Abstract
Establishment of enduring sex differences in brain and behavior occurs during pre- or perinatal development, depending on species. For over 50 years the focus has been on gonadal steroid production by male fetuses and the impact on developing brain. An increasing awareness of the importance of sex chromosome complement has broadened the focus but identifying specific roles in development has yet to be achieved. Recent emphasis on transcriptomics has revealed myriad and unexpected differences in gene expression in specific regions of male and female brains which may produce sex differences, serve a compensatory role or provide latent sex differences revealed only in response to challenge. More surprising, however, has been the consistent observation of a central role for inflammatory signaling molecules and immune cells in masculinization of brain and behavior. The signal transduction pathways and specific immune cells vary by brain region, as does the neuroanatomical substrate subject to differentiation, reflecting substantial complexity emerging from what may be a common origin, the maternal immune system. A working hypothesis integrating these various ideas is proposed.
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References
Amateau SK, McCarthy MM (2004) Induction of PGE(2) by estradiol mediates developmental masculinization of sex behavior. Nat Neurosci 7:643–650
Argue KJ, McCarthy MM (2015) Characterization of juvenile play in rats: importance of sex of self and sex of partner. Biol Sex Differ 6:16
Arnold AP, Xu J, Grisham W, Chen X, Kim YH, Itoh Y (2004) Minireview: Sex chromosomes and brain sexual differentiation. Endocrinology 145:1057–1062
Arnold AP, Reue K, Eghbali M, Vilain E, Chen X, Ghahramani N, Itoh Y, Li J, Link JC, Ngun T, Williams-Burris SM (2016) The importance of having two X chromosomes. Philos Trans R Soc Lond Ser B Biol Sci 371:20150113
Barrett TJaS, Thomas C (1998) Steroid receptors at the nexus of transcriptional regulation. J Cell Biochem Suppl 30:198–193
Beato M, Klug J (2000) Steroid hormone receptors: an update. Hum Reprod Update 6:225–236
Beery AK, Zucker I (2010) Sex bias in neuroscience and biomedical research. Neurosci Biobehav Rev 35:565–572
Bianchi I, Lleo A, Gershwin ME, Invernizzi P (2012) The X chromosome and immune associated genes. J Autoimmun 38:J187–J192
Bredewold R, Smith CJ, Dumais KM, Veenema AH (2014) Sex-specific modulation of juvenile social play behavior by vasopressin and oxytocin depends on social context. Front Behav Neurosci 8:216
Brown GC, Neher JJ (2014) Microglial phagocytosis of live neurons. Nat Rev Neurosci 15:209–216
Carruth LL, Reisert I, Arnold AP (2002) Sex chromosome genes directly affect brain sexual differentiation. Nat Neurosci 5:933–934
Chen X, McClusky R, Itoh Y, Reue K, Arnold AP (2013) X and Y chromosome complement influence adiposity and metabolism in mice. Endocrinology 154:1092–1104
Clarkson J, Herbison AE (2006) Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone neurons. Endocrinology 147:5817–5825
Davis EC, Popper P, Gorski RA (1996a) The role of apoptosis in sexual differentiation of the rat sexually dimorphic nucleus of the preoptic area. Brain Res 734:10–18
Davis EC, Shryne JE, Gorski RA (1996b) Structural sexual dimorphisms in the anteroventral periventricular nucleus of the rat hypothalamus are sensitive to gonadal steroids perinatally, but develop peripubertally. Neuroendocrinology 63:142–148
De Vries GJ, Rissman EF, Simerly RB, Yang LY, Scordalakes EM, Auger CJ, Swain A, Lovell-Badge R, Burgoyne PS, Arnold AP (2002) A model system for study of sex chromosome effects on sexually dimorphic neural and behavioral traits. J Neurosci 22:9005–9014
Dewing P, Shi T, Horvath S, Vilain E (2003) Sexually dimorphic gene expression in mouse brain precedes gonadal differentiation. Brain Res Mol Brain Res 118:82–90
Du S, Itoh N, Askarinam S, Hill H, Arnold AP, Voskuhl RR (2014) XY sex chromosome complement, compared with XX, in the CNS confers greater neurodegeneration during experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 111:2806–2811
Forger NG (2006) Cell death and sexual differentiation of the nervous system. Neuroscience 138:929–938
Forger NG (2009) Control of cell number in the sexually dimorphic brain and spinal cord. J Neuroendocrinol 21:393–399
Ghahramani NM, Ngun TC, Chen PY, Tian Y, Krishnan S, Muir S, Rubbi L, Arnold AP, de Vries GJ, Forger NG, Pellegrini M, Vilain E (2014) The effects of perinatal testosterone exposure on the DNA methylome of the mouse brain are late-emerging. Biol Sex Differ 5:8
Ginhoux F, Lim S, Hoeffel G, Low D, Huber T (2013) Origin and differentiation of microglia. Front Cell Neurosci 7:45
Goodfellow PN, Lovell-Badge R (1993) SRY and sex determination in mammals. Annu Rev Genet 27:71–92
Gorski RA, Barraclough CA (1963) Effects of low dosages of androgen on the differentiation of hypothalamic regulatory control of ovulation in the rat. Endorcrinology 73:210–216
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 193:529–539
Gu GB, Simerly RB (1997) Projections of the sexually dimorphic anteroventral periventricular nucleus in the female rat. J Comp Neurol 384:142–164
Hull EM, Dominguez JM (2007) Sexual behavior in male rodents. Hormones Behav 52:45–55
Jacobson CD, Gorski RA (1981) Neurogenesis of the sexually dimorphic nucleus of the preoptic area in the rat. J Comp Neurol 196:519–529
Krishnan S, Intlekofer KA, Aggison LK, Petersen SL (2009) Central role of TRAF-interacting protein in a new model of brain sexual differentiation. Proc Natl Acad Sci USA 106:16692–16697
Labonte B et al (2017) Sex-specific transcriptional signatures in human depression. Nat Med
Lazarus M, Yoshida K, Coppari R, Bass CE, Mochizuki T, Lowell BB, Saper CB (2007) EP3 prostaglandin receptors in the median preoptic nucleus are critical for fever responses. Nat Neurosci 10:1131–1133
Lenz KM, Wright CL, Martin RC, McCarthy MM (2011) Prostaglandin E regulates AMPA receptor phosphorylation and promotes membrane insertion in preoptic area neurons and glia during sexual differentiation. PloS One 6:e18500
Lenz KM, Nugent BM, Haliyur R, McCarthy MM (2013) Microglia are essential to masculinization of brain and behavior. J Neurosci 33:2761–2772
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 38:8044–8059
Matsuda KI, Mori H, Nugent BM, Pfaff DW, McCarthy MM, Kawata M (2011) Histone deacetylation during brain development is essential for permanent masculinization of sexual behavior. Endocrinology 152:2760–2767
McCarthy MM (2019) Sex differences in neuroimmunity as an inherent risk factor. Neuropsychopharmacology 44:38–44
McCarthy MM, De Vries GJ, Forger NG (2017) Sexual differentiation of the brain: a Fresh look at mode, mechanisms and meaning. Hormones, brain and behavior. Pfaff DaJ, San Diego, pp 3–32
McCarthy MM, Nugent BM, Lenz KM (2017) Neuroimmunology and neuroepigenetics in the establishment of sex differences in the brain. Nat Rev Neurosci 18:471–484
Meaney MJ, McEwen BS (1986) Testosterone implants into the amygdala during the neonatal period masculinize the social play of juvenile female rats. Brain Res 398:324–328
Nugent BM, Wright CL, Shetty AC, Hodes GE, Lenz KM, Mahurkar A, Russo SJ, Devine SE, McCarthy MM (2015) Brain feminization requires active repression of masculinization via DNA methylation. Nat Neurosci 18:690–697
Numan M (1994) Maternal behavior. In: Knobil E, Neill JD (eds) Physiology of reproduction. Raven Press, New York, pp 108–302
Ottem EN, Godwon JG, Krishnan S, Petersen SL (2004) Dual-phenotype GABA/glutamate neurons in adult preoptic area: Sexual dimorphism and function. J Neurosci 24:8097–8105
Petersen SL, Krishnan S, Aggison LK, Intlekofer KA, Moura PJ (2012) Sexual differentiation of the gonadotropin surge release mechanism: a new role for the canonical NfkappaB signaling pathway. Front Neuroendocr 33:36–44
Phoenix CH, Goy RW, Gerall AA, Young WC (1959) Organizing action of prenatally administered testosterone proprionate on the tissues mediating mating behavior in the female guinea pig. Endocrinology 65:369–382
Pinheiro I, Dejager L, Libert C (2011) X-chromosome-located microRNAs in immunity: might they explain male/female differences? The X chromosome-genomic context may affect X-located miRNAs and downstream signaling, thereby contributing to the enhanced immune response of females. BioEssays News Rev Mol Cell Dev Biol 33:791–802
Polston EK, Simerly RB (2006) Ontogeny of the projections from the anteroventral periventricular nucleus of the hypothalamus in the female rat. J Comp Neurol 495:122–132
Quadros PS, Goldstein AY, De Vries GJ, Wagner CK (2002) Regulation of sex differences in progesterone receptor expression in the medial preoptic nucleus of postnatal rats. J Neuroendocrinol 14:761–767
Roselli C, Balthazart J (2011) Sexual differentiation of sexual behavior and its orientation. Front Neuroendocr 32:109
Shen EY, Ahern TH, Cheung I, Straubhaar J, Dincer A, Houston I, de Vries GJ, Akbarian S, Forger NG (2015) Epigenetics and sex differences in the brain: a genome-wide comparison of histone-3 lysine-4 trimethylation (H3K4me3) in male and female mice. Exp Neurol 268:21–29
Shivers BD, Harlan RE, Morrell JI, Pfaff DW (1983) Absence of oestradiol concentration in cell nuclei of LHRH-immunoreactive neurones. Nature 304:345–347
Silver R, Curley JP (2013) Mast cells on the mind: new insights and opportunities. Trends Neurosci 36:513–521
Simerly RB, Zee MC, Pendleton JW, Lubahn DB, Korach KS (1997) Estrogen receptor-dependent sexual differentiation of dopaminergic neurons in the preoptic region of the mouse. Proc Natl Acad Sci USA 94:14077–14082
Sugimoto Y, Narumiya S (2007) Prostaglandin E receptors. J Biol Chem 282:11613–11617
Theoharides TC, Alysandratos KD, Angelidou A, Delivanis DA, Sismanopoulos N, Zhang B, Asadi S, Vasiadi M, Weng Z, Miniati A, Kalogeromitros D (2012) Mast cells and inflammation. Biochim Biophys Acta 1822:21–33
Trabzuni D, Ramasamy A, Imran S, Walker R, Smith C, Weale ME, Hardy J, Ryten M (2013) Widespread sex differences in gene expression and splicing in the adult human brain. Nat Commun 4:2771North American Brain Expression C
VanRyzin JW, Yu SJ, Perez-Pouchoulen M, McCarthy MM (2016) Temporary depletion of microglia during the early postnatal period induces lasting sex-dependent and sex-independent effects on behavior in rats. eNeuro 3
VanRyzin JW, Marquardt AE, Argue KJ, Vecchiarelli HA, Ashton SE, Arambula SE, Hill MN, McCarthy MM (2019) Microglial phagocytosis of newborn cells is induced by endocannabinoids and sculpts sex differences in Juvenile Rat Social Play. Neuron
Werling DM, Parikshak NN, Geschwind DH (2016) Gene expression in human brain implicates sexually dimorphic pathways in autism spectrum disorders. Nat Commun 7:10717
Wilkinson AC, Nakauchi H, Gottgens B (2017) Mammalian transcription factor networks: recent advances in interrogating biological complexity. Cell Syst 5:319–331
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
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This work was supported by RO1MH52716 and R01DA039062 to MMM.
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McCarthy, M.M. A new view of sexual differentiation of mammalian brain. J Comp Physiol A 206, 369–378 (2020). https://doi.org/10.1007/s00359-019-01376-8
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DOI: https://doi.org/10.1007/s00359-019-01376-8