lindenberg, A., Domes, G., Kirsch, P., Heinrichs, M., Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine. Nat Rev Neurosci 12 (2011), 524–538.
61. Neumann, I.D., Landgraf, R., Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci 35 (2012), 649–659.
62. Rutter, M., Caspi, A., Moffitt, T.E., Using sex differences in psychopathology to study causal mechanisms: unifying issues and research strategies. J Child Psychol Psychiatry 44 (2003), 1092–1115.
63. World Health Organization, Gender Disparities in Mental Health. 2016.
64. Paxinos, G., Watson, C., The Rat Brain in Stereotaxic Coordinates. 2007, Academic Press.