Neural fundamentals: Sex differences in the nervous system

The brain is an intricate, plastic organ and scientists are only beginning to understand that differences between male and female brains are extremely complex and influenced by genetics, physiology, experience, and learning.

                Neuroscience research in the early 1990s focused on sexual dimorphism of the central nervous system (CNS) in terms of developmental sensitivity to hormones like estrogen, testosterone, and progesterone. This work found that during the process of sexual differentiation, regions of the brain are influenced by their hormonal environment, including their concentrations and metabolism in the CNS.¹ Follow up research showed that genetic mechanisms, rather than strictly steroid-dependent ones,² may trigger sexual differentiation of the brain.¹

                Approximately a decade ago, researchers Michael Rhodes and Robert Rubin realized in the course of studying the nervous system that differences between the sexes went further than sexual dimorphism.  Instead of looking at just the phenotypic differences between males and females as the result of variations in function, Rhodes and Rubin coined the term ‘sexual diergism’ to describe differences in terms of physiology, biochemistry, and underlying behaviors.¹ In particular, Rhodes and Rubin were interested in sex differences of the mammalian CNS and its relationship to the hypothalamic–pituitary–adrenal (HPA) axis. What they discovered was counter-intuitive: sex differences within the brain may allow male and female mammals to display remarkably similar behaviors, despite major differences in their physiological and hormonal conditions. In other words, sexual dimorphism may counteract sexual diergism.

Additional studies conducted over the years have further clarified the roles of neurotransmitters and the environment in defining sex differences in the nervous system, as well as the effects of dimorphism and diergism on disease prevalence.

The effect of the environment on the nervous system

Research conducted by Janice Juraska at the University of Illinois concluded that the environment plays a critical role on dimorphism and differentiation of the CNS.³ More specifically, Juraska found that sexual dimorphism of the hippocampus accounts for differences in the performance of rats in maze learning, where male rats outperform females.

Rat forebrain areas like the cerebral cortex and hippocampus exhibited sexual dimorphism in response to the environment: male rats had thicker dendritic branching in cortex pyramidal neurons and dentate gyral cells of the hippocampus.³ The branching in both brain areas was increased further in male rats by producing a stimulating environment, whereas this increased branching was not seen in females. These results suggest that sex differences in the size of an organism’s dendritic tree may lead to differences in how the organism interacts with its environment.  Meanwhile, the environment itself also influences how each sex interacts with its surroundings.

Dimorphism, diergism, and neurological disease

Past studies on female rats have found that there is a higher vulnerability of the septo-hippocampal pathway to neurotoxins, which may imply a higher risk for neurological diseases.¹ This finding may extend to humans. As recorded by a 2010 study done at the University of Valencia, women are more susceptible to Alzheimer’s disease, even after adjusting for the fact that females, on average, have longer life spans than males.⁷ According to Dr. Victor Henderson at the Stanford School of Medicine, this phenomenon could be the result of an accelerated degeneration of the CNS in women.⁸

In terms of other diseases, overproduction of dopamine receptors in the striatum and nucleus accumbens have been known to result in hyperactivity.¹ A study conducted in the late 1990s by Dr. Susan Anderson at McClean Hospital in Massachusetts showed that overproduction of dopamine receptors in males compared to females during prepubertal development can possibly explain why more males than females are afflicted with attention-deficit/hyperactivity disorder (ADHD) and Tourette’s syndrome.⁹

Furthermore, differences in rates of psychiatric illness between the sexes are most pronounced before and after puberty. For females, illnesses increase dramatically after puberty while the reverse is true for males.^[1] This further suggests hormones play a large role in influencing normal and pathological CNS function.

Neurotransmitters and sexual diergism

University of California Berkeley scientist Lynwood Clemens suggested that many behaviors which are expressed differently in male and female mammals could be the result of sexual diergism of neurotransmitter systems, or a combination of dimorphism and diergism.⁴ Behaviors Clemens looked at included sexual and social behavior, learning, vocalization, and regulation of food and water intake. Pharmacological studies suggest that both estrogen and testosterone (by conversion to estrogen), in addition to other neurotransmitters such as norepinephrine, can promote lordosis behavior (presenting an arched back and other postures to indicate receptivity to copulation) in rats. ⁴ In the late 1980s, psychologist James Pfaus also discovered beta-endorphin also might inhibit female sexual behavior.⁵

Currently it is well documented that the effects of castration on male sexual behavior can be reversed with both estrogen and testosterone treatments.⁶ Additionally, studies done throughout the 1990s suggest that serotonin and dopamine have regulatory roles: serotonin inhibits male sexual behavior while dopamine both inhibits and promotes it.¹

When Rhodes and Rubin examined sexual dimorphism in the CNS in the late 1990s, they had to create a whole new term. They defined diergism as functional or physiological differences, which is oftentimes a byproduct of sexual dimorphism. Rhodes and Rubin realized that the genetics underlying sexual differences in the CNS is more complex than just steroid-dependent mechanisms and the environment plays a role in sexual differentiation as well.  Current studies of dimorphism and diergism focus on furthering our understanding of the neurochemical basis of sexually dimorphic behavior and the mechanisms of disease.

References

1. 1. Rhodes M, Rubin R (1999) Functional sex differences (‘sexual diergism’) of central nervous system cholinergic systems, vasopressin, and hypothalamic–pituitary–adrenal axis activity in mammals: a selective review. Brain Research Reviews 30(2):135–152. doi: 10.1016/S0165-0173(99)00011-9
2. 2. Breedlove M (1992) Sexual Dimorphism in the Vertebrate Nervous System.The Journal of Neuroscience 12(11):4133-4142.
3. 3. Juraska J (1991) Sex differences in ‘cognitive’ regions of the rat brain. Psychoneuroendocrinology 16(1-3): 109–155. doi: 10.1016/0306-4530(91)90073-3
4. 4. Clemens L, Barr P, Dohanich G (1989) Cholinergic regulation of female sexual behavior in rats demonstrated by manipulation of endogenous acetylcholine. Physiology & Behavior 45(2):437–442. doi: 10.1016/0031-9384(89)90152-2
5. 5. Pfaus J, Gorzalka B (1987) Opioids and sexual behavior. Neuroscience & Behavioral Reviews 11:1–34.
6. 6. Chen T, Wen T (1992) Sex differences in estrogen and androgen receptors in hamster brain. Life Sciences 50:1639–1647.
7. 7. Vina J, Lloret A (2010) Why women have more Alzheimer's disease than men: gender and mitochondrial toxicity of amyloid-beta peptide.Journal of Alzheimer’s Disease 20(Suppl 2):S527-533. doi: 10.3233/JAD-2010-100501
8. 8. Henderson V, Buckwalter J (1994) Cognitive deficits of men and women with Alzheimer’s disease. Neurology 44:90–96.
9. 9. Teicher MH et al. (1997) Sex differences in dopamine receptor overproduction and elimination. NeuroReport 8(6):1495–1498.