Multifaceted origins of sex differences in the brain

Abstract

Studies of sex differences in the brain range from reductionistic cell and molecular analyses in animal models to functional imaging in awake human subjects, with many other levels in between. Interpretations and conclusions about the importance of particular differences often vary with differing levels of analyses and can lead to discord and dissent. In the past two decades, the range of neurobiological, psychological and psychiatric endpoints found to differ between males and females has expanded beyond reproduction into every aspect of the healthy and diseased brain, and thereby demands our attention. A greater understanding of all aspects of neural functioning will only be achieved by incorporating sex as a biological variable. The goal of this review is to highlight the current state of the art of the discipline of sex differences research with an emphasis on the brain and to contextualize the articles appearing in the accompanying special issue.

Keywords: hypothalamus; sex chromosomes; steroid hormones.

Figure 1.

Multifaceted origins of sex differences in the brain. The number of known variables impacting how sex differences in the brain are established and maintained are numerous. They vary from the purely biological, such as hormones and genetics, to those impacted by experience and environment, such as epigenetics. Cultural and societal expectations may also exert biological influences on the brain but determining these is a challenge. Media reports exaggerating the significance of sex differences confound efforts to have reasoned data-based discussions by the diverse community of scientists addressing this topic. (Online version in colour.)

Figure 2.

Sex differences in the brain do not equal sex differences in behaviour. The ability to constrain variables such as genetics, age and experience in animal models has allowed for the reliable detection of robust neuroanatomical and physiological sex differences. These can be found at the level of individual neurons, their connections, the signal transduction pathways activated and neuronal physiology. But sex differences in any one of these parameters do not perfectly predict behaviour as many variables across a wide neural network must be integrated in order for a particular behaviour to be executed. There are circumstances in which the predictability is greater, such as mating behaviour where the neural substrates are well known and the motor execution is distinctly different in males and females. Others are far more challenging. These would include cognitive and affective behaviours that can diverge in males and females in response to stress or other external variables and for which the neural substrates are diffuse and often ill defined. (Online version in colour.)

Figure 3.

Gender bias in neurologic and neuropsychiatric disorders. A compelling reason for studying sex as a biological variable is the pervasive gender bias in the frequency of diagnosis of numerous disorders. Many factors go into the determination of a disease state, but identification of biological variables clarifies those influences that are not biological in origin (i.e. diagnosis bias, different symptomology, etc.). This diagram presents only a small number of the many diseases and disorders known to differ in frequency between boys and girls, men and women. The size of the wedge for each disorder represents the relative degree of bias in favour of females (left) versus males (right) and is loosely based on [–87]. ADHD, attention deficit hyperactivity disorder; PTSD, post-traumatic stress disorder. (Online version in colour.)