The major research focus of my laboratory is, and has been, the development and function of sex differences in the brain. Ever since discovering the sexually dimorphic nature of vasopressin innervation of the brain, we have studied the physiology of this system from the molecular to the behavioral level. Work from my lab has contributed significantly to our understanding of the mechanisms of sexual differentiation of vasopressin innervation, demonstrating that sex differences in this system depend on organizing and activating effects of gonadal hormones as well as on direct sex chromosomal effects. We also studied the functional consequences of sex differences in this system, which led us to propose that sex differences in the brain may cause as well as prevent sex differences in overt functions and behaviors. Finally, my lab has mapped the distribution and traced the origin of vasopressin and oxytocin innervation in rat and, recently, mouse brains. We have used comparative methods as well as genetically modified mice to test our hypotheses.
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First anatomical demonstration of a sex difference in a neurotransmitter system
At the time we discovered the sex difference in vasopressin system, no other anatomical sex difference had ever been reported for any neurotransmitter systems in the mammalian brain. Studying the nature and significance of this sex difference has been very rewarding. It allowed us to map vasopressin innervation of the brain, be the first to show what is still regarded one of the most robust effects of sex steroids on the brain, develop a general theory on the function of sex differences in the brain (see below), provided the first strong example of a neurotransmitter system controlled by androgens and estrogens, and provide the first evidence of direct effects of sex chromosomes on the brain (see below as well). The robust nature of the sex differences in, and steroid effects on, vasopressin innervation has made it into one the most frequently studied sexually dimorphic neurotransmitter systems in the brain.
De Vries GJ, Wang ZX, Bullock NA, Numan S. 1994. Sex differences in the effects of testosterone and its metabolites on vasopressin messenger RNA levels in the bed nucleus of the stria terminalis of rats. Journal of Neuroscience 14: 1789-1794.
De Vries GJ, Panzica GC. 2006. Sexual differentiation of central vasopressin and vasotocin systems in vertebrates: different mechanisms, similar endpoints. Neuroscience 138: 947-955.
Organization of Vasopressin and Oxytocin Innervation in the Brain
Central vasopressin and oxytocin innervation was originally thought to stem exclusively from the hypothalamus. We confirmed that this was by and large true for oxytocin but not for vasopressin. Using a combination of various anatomical techniques, we generated the first comprehensive map of vasopressin innervation in the rat and showed that telencephalic sources, especially the bed nucleus of the stria terminalis and amygdala, made a major contribution. We also showed that the various parts of the vasopressin innervation are regulated independently by a variety of physiological and endocrine conditions. More precise knowledge of the origin of vasopressin innervation now allows our lab to test the function of specific components independently, using a variety of state-of-the-art genetic techniques that target specific cell groups.
DeVries GJ, Buijs RM, Van Leeuwen FW, Caffé AR, Swaab DF. 1985. The vasopressinergic innervation of the brain in normal and castrated rats. Journal of Comparative Neurology 233: 236-254.
Rood BD, Stott RT, You S, Smith CJ, Woodbury ME, de Vries GJ. 2013. Site of origin of and sex differences in the vasopressin innervation of the mouse (Mus musculus) brain. Journal of Comparative Neurology 521: 2321-2358.
Function of Sex Differences in the Brain
We have a long-standing interest in the functional consequences of sex differences in the brain. We proposed that the sex difference in vasopressin innervation may not only cause sex differences in behavior, for example, in stimulating aggressive behavior, but may prevent them in others. We have shown this, for example, for parental behavior in prairie voles, which depends on vasopressin in males but not in females. This duality in function appears to be a common feature of sexually dimorphic systems and suggests that for many centrally regulated functions and behaviors the underlying neurochemistry differs in males and females. In other words, some sex differences compensate for other differences to promote similarity in function rather than differences. We have recently pointed out that these other differences may reside in any portion of the body that communicates with the brain. This has, of course, direct consequences for sex differences in vulnerability to behavioral and neurological disorders.
De Vries GJ. 2004. Sex differences in adult and developing brains; compensation, compensation, compensation. Endocrinology, 145: 1063-1068.
De Vries GJ, Forger NG. 2015. Sex differences in the brain: a whole body perspective. Biology of Sex Differences 6: 15.
Molecular Basis of Sexual Differentiation
An ongoing interest of my lab is the cellular and molecular basis of sexual differentiation of the brain, focusing on vasopressin innervation. For example, to study factors underlying sexual differentiation of the brain, our lab joined a multi-PI collaboration, which showed that, in addition to androgens and estrogens, sex chromosomes have a direct influence on sexual differentiation of this system. For this research, we developed a mouse model (the four core genotype mice), which allowed us to compare males and females that both have XX chromosomes with males and females that both have XY chromosomes, thereby showing that animals with a Y chromosome express more vasopressin, irrespective as to whether they are male or female.
De Vries GJ, Rissman EF, Simerly RB, Yang LY, Scordalakes EM, Auger CJ, Swain A, Lovell-Badge R, Burgoyne PS, Arnold AP. 2002. A model system for study of sex chromosome effects on sexually dimorphic neural and behavioral traits. Journal of Neuroscience 22: 9005-9014.
De Vries GJ, Jardon D, Reza M, Rosen GJ, Immerman E, Forger NG. 2008. Sexual differentiation of vasopressin innervation of the brain: cell death versus phenotypic differentiation. Endocrinology 149: 4632-4637.