The genetics of sex differences in brain and behavior

Abstract

Biological differences between men and women contribute to many sex-specific illnesses and disorders. Historically, it was argued that such differences were largely, if not exclusively, due to gonadal hormone secretions. However, emerging research has shown that some differences are mediated by mechanisms other than the action of these hormone secretions and in particular by products of genes located on the X and Y chromosomes, which we refer to as direct genetic effects. This paper reviews the evidence for direct genetic effects in behavioral and brain sex differences. We highlight the 'four core genotypes' model and sex differences in the midbrain dopaminergic system, specifically focusing on the role of Sry. We also discuss novel research being done on unique populations including people attracted to the same sex and people with a cross-gender identity. As science continues to advance our understanding of biological sex differences, a new field is emerging that is aimed at better addressing the needs of both sexes: gender-based biology and medicine. Ultimately, the study of the biological basis for sex differences will improve healthcare for both men and women.

Figure 1

The catecholaminergic pathway is sexually differentiated TH: Tyrosine hydroxylase, L-DOPA: L-dihydroxyphenylalanine, NE: norepinephrine. (A) Chronic physical stress results in sexually dimorphic responses. Dopamine (DA) activity is upregulated exclusively in males flight blue arrow) while norepinephrine activity is upregulated exclusively in females (yellow arrow) [58]. Only males experience impaired memory. (B) Control of TH expression differs between the sexes. SRY, the testis determining gene, which is not found in females, directly regulates TH expression in males [49; 270]. 17β-estradiol increases TH expression only in males flight blue arrows) [353]. Aromatase activity is more responsive to dihydrotestosterone (DHT) in males than in females (dark blue arrow) [354]. (C) Male rats have higher NE levels than female ones in the amygdala (A) and hypothalamus (HT) early in life [62]. When the rats reach day 300, the direction of this difference is reversed.

Figure 2

Serotonin (5-HT) is sexually differentiated on multiple levels. In addition to the differences illustrated above, some of the loci that influence 5-HT levels in the blood are also sexually dimorphic [66]. References: 1 - [67], 2 - [68], 3 - [65], 4 - [69].

Figure 3

2×2 comparison in the four core genotypes model. In this comparison, the factors are gonadal sex and sex chromosome complement.

Figure 4

Sry regulates tyrosine hydroxylase (TH) levels and motor behavior. (A) Sry and TH colocalize in the locus coeruleus (LC), ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) [49; 270]. (B) Knockdown of Sry expression in the SNc leads to a reduction in the number of TH-immunoreactive (TH-ir) neurons. Unilateral infusion of antisense oligodeoxynucleotides (ODN) against Sry decreased the number of TH-if neurons by 38% compared to the contralateral side infused with sense ODN [49]. (C) Unilateral downregulation of TH expression by Sry leads to asymmetric limb use. Animals preferentially used the forelimb ipsilateral to the side of the antisense ODN infusion (preferred limb highlighted in yellow) [49].