Biological factors underlying sex differences in neurological disorders

Abstract

The prevalence, age of onset, pathophysiology, and symptomatology of many neurological and neuropsychiatric conditions differ significantly between males and females. Females suffer more from mood disorders such as depression and anxiety, whereas males are more susceptible to deficits in the dopamine system including Parkinson's disease (PD), attention-deficit hyperactivity disorder (ADHD), schizophrenia, and autism spectrum disorders (ASD). Until recently, these sex differences have been explained solely by the neuroprotective actions of sex hormones in females. Emerging evidence however indicates that the sex chromosome genes (i.e. X- and Y-linked genes) also contribute to brain sex differences. In particular, the Y-chromosome gene, SRY (Sex-determining Region on the Y chromosome) is an interesting candidate as it is expressed in dopamine-abundant brain regions, where it regulates dopamine biosynthesis and dopamine-mediated functions such as voluntary movement in males. Furthermore, SRY expression is dysregulated in a toxin-induced model of PD, suggesting a role for SRY in the pathogenesis of dopamine cells. Taken together, these studies highlight the importance of understanding the interplay between sex-specific hormones and sex-specific genes in healthy and diseased brain. In particular, better understanding of regulation and function of SRY in the male brain could provide entirely novel and important insights into genetic factors involved in the susceptibility of men to neurological disorders, as well as development of novel sex-specific therapies.

Introduction

Aside from generating distinct sexual reproductive behaviours, brain sex differences significantly influence brain anatomy, biochemistry, as well as various psychological and cognitive processes. A meta analysis reviewing 20 years of research into brain structural differences revealed that males on average have 8–13% larger brain volumes compared to females (Ruigrok et al., 2014), although sexual dimorphisms of adult brain volumes are not diffusely spread across the brain but rather are region specific (Goldstein et al., 2001). A diffusion tensor imaging (DTI) study showed sex differences in the structural connectome of the human brain, where the male brains are optimized for intra-hemispheric and female brains for inter-hemispheric communication (Ingalhalikar et al., 2014). Furthermore, genome-wide analysis performed on 137 human post mortem brains showed that 2.5% of genes are differentially expressed and spliced between males and females (Trabzuni et al., 2013). These fundamental sex differences in the anatomy and genetic network of the healthy brain are likely to underlie the pronounced sex differences in susceptibility, progression, symptom severity, and pathology of neurological disorders (Cahill, 2006, Cosgrove et al., 2007, Gillies and McArthur, 2010, McCarthy et al., 2012, Ngun et al., 2011). For example, females are more likely than males to develop depression, anxiety (Nolen-Hoeksema, 1987, Weissman et al., 1996) and Alzheimer's disease (Hebert et al., 2013), whilst males are more likely to be diagnosed with Parkinson's disease (PD) (Wooten et al., 2004), attention deficit hyperactivity disorder (ADHD) (Balint et al., 2009), and autism spectrum disorders (ASD) (Gillberg et al., 2006). Hence, better understanding of the biology underlying sex differences in the healthy and diseased brain will be vital for designing novel therapeutic agents that will have optimal effectiveness in each sex. Historically, the sex differences in neurological disorders have been explained by the protective actions of sex hormones in females (Auyeung et al., 2009, Gillies and McArthur, 2010, Riecher Rossler, 1994). However, emerging evidence suggests that genetic factors, in particular sex chromosome genes, also contribute to brain sex differences (Arnold et al., 2004, Beyer et al., 1992, Carruth et al., 2002, Dewing et al., 2003). Here we review studies of hormonal and genetic factors underlying the sex dimorphism in neurological disorders. We will contend that genetic factors play a far more important role than previously suspected. In particular, we highlight evidence that the Y-chromosome gene, SRY, regulates dopamine biochemistry and function in the male brain. Based on SRY expression in brain regions associated with the symptoms of dopamine (DA)-associated disorders, we speculate upon how dysregulation of SRY may be a contributing factor to male-susceptibility in disorders such as PD and ADHD.