I received an undergraduate degree in Mathematics and Psychology from Dartmouth College in 1981, and a PhD in Endocrinology from the University of California, Berkeley in 1986. For the past 25 years I have been studying early influences on neural development, with a special focus on the development of sex differences in the brain and spinal cord. The contributions of the Forger lab to several topics of interest, past and present, are summarized below.
Epigenetics and sexual differentiation of the brain and behavior
(For a description of this ongoing project, see Research Tab.)
Shen EY, Ahern TH, Cheung I, Straubhaar J, Dincer A, Houston I, de Vries GJ, Akbarian S, Forger NG (2015) Epigenetics and sex differences in the brain: A Genome-Wide Comparison of Histone-3 Lysine-4 Trimethylation (H3K4me3) in Male and Female Mice. Experimental Neurology, 268:21-29.
Ghahramani NM, Ngun TC, Chen PY, Tian Y, Krishnan S, Muir S, Rubbi L, Arnold AP, de Vries GJ, Forger NG, Pellegrini M, Vilain E (2014) The effects of perinatal testosterone exposure on the DNA methylome of the mouse brain are late-emerging. Biology of Sex Differences Jun 13;5:8.
McCarthy MM, Auger AP, Bale TL, De Vries GJ, Dunn GA, Forger NG, Murray EK, Nugent BM, Schwarz JM, Wilson ME (2009) The epigenetics of sex differences in the brain. Journal of Neuroscience 29:12815-12823.
Murray EK, Hien A, de Vries GJ, Forger NG (2009) Epigenetic control of sexual differentiation of the bed nucleus of the stria terminalis. Endocrinology 150:4241-4247.
The role of cell death in the development of sex differences
(For a description of this ongoing project, see Research Tab.)
Ahern TH, Krug S, Carr AV, Murray E, Fizpatrick E, Bengston L, McCutcheon J, De Vries GJ, Forger NG (2013) Cell death atlas of the postnatal mouse ventral forebrain and hypothalamus: Effects of age and sex. J. Comparative Neurology 521:2551-2569.
Gilmore RF, Varnum MM, Forger NG (2012) Effects of blocking developmental cell death on sexually dimorphic calbindin cell groups in the preoptic area and bed nucleus of the stria terminalis. Biology of Sex Differences 15;3:5.
de Vries GJ, Jardon M, 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.
Jacob DA, Bengston CL, Forger NG (2005) Effects of Bax gene deletion on muscle and
motoneuron degeneration in a sexually dimorphic neuromuscular system. Journal of Neuroscience 25:5638-44.
Forger NG, Rosen GJ, Waters EM, Jacob D, Simerly RB, de Vries GJ (2004) Deletion of Bax eliminates sex differences in the mouse forebrain. Proc. Natl. Acad. Sci. USA 101:13666-13671.
Zup SL, Carrier H, Waters EM, Tabor A, Bengston L, Rosen GJ, Simerly RB, Forger NG (2003) Overexpression of bcl-2 reduces sex differences in neuron number in the brain and spinal cord. Journal of Neuroscience 23:2357-62.
Effects of Sex and Social status on the Brain of a Eusocial Mammal
The vast majority of work on sexual differentiation of the nervous system has relied on a tiny number species (primarily, rats and mice). We showed that the rules may differ in animals with a very different social structure. Naked mole-rats live in large, underground colonies of up to 300 individuals. Only one female – the queen – and one to three males mate; all other colony members are non-reproductive subordinates. Subordinates are highly sexually monomorphic. The genitalia appear very similar in male and female subordinate, and their behavior does not differ. Nonetheless, subordinates are not sterile, and they can become breeders if removed from the colony and housed with an opposite sex mate. We found that sex differences found in other rodent species are absent in the naked mole rat brain and spinal cord. However, significant changes in the brain and spinal cord occur in both sexes when a subordinate attains reproductive status. Thus, in this highly social species, social status rather than sex, plays the dominant role in determining neural morphology.
Holmes MM, Goldman BD, Goldman S, Seney ML, Forger NG (2009) Neuroendocrinology and sexual differentiation in eusocial mammals. Frontiers in Neuroendocrinology 30:519-533.
Rosen GJ, De Vries GJ, Goldman SL, Goldman BD, Forger NG (2008) Distribution of oxytocin in the brain of a eusocial rodent. Neuroscience 155:809-817.
Rosen GJ, De Vries GJ, Goldman BD, Forger NG (2007) Distribution of vasopressin in the brain of the eusocial naked mole-rat. Journal of Comparative Neurology 500:1093-1105.
Holmes MM, Rosen GJ, Jordan CL, De Vries GJ, Goldman BD, Forger NG (2007) Social control of brain morphology in a eusocial mammal. Proc. Natl. Acad. Sci. USA 104:10548-10552.
Sexual differentiation in hyenas, dogs, and humans
Spotted hyenas are of interest to anyone wishing to understand sexual differentiation because the females are highly virilized. Female spotted hyenas have an enlarged, erectile phallus and their labia are fused to form a pseudo-scrotum. They do not have a separate vagina, but urinate, copulate, and give birth through a single urogenital sinus. These traits are androgen-dependent in all other mammals. Female hyenas are also more aggressive than males and dominate them in social encounters (also traits that reflect androgen exposure in other mammals). The nervous systems of hyenas had never been examined, and we set out to do so, asking in particular whether the brains of females showed masculine traits. We find that some neural systems (the perineal muscles and motoneurons, and a nucleus in the hypothalamus) are sexually differentiated in the “ordinary” mammalian pattern (i.e., female hyenas are not masculinized). An interesting exception is vasopressin innervation of the brain – female spotted hyenas have vasopressin innervation of the septum that is at least as dense as in males, which sets them apart from other mammals.
We also took advantage of the availability of neural tissue from beagle dogs and humans to ask whether a sex difference in the spinal cord (seen to that point only in rodents) was also present in canines and humans. We showed that it was. Moreover, in female dogs treated with androgens in utero this sex difference was eliminated (as is also the case in rats and mice). We also showed that the treatment of male hyenas with anti-androgens in utero prevented masculinization of the spinal nucleus, demonstrating that the androgen dependence of the difference is likely to apply widely across species.
Rosen GJ, De Vries GJ, Villalba C, Weldele ML, Place NJ, Coscia EM, Glickman SE, Forger NG (2006) The distribution of vasopressin in the forebrain of spotted hyenas. Journal of Comparative Neurology 498:80-92.
Fenstemaker SB, Zup SL, Frank LG, Glickman SE, and Forger NG (1999) A Sex difference in the hypothalamus of spotted hyenas. Nature Neuroscience 2:943-945.
Forger NG, Frank L, Breedlove SM, and Glickman S (1996) Sexual dimorphism of perineal muscles and motoneurons in spotted hyenas. Journal of Comparative Neurology 375:333-343.
Forger NG and Breedlove SM (1986) Sexual dimorphism in human and canine spinal cord: Role of early androgen. Proc. Natl. Acad. Sci. USA 83:7527-7531.
Neurotrophic factors and sexual differentiation
We demonstrated a role for neurotrophic factors in sexual differentiation of the nervous system, and were the first to show that a blockade of specific neurotrophic factor(s) could prevent the survival of spinal motoneurons in vivo. Prior to our work, several investigators had demonstrated that the application of exogenous trophic factors, in vitro or in vivo, could enhance motoneuron survival, but motoneuron number was not altered in knockout mice lacking specific trophic factors. Our study demonstrated the requirement for specific endogenous trophic factor(s) in motoneuron rescue in vivo.
Xu J, Gingras KM, Bengston L, Di Marco A, and Forger NG (2001) Blockade of endogenous neurotrophic factors prevents the androgenic rescue of rat spinal motoneurons. Journal of Neuroscience 21:4366-4372.
Forger NG, Wagner CK, Contois M, Bengston L, and MacLennan AJ (1998) Ciliary neurotrophic factor receptor a (CNTFRa) in spinal motoneurons is regulated by gonadal hormones. Journal of Neuroscience 18:8720-8729.
Forger NG, Howell ML, Bengston L, MacKenzie L, DeChiara TM, and Yancopoulos GD (1997) Sexual dimorphism in the spinal cord is absent in mice lacking the ciliary neurotrophic factor receptor. Journal of Neuroscience 17:9605-9612.
Forger NG, Roberts SL, Wong V, and Breedlove SM (1993) Ciliary neurotrophic factor rescues rat motoneurons during developmental cell death. Journal of Neuroscience 13:4720-4726.