Epigenetic mechanisms in sexual differentiation of the brain and behaviour

Abstract

Circumstantial evidence alone argues that the establishment and maintenance of sex differences in the brain depend on epigenetic modifications of chromatin structure. More direct evidence has recently been obtained from two types of studies: those manipulating a particular epigenetic mechanism, and those examining the genome-wide distribution of specific epigenetic marks. The manipulation of histone acetylation or DNA methylation disrupts the development of several neural sex differences in rodents. Taken together, however, the evidence suggests there is unlikely to be a simple formula for masculine or feminine development of the brain and behaviour; instead, underlying epigenetic mechanisms may vary by brain region or even by dependent variable within a region. Whole-genome studies related to sex differences in the brain have only very recently been reported, but suggest that males and females may use different combinations of epigenetic modifications to control gene expression, even in cases where gene expression does not differ between the sexes. Finally, recent findings are discussed that are likely to direct future studies on the role of epigenetic mechanisms in sexual differentiation of the brain and behaviour.

Keywords: DNA methylation; bed nucleus of the stria terminalis; histone; medial preoptic area; sex difference.

Figure 1.

Neonatal treatment with the HDAC inhibitor, VPA, prevents masculinization of neuron number in the principal nucleus of the bed nucleus of the stria terminalis (BNSTp) of mice. Males, females and females treated with testosterone propionate (TP) received VPA or saline (sal) at birth and cell counts were made at weaning. (a) VPA reduced cell number in the BNSTp of males and females + TP but did not affect cell number in the BNSTp of females. (b) VPA did not affect cell number in the suprachiasmatic nucleus (SCN) of any group. Adapted with permission from [9].

Figure 2.

Neonatal DNMT inhibition masculinizes dendritic spine density in the mPOA and male copulatory behaviour in rats. (a) Newborn rats were treated with vehicle or a DNMT inhibitor, zebularine (zeb) or RG108, on postnatal day (PN) 0 and 1; all animals were gonadectomized and given hormone replacement at PN40, and behaviour testing and brain collection were performed in adulthood (PN60). (b) Dendritic spine density at PN60 is greater in control males than in control females and treatment with zebularine or RG108 masculinized spine density in females. (c) Male copulatory behaviours (mounts and thrusts) were also masculinized in DNMT-treated females. Adapted with permission of Nature Publishing from [36]. (Online version in colour.)

Figure 3.

Calbindin and oestrogen receptor α immunoreactivity (ERα-ir) in the mPOA at weaning in male and female mice that received saline or zebularine (zeb) on the day of birth. (a) Control males have more calbindin-ir; neonatal DNMT inhibition significantly increased calbindin-ir in both sexes, but did not eliminate the sex difference. (b) Control females have more ERα-ir than males; neonatal DNMT inhibition increased ERα-ir in males and eliminated the sex difference [41].

Figure 4.

(a) Treatment of female mice with testosterone on postnatal day (PN) 0 influences DNA methylation in a small number of genes at PN4, but many more at PN60 in both the striatum and BNST/POA. (b) Most of the genes affected by neonatal testosterone treatment of female mice showed increased (hyper-) methylation (blue) relative to that in control females. This was seen at both ages and in both brain regions [50]. (Online version in colour.)

Figure 5.

The distribution of genes with differential H3K4me3 in the BNST/POA of adult mice showed a sex bias; most of the genes had more of this histone mark in females than in males (red and pink shading). This was true for both autosomal and X-chromosome genes [52]. (Online version in colour.)