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Annual Review of Neuroscience

Volume 46, 2023

Neural Control of Sexually Dimorphic Social Behavior: Connecting Development to Adulthood

Abstract

Rapid advances in the neural control of social behavior highlight the role of interconnected nodes engaged in differential information processing to generate behavior. Many innate social behaviors are essential to reproductive fitness and therefore fundamentally different in males and females. Programming these differences occurs early in development in mammals, following gonadal differentiation and copious androgen production by the fetal testis during a critical period. Early-life programming of social behavior and its adult manifestation are separate but yoked processes, yet how they are linked is unknown. This review seeks to highlight that gap by identifying four core mechanisms (epigenetics, cell death, circuit formation, and adult hormonal modulation) that could connect developmental changes to the adult behaviors of mating and aggression. We further propose that a unique social behavior, adolescent play, bridges the preweaning to the postpubertal brain by engaging the same neural networks underpinning adult reproductive and aggressive behaviors.

Keyword(s): aggression, aromatase, epigenetics, GABA neurons, social behavior network, social play
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/content/journals/10.1146/annurev-neuro-121522-110856
2023-07-10
2024-04-27
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Literature Cited

  1. Ahmed EI, Zehr JL, Schulz KM, Lorenz BH, DonCarlos LL, Sisk CL. 2008. Pubertal hormones modulate the addition of new cells to sexually dimorphic brain regions. Nat. Neurosci. 11:995–97
     [Google Scholar]
  2. Amateau SK, McCarthy MM. 2002a. A novel mechanism of dendritic spine plasticity involving estradiol induction of prostaglandin-E2. J. Neurosci. 22:8586–96
     [Google Scholar]
  3. Amateau SK, McCarthy MM. 2002b. Sexual differentiation of astrocyte morphology in the developing rat preoptic area. J. Neuroendocrinol. 14:904–10
     [Google Scholar]
  4. Amateau SK, McCarthy MM. 2004. Induction of PGE2 by estradiol mediates developmental masculinization of sex behavior. Nat. Neurosci. 7:643–50
     [Google Scholar]
  5. Bale TL, Baram TZ, Brown AS, Goldstein JM, Insel TR et al. 2010. Early life programming and neurodevelopmental disorders. Biol. Psychiatry 68:314–19
     [Google Scholar]
  6. Bayless DW, Yang T, Mason MM, Susanto AAT, Lobdell A, Shah NM. 2019. Limbic neurons shape sex recognition and social behavior in sexually naive males. Cell 176:1190–205.e20
     [Google Scholar]
  7. Berenbaum SA. 1999. Effects of early androgens on sex-typed activities and interests in adolescents with congenital adrenal hyperplasia. Horm. Behav. 35:102–10
     [Google Scholar]
  8. Bergan JF, Ben-Shaul Y, Dulac C. 2014. Sex-specific processing of social cues in the medial amygdala. eLife 3:e02743
     [Google Scholar]
  9. Blake BE, McCoy KA. 2015. Hormonal programming of rat social play behavior: Standardized techniques will aid synthesis and translation to human health. Neurosci. Biobehav. Rev. 55:184–97
     [Google Scholar]
  10. Borland JM, Walton JC, Norvelle A, Grantham KN, Aiani LM et al. 2020. Social experience and sex-dependent regulation of aggression in the lateral septum by extrasynaptic δGABAA receptors. Psychopharmacology 237:329–44
     [Google Scholar]
  11. Bupesh M, Legaz I, Abellan A, Medina L. 2011. Multiple telencephalic and extratelencephalic embryonic domains contribute neurons to the medial extended amygdala. J. Comp. Neurol. 519:1505–25
     [Google Scholar]
  12. Chen PB, Hu RK, Wu YE, Pan L, Huang S et al. 2019. Sexually dimorphic control of parenting behavior by the medial amygdala. Cell 176:1206–21.e18
     [Google Scholar]
  13. Christensen A, Dewing P, Micevych P. 2011. Membrane-initiated estradiol signaling induces spinogenesis required for female sexual receptivity. J. Neurosci. 31:17583–89
     [Google Scholar]
  14. Chung WC, Swaab DF, De Vries GJ. 2000. Apoptosis during sexual differentiation of the bed nucleus of the stria terminalis in the rat brain. J. Neurobiol. 43:234–43
     [Google Scholar]
  15. Cisternas CD, Cortes LR, Golynker I, Castillo-Ruiz A, Forger NG. 2020. Neonatal inhibition of DNA methylation disrupts testosterone-dependent masculinization of neurochemical phenotype. Endocrinology 161:bqz022
     [Google Scholar]
  16. Dalpian F, Rasia-Filho AA, Calcagnotto ME. 2019. Sexual dimorphism, estrous cycle and laterality determine the intrinsic and synaptic properties of medial amygdala neurons in rat. J. Cell Sci. 132:jcs227793
     [Google Scholar]
  17. Davis EC, Popper P, Gorski RA. 1996. The role of apoptosis in sexual differentiation of the rat sexually dimorphic nucleus of the preoptic area. Brain Res. 734:10–18
     [Google Scholar]
  18. Demir E, Li K, Bobrowski-Khoury N, Sanders JI, Beynon RJ et al. 2020. The pheromone darcin drives a circuit for innate and reinforced behaviours. Nature 578:137–41
     [Google Scholar]
  19. Dulac C, O'Connell LA, Wu Z. 2014. Neural control of maternal and paternal behaviors. Science 345:765–70
     [Google Scholar]
  20. Forger NG, Rosen GJ, Waters EM, Jacob D, Simerly RB, De Vries GJ. 2004. Deletion of Bax eliminates sex differences in the mouse forebrain. PNAS 101:13666–71
     [Google Scholar]
  21. Gatewood JD, Wills A, Shetty S, Xu J, Arnold AP et al. 2006. Sex chromosome complement and gonadal sex influence aggressive and parental behaviors in mice. J. Neurosci. 26:2335–42
     [Google Scholar]
  22. Gegenhuber B, Wu MV, Bronstein R, Tollkuhn J. 2022. Gene regulation by gonadal hormone receptors underlies brain sex differences. Nature 606:153–59
     [Google Scholar]
  23. Ghahramani NM, Ngun TC, Chen PY, Tian Y, Krishnan S et al. 2014. The effects of perinatal testosterone exposure on the DNA methylome of the mouse brain are late-emerging. Biol. Sex Differ. 5:8
     [Google Scholar]
  24. Gorski RA, Harlan RE, Jacobson CD, Shryne JE, Southam AM. 1980. Evidence for the existence of a sexually dimorphic nucleus in the preoptic area of the rat. J. Comp. Neurol. 193:529–39
     [Google Scholar]
  25. Haller J, Fuchs E, Halasz J, Makara GB. 1999. Defeat is a major stressor in males while social instability is stressful mainly in females: towards the development of a social stress model in female rats. Brain Res. Bull. 50:33–39
     [Google Scholar]
  26. Harlan RE, Shivers BD, Pfaff DW. 1984. Lordosis as a sexually dimorphic neural function. Prog. Brain Res. 61:239–55
     [Google Scholar]
  27. Hashikawa K, Hashikawa Y, Lischinsky J, Lin D. 2018. The neural mechanisms of sexually dimorphic aggressive behaviors. Trends Genet. 34:755–76
     [Google Scholar]
  28. Hirata T, Li P, Lanuza GM, Cocas LA, Huntsman MM, Corbin JG. 2009. Identification of distinct telencephalic progenitor pools for neuronal diversity in the amygdala. Nat. Neurosci. 12:141–49
     [Google Scholar]
  29. Hoffmann C. 2000. COX-2 in brain and spinal cord implications for therapeutic use. Curr. Med. Chem. 7:1113–20
     [Google Scholar]
  30. Hong W, Kim DW, Anderson DJ. 2014. Antagonistic control of social versus repetitive self-grooming behaviors by separable amygdala neuronal subsets. Cell 158:1348–61
     [Google Scholar]
  31. Hu RK, Zuo Y, Ly T, Wang J, Meera P et al. 2021. An amygdala-to-hypothalamus circuit for social reward. Nat. Neurosci. 24:831–42
     [Google Scholar]
  32. Hull EM, Dominguez JM. 2007. Sexual behavior in male rodents. Horm. Behav. 52:45–55
     [Google Scholar]
  33. Hunt J, Breuker CJ, Sadowski JA, Moore AJ. 2009. Male-male competition, female mate choice and their interaction: determining total sexual selection. J. Evol. Biol. 22:13–26
     [Google Scholar]
  34. Inoue S, Yang R, Tantry A, Davis CH, Yang T et al. 2019. Periodic remodeling in a neural circuit governs timing of female sexual behavior. Cell 179:1393–408.e16
     [Google Scholar]
  35. Janak PH, Tye KM. 2015. From circuits to behaviour in the amygdala. Nature 517:284–92
     [Google Scholar]
  36. Jennings KJ, de Lecea L. 2020. Neural and hormonal control of sexual behavior. Endocrinology 161:bqaa150
     [Google Scholar]
  37. Joel D, McCarthy MM. 2017. Incorporating sex as a biological variable in neuropsychiatric research: Where are we now and where should we be?. Neuropsychopharmacology 42:379–85
     [Google Scholar]
  38. Kaufmann W, Andreasson K, Isakson P, Worley P. 1997. Cyclooxygenases and the central nervous system. Prostaglandins 54:601–24
     [Google Scholar]
  39. Knoedler JR, Inoue S, Bayless DW, Yang T, Tantry A et al. 2022. A functional cellular framework for sex and estrous cycle-dependent gene expression and behavior. Cell 185:654–71.e22
     [Google Scholar]
  40. Kopec AM, Smith CJ, Ayre NR, Sweat SC, Bilbo SD. 2018. Microglial dopamine receptor elimination defines sex-specific nucleus accumbens development and social behavior in adolescent rats. Nat. Commun. 9:3769
     [Google Scholar]
  41. Kow LM, Harlan R, Shivers BD, Pfaff DW. 1985. Inhibition of lordosis reflex in rats by intrahypothalamic infusion of neural excitatory agents: evidence that the hypothalamus contains separate inhibitory and facilitatory elements. Brain Res. 341:26–34
     [Google Scholar]
  42. Lenz KM, Pickett LA, Wright CL, Davis KT, Joshi A, McCarthy MM. 2018. Mast cells in the developing brain determine adult sexual behavior. J. Neurosci. 38:8044–59
     [Google Scholar]
  43. Lenz KM, Wright CL, Martin RC, McCarthy MM. 2011. Prostaglandin E2 regulates AMPA receptor phosphorylation and promotes membrane insertion in preoptic area neurons and glia during sexual differentiation. PLOS ONE 6:e18500
     [Google Scholar]
  44. Li Y, Mathis A, Grewe BF, Osterhout JA, Ahanonu B et al. 2017. Neuronal representation of social information in the medial amygdala of awake behaving mice. Cell 171:1176–90.e17
     [Google Scholar]
  45. Lin D, Boyle MP, Dollar P, Lee H, Lein ES et al. 2011. Functional identification of an aggression locus in the mouse hypothalamus. Nature 470:221–26
     [Google Scholar]
  46. Lischinsky JE, Lin D. 2020. Neural mechanisms of aggression across species. Nat. Neurosci. 23:1317–28
     [Google Scholar]
  47. Lischinsky JE, Sokolowski K, Li P, Esumi S, Kamal Y et al. 2017. Embryonic transcription factor expression in mice predicts medial amygdala neuronal identity and sex-specific responses to innate behavioral cues. eLife 6:e21012
     [Google Scholar]
  48. Marquardt AE, VanRyzin JW, Fuquen RW, McCarthy MM. 2023. Social play experience in juvenile rats is indispensable for appropriate socio-sexual behavior in adulthood in males but not females. Front. Behav. Neurosci. 16:1076765
     [Google Scholar]
  49. McCarthy MM, Arnold AP. 2011. Reframing sexual differentiation of the brain. Nat. Neurosci. 14:677–83
     [Google Scholar]
  50. McCarthy MM, Coirini H, Schmacher M, Johnson AE, Pfaff DW, McEwen BS. 1991. Excitatory amino acid modulation of lordosis in the rat. Neurosci. Lett. 126:94–97
     [Google Scholar]
  51. McCarthy MM, Nugent BM, Lenz KM. 2017. Neuroimmunology and neuroepigenetics in the establishment of sex differences in the brain. Nat. Rev. Neurosci. 18:471–84
     [Google Scholar]
  52. McCarthy MM, Rissman EF 2014. Epigenetics of reproduction. Knobil and Neill's Physiology of Reproduction T Plant, A Zeleznik 2439–501. Cambridge, MA: Academic
     [Google Scholar]
  53. Meaney MJ, McEwen BS. 1986. Testosterone implants into the amygdala during the neonatal period masculinize the social play of juvenile female rats. Brain Res. 398:324–28
     [Google Scholar]
  54. Meaney MJ, Stewart J, Poulin P, McEwen BS. 1983. Sexual differentiation of social play in rat pups is mediated by the neonatal androgen-receptor system. Neuroendocrinology 37:85–90
     [Google Scholar]
  55. Meisel RL, Sachs BD 1994. The physiology of male sexual behavior. Physiology of Reproduction E Knobil, JD Neill 3–106. New York: Raven Press
     [Google Scholar]
  56. Mermelstein PG, Micevych PE. 2008. Nervous system physiology regulated by membrane estrogen receptors. Rev. Neurosci. 19:413–24
     [Google Scholar]
  57. Metcalfe DD, Baram D, Mekori YA. 1997. Mast cells. Physiol. Rev. 77:1033–79
     [Google Scholar]
  58. Micevych P, Kuo J, Christensen A. 2009. Physiology of membrane oestrogen receptor signalling in reproduction. J. Neuroendocrinol. 21:249–56
     [Google Scholar]
  59. Mizukami S, Nishizuka M, Arai Y. 1983. Sexual difference in nuclear volume and its ontogeny in the rat amygdala. Exp. Neurol. 79:569–75
     [Google Scholar]
  60. Murray EK, Hien A, de Vries GJ, Forger NG. 2009. Epigenetic control of sexual differentiation of the bed nucleus of the stria terminalis. Endocrinology 150:4241–47
     [Google Scholar]
  61. Nugent BM, Wright CL, Shetty AC, Hodes GE, Lenz KM et al. 2015. Brain feminization requires active repression of masculinization via DNA methylation. Nat. Neurosci. 18:690–97
     [Google Scholar]
  62. Numan M, Rosenblatt JS, Komisaruk BR. 1977. Medial preoptic area and onset of maternal behavior in the rat. J. Comp. Physiol. Psychol. 91:146–64
     [Google Scholar]
  63. Ogawa S, Lubahn DB, Korach KS, Pfaff DW. 1997. Behavioral effects of estrogen receptor gene disruption in male mice. PNAS 94:1476–81
     [Google Scholar]
  64. Padilla SL, Qiu J, Soden ME, Sanz E, Nestor CC et al. 2016. Agouti-related peptide neural circuits mediate adaptive behaviors in the starved state. Nat. Neurosci. 19:734–41
     [Google Scholar]
  65. Pellis SM, Pellis VC, Pelletier A, Leca JB. 2019. Is play a behavior system, and, if so, what kind?. Behav. Process. 160:1–9
     [Google Scholar]
  66. Pfaff DW, Sakuma Y. 1979a. Deficit in the lordosis reflex of female rats caused by lesions in the ventromedial nucleus of the hypothalamus. J. Physiol. 288:203–10
     [Google Scholar]
  67. Pfaff DW, Sakuma Y. 1979b. Facilitation of the lordosis reflex of female rats from the ventromedial nucleus of the hypothalamus. J. Physiol. 288:189–202
     [Google Scholar]
  68. Pickett LA, VanRyzin JW, Marquardt AE, McCarthy MM. 2023. Microglia phagocytosis mediates the volume and function of the rat sexually dimorphic nucleus of the preoptic area. PNAS 120:e2212646120
     [Google Scholar]
  69. Polston EK, Gu G, Simerly RB. 2004. Neurons in the principal nucleus of the bed nuclei of the stria terminalis provide a sexually dimorphic GABAergic input to the anteroventral periventricular nucleus of the hypothalamus. Neuroscience 123:793–803
     [Google Scholar]
  70. Powers JB, Newman SW, Bergondy ML. 1987. MPOA and BNST lesions in male Syrian hamsters: differential effects on copulatory and chemoinvestigatory behaviors. Behav. Brain Res. 23:181–95
     [Google Scholar]
  71. Raam T, Hong W. 2021. Organization of neural circuits underlying social behavior: a consideration of the medial amygdala. Curr. Opin. Neurobiol. 68:124–36
     [Google Scholar]
  72. Remedios R, Kennedy A, Zelikowsky M, Grewe BF, Schnitzer MJ, Anderson DJ. 2017. Social behaviour shapes hypothalamic neural ensemble representations of conspecific sex. Nature 550:388–92
     [Google Scholar]
  73. Roselli CE, Balthazart J. 2011. Sexual differentiation of sexual behavior and its orientation. Front. Neuroendocrinol. 32:109
     [Google Scholar]
  74. Schwark RW, Fuxjager MJ, Schmidt MF. 2022. Proposing a neural framework for the evolution of elaborate courtship displays. eLife 11:e74860
     [Google Scholar]
  75. Schwarz JM, Liang S-L, Thompson SM, McCarthy MM. 2008. Estradiol induces hypothalamic dendritic spines by enhancing glutamate release: a mechanism for organizational sex differences. Neuron 58:584–98
     [Google Scholar]
  76. Schwarz JM, McCarthy MM. 2008a. Cellular mechanisms of estradiol-mediated masculinization of the brain. J. Steroid Biochem. Mol. Biol. 109:300–6
     [Google Scholar]
  77. Schwarz JM, McCarthy MM. 2008b. Steroid-induced sexual differentiation of the brain: multiple pathways, one goal. J. Neurochem. 105:1561–72
     [Google Scholar]
  78. Schwarz JM, Nugent BM, McCarthy MM. 2010. Developmental and hormone-induced epigenetic changes to estrogen and progesterone receptor genes in brain are dynamic across the life span. Endocrinology 151:4871–81
     [Google Scholar]
  79. Silver R, Curley JP. 2013. Mast cells on the mind: new insights and opportunities. Trends Neurosci. 36:513–21
     [Google Scholar]
  80. Simerly RB. 2002. Wired for reproduction: organization and development of sexually dimorphic circuits in the mammalian forebrain. Annu. Rev. Neurosci. 25:507–36
     [Google Scholar]
  81. Simerly RB, Swanson LW. 1996. The organization of neural inputs to the medial preoptic nucleus of the rat. J. Comp. Neurol. 246:312–46
     [Google Scholar]
  82. Sugimoto Y, Narumiya S. 2007. Prostaglandin E receptors. J. Biol. Chem. 282:11613–17
     [Google Scholar]
  83. Swanson LW. 2003. The amygdala and its place in the cerebral hemisphere. Ann. N. Y. Acad. Sci. 985:174–84
     [Google Scholar]
  84. Theoharides TC, Alysandratos KD, Angelidou A, Delivanis DA, Sismanopoulos N et al. 2012. Mast cells and inflammation. Biochim. Biophys. Acta 1822:21–33
     [Google Scholar]
  85. Toda K, Okada T, Takeda K, Akira S, Saibara T et al. 2001. Oestrogen at the neonatal stage is critical for the reproductive ability of male mice as revealed by supplementation with 17β-oestradiol to aromatase gene (Cyp19) knockout mice. J. Endocrinol. 168:455–63
     [Google Scholar]
  86. Todd BJ, Schwarz JM, McCarthy MM. 2005. Prostaglandin-E2: a point of divergence in estradiol-mediated sexual differentiation. Horm. Behav. 48:512–21
     [Google Scholar]
  87. Tsukahara S, Morishita M. 2020. Sexually dimorphic formation of the preoptic area and the bed nucleus of the stria terminalis by neuroestrogens. Front. Neurosci. 14:797
     [Google Scholar]
  88. Unger EK, Burke KJ Jr., Yang CF, Bender KJ, Fuller PM, Shah NM. 2015. Medial amygdalar aromatase neurons regulate aggression in both sexes. Cell Rep. 10:453–62
     [Google Scholar]
  89. Vanderschuren LJ, Achterberg EJ, Trezza V. 2016. The neurobiology of social play and its rewarding value in rats. Neurosci. Biobehav. Rev. 70:86–105
     [Google Scholar]
  90. VanRyzin JW, Marquardt AE, Argue KJ, Vecchiarelli HA, Ashton SE et al. 2019. Microglial phagocytosis of newborn cells is induced by endocannabinoids and sculpts sex differences in juvenile rat social play. Neuron 102:2435–49.e6
     [Google Scholar]
  91. Walker DM, Zhou X, Ramakrishnan A, Cates HM, Cunningham AM et al. 2020. Adolescent social isolation reprograms the medial amygdala: transcriptome and sex differences in reward. bioRxiv 2020.02.18.955187. https://doi.org/10.1101/2020.02.18.955187
  92. Wei D, Talwar V, Lin D. 2021. Neural circuits of social behaviors: innate yet flexible. Neuron 109:1600–20
     [Google Scholar]
  93. Wiegand SJ, Terasawa E, Bridson WE. 1978. Persistent estrus and blockade of progesterone-induced LH release follows lesions which do not damage the suprachiasmatic nucleus. Endocrinology 102:1645–48
     [Google Scholar]
  94. Wright CL, Burks SR, McCarthy MM. 2008. Identification of prostaglandin E2 receptors mediating perinatal masculinization of adult sex behavior and neuroanatomical correlates. Dev. Neurobiol. 68:1406–19
     [Google Scholar]
  95. Wright CL, McCarthy MM. 2009. Prostaglandin E2-induced masculinization of brain and behavior requires protein kinase A, AMPA/kainate, and metabotropic glutamate receptor signaling. J. Neurosci. 29:13274–82
     [Google Scholar]
  96. Wu MV, Tollkuhn J. 2017. Estrogen receptor alpha is required in GABAergic, but not glutamatergic, neurons to masculinize behavior. Horm. Behav. 95:3–12
     [Google Scholar]
  97. Yamaguchi T, Wei D, Song SC, Lim B, Tritsch NX, Lin D. 2020. Posterior amygdala regulates sexual and aggressive behaviors in male mice. Nat. Neurosci. 23:1111–24
     [Google Scholar]
  98. Zuloaga DG, Puts DA, Jordan CL, Breedlove SM. 2008. The role of androgen receptors in the masculinization of brain and behavior: what we've learned from the testicular feminization mutation. Horm. Behav. 53:613–26
     [Google Scholar]
  99. Zup SL, Carrier H, Waters EM, Tabor A, Bengston L et al. 2003. Overexpression of Bcl-2 reduces sex differences in neuron number in the brain and spinal cord. J. Neurosci. 23:2357–62
     [Google Scholar]
/content/journals/10.1146/annurev-neuro-121522-110856
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Neural Control of Sexually Dimorphic Social Behavior: Connecting Development to Adulthood
Annual Review of Neuroscience 46, 321 (2023); https://doi.org/10.1146/annurev-neuro-121522-110856
/content/journals/10.1146/annurev-neuro-121522-110856
/content/journals/10.1146/annurev-neuro-121522-110856
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