BIO254:SexualDimorphism

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WIKIPEDIA BIO154/254: Molecular and Cellular Neurobiology

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Overview

Sexual dimorphism is the existence of gender-specific differences between males and females of the same species. In the nervous system, sexual dimorphism can arise through differential effects of hormones on neural circuitry during development. There are indications that genetic mechanisms preceding the hormonal effects could also be involved. Sexually dimorphic regions of the brain and spinal cord regulate sex-specific behaviors that facilitate mating and confer reproductive fitness.

The role of hormones

Sexual dimorphism of the nervous system is mainly generated through sex-specific effects of steroid hormones. In male mammals, the sex-determining region Y (SRY) gene on the Y chromosome encodes testis determining factor (TDF). Expression of the TDF protein promotes the development of the testes, the male gonads. The testes secrete testosterone, a steroid hormone that travels through the blood and into the developing brain. Due to its hydrophobic nature, testosterone freely diffuses through the neuronal cell membrane (Figure 1). In the cytoplasm, testosterone can be enzymatically converted into dihydrotestosterone (DHT) by 5α-reductase or estrogen by aromatase. Binding of DHT to the androgen receptor or estrogen to the estrogen receptor enables translocation of the hormone-receptor complex into the nucleus where it acts as a transcription factor to drive gene expression (Kandel, E.R. 2000).

Image:Testosterone.png

Female mammals do not have a Y chromosome and hence lack the SRY gene. The absence of TDF expression leads to the development of the ovaries, the estrogen-secreting female gonads. During early development, estrogen is bound by α-fetoprotein in the blood and is thus prevented from influencing gene transcription in the developing brain. Down-regulation of α-fetoprotein in later stages of life allows estrogen, like testosterone, to exert transcriptional effects on hormone-sensitive neurons.

Although steroid hormones such as testosterone and estrogen can diffuse into any cell, they only mediate gene transcription in cells that express the appropriate steroid receptors. For example, estrogen receptors are highly expressed in the preoptic area, hypothalamus, and anterior pituitary of the rat (Figure 2). Notably, these regions are involved in regulating sexual behavior (Purves, D. et al., 2001).

Image:Estrogen.png

While sexual dimorphism of the nervous system is believed to be mainly caused by hormones, recent studies indicate that genetic mechanisms preceding or in parallel with hormonal effects are critical for dimorphism in the nervous system (Carrer, 2002). Before the surge of testosterone that determines development of the male brain, mesencephalic dissociated neurons in female rats express more dopamine than neurons from male rats. When these neurons are treated in culture with estradiol, the neurons from males display higher levels of axon growth and produce increased levels of TrkB and IGF-IR receptors.

Sexual dimorphism in different species

1. Sexual dimorphism in the rodent brain

Testosterone may influence the neuronal circuitry underlying sex-specific behaviors through its actions on androgen receptor (AR)-expressing neurons. Three brain regions have been identified in which the number of AR-expressing neurons is greater in male mice than in female mice: the bed nucleus of the stria terminalis (BNST), the preoptic area of the hypothalamus (POA), and the basal forebrain (Figure 3). AR-expressing neurons in the BNST and POA are activated in male mice during mating, providing further evidence that these sexually dimorphic brain regions are involved in reproductive behavior (Shah et al., 2004).

Image:Mouse_sexual_dimorphism.png

Along with a difference in the number of AR-expressing neurons, POA in male rats is five to six times larger than its counterpart in females (Breedlove, 1992). Treating neonatal females with testosterone or estradiol metabolites increases the size of the POA, while neonatal castration of males decreases the size of the POA. (Squire, 2003).

2. Sexual dimorphism in the rat spinal cord

The spinal nucleus of the bulbocalvernosus (SNB) is a sexually dimorphic region in the rat spinal cord that is densely packed with cell bodies in the male, but not the female (Figure 4; Breedlove and Arnold, 1981). The cell bodies of SNB motor neurons lie between the 5th and 6th lumbar segments and project to the levator ani and bulbocavernosus muscles. These muscles are involved in urination and copulatory behavior in the male rat, but largely degenerate in the developing female due to the lack of testosterone (Purves, D. et al., 2001).

Image:SNB_sexual_dimorphism.png

3. Sexual dimorphism in the songbird brain

Male oscine songbirds attract female mates by singing elaborate learned songs. The females, however, do not sing. In correlation with this sex-specific behavior, sexual dimorphism exists in three nuclei of a neural pathway involved in the acquisition and production of learned song (Figure 5). Three nuclei of the posterior descending pathway (HVC, high vocal center; RA, robust nucleus of the arcopallium; and nXIIts, nucleus of the 12th nerve) are larger in males than in females (Nottebohm, F. 2005).

Image:Songbird_sexual_dimorphism.png

4. Sexual dimorphism in the fly antennal lobe

The fruitless gene is differentially spliced in Drosophila melanogaster males and females. Expression of the male-specific isoform (FruM) from the P1 promotor is necessary and sufficient for male courtship behavior (Demir, E & Dickson, BJ, 2005). Sexual dimorphism exists in three glomeruli of the fly antennal lobe that are innervated by fruP1-expressing olfactory sensory neurons (Figure 6). The enlargement of the DA1, VL2a, and VA1v glomeruli in male flies suggests that the odorants detected by the olfactory sensory neurons that innervate these glomeruli may have sex-specific behavioral relevance (Stockinger, P. et al., 2005).


Image:Fly_antennal_lobe.png


This differentiation between gene expression in males and females leads to what can be described as sexually dimorphic behavior. In a study performed on Drosophila melanogaster by Dauwalder and colleagues it was revealed that specific pathways of regulatory genes have the ability to control somatic sexual identity. The Fru protein is necessary for male sexual differentiation in the CNS and is the cause of male courtship behavior. Dauwalder knocked out the fru gene in a generation of male Drosophila and observed males that developed physical characteristics of wild type flies but failed to perform male courtship behavior. These flies were unable to distinguish between males and females and were receptive to advances of wild type males, thus exhibiting the lack of properly functioning olfactory systems. When females are injected with male specific fru in the same areas of the CNS as it naturally occurs in males, they begin to exhibit male courtship behavior. They approach wildtype females and attempt mating. When approached by males they reject their advances with a male typical response rather than that of females. (Dauwalder, 2002).


5. Sexual dimorphism in the human brain

Sexual dimorphism in the human brain is a controversial subject. Since the effects of hormones and the environment are often convoluted, it is also a difficult field to study. Between males and females, experiments suggest that there is a difference in brain weight that is roughly proportional to differences in height. There also seems to be a difference in the corpus callosum (although only in shape (Breedlove, 1992)), as well as in cerebellar mass and protein expression (Nguon, 2005). Many of the homologues of sexually dimorphic nuclei in rats, such as the SNB and POA, are also dimorphic in the human brain.

Sexual dimorphism in the human anterior hypothalamus

The hypothalamus influences sexual behavior in humans by secreting hormones such as gonadotropin releasing hormone (GnRH) to trigger the release of sex steroids from the gonads. In 1989, Laura Allen and colleagues first described sexual dimorphism in the 3rd interstitial nucleus of the anterior hypothalamus (INAH-3, Figure 7;Allen, L.S. et al., 1989). Further studies showed that INAH-3 is consistently more than twice as large in adult heterosexual men as in adult women; however, the INAH-3 is a similar size in adult homosexual men and women (LeVay, S. 1991). This finding suggests that sexually dimorphic areas of the brain may influence many different aspects of sexual behavior.

Image:Human_inah.png

References

Allen, L. S., Hines, M., Shryne, J. E. & Gorski, R. A. Two sexually dimorphic cell groups in the human brain. J Neurosci 9, 497-506 (1989).

Breedlove, SM. Sexual dimorphism in the vertebrate nervous system. J Neurosci 12, 4133-4142 (1992).

Breedlove, S. M. & Arnold, A. P. Sexually dimorphic motor nucleus in the rat lumbar spinal cord: response to adult hormone manipulation, absence in androgen-insensitive rats. Brain Res 225, 297-307 (1981).

Carrer HF, Cambiasso MJ. Sexual differentiation of the brain: genes, estrogen, and neurotrophic factors. Cell Mol Neurobiol 22, 479-500 (2002).

Demir, E. & Dickson, B. J. fruitless splicing specifies male courtship behavior in Drosophila. Cell 121, 785-94 (2005).

Ellis, J. A., Sinclair, R. & Harrap, S. B. Androgenetic alopecia: pathogenesis and potential for therapy. Expert Rev Mol Med 2002, 1-11 (2002).

Kandel, ER, Schwartz JH, Jessell TM (2000). Principles of Neural Science, 4th ed., New York: McGraw-Hill. Chapter 57

LeVay, S. A difference in hypothalamic structure between heterosexual and homosexual men. Science 253, 1034-7 (1991).

Nguon K, Ladd B, Baxter MG, Sajdel-Sulkowska EM. Sexual dimorphism in cerebellar structure, function, and response to environmental perturbations. Prog Brain Res. 148, 341-51 (2005).

Nottebohm, F. The neural basis of birdsong. PLoS Biol 3, e164 (2005).

Purves D, Augustine GJ, Fitzpatrick D, Katz LC, LaMantia, LS, McNamara, JO, Williams, SM. (2001) Neuroscience, 2nd ed. Sinauer Associates, Inc. Ch. 30

Shah, N. M. et al. Visualizing sexual dimorphism in the brain. Neuron 43, 313-9 (2004).

Squire LR, et al. Fundamental Neuroscience. Academic Press, Boston, 2003.

Stockinger, P., Kvitsiani, D., Rotkopf, S., Tirian, L. & Dickson, B. J. Neural circuitry that governs Drosophila male courtship behavior. Cell 121, 795-807 (2005).

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