Richard Simerly

Senior Scientist, Oregon Regional Primate Research Center

Developmental Neurobiology

The development of the brain is dependent on complex interactions between genetic factors and environmental influences such as neuronal activity, growth factors and circulating hormones. Sex steroid hormones secreted by the gonads can determine the number and chemical phenotype of specific sets of neurons during development, as well as the connections they form with other parts of the brain. Our laboratory is studying the organization and development of hormone sensitive neural pathways in the mammalian forebrain. Having identified distinct differences in neural connectivity and relative amounts of certain neurotransmitters in the brains of male and female animals, we are studying how gonadal steroid hormones direct the development of these sexual dimorphisms. Two experimental approaches are used in this research. Developmental changes in the organization of neural circuits and neurotransmitter expression are studied in vivo by applying axonal labeling combined with histochemical techniques that allow visualization of neural connections and gene expression events at the level of single identified cells. In addition, we are studying how hormones regulate neuronal survival and maturation in vitro by using a slice explant tissue culture method and confocal microscopy to observe and manipulate axonal guidance and cellular differentiation in living tissue samples maintained under defined conditions. Together with evidence from other laboratories, this work indicates that sex steroid hormones specify the architecture of sexually dimorphic forebrain pathways by regulating neuronal survival, the strength of connections between cells, and the expression of neurotransmitters in a cell type specific way. We are also studying the organization and development of forebrain pathways that regulate feeding and energy homeostasis. By using axonal labeling methods, and both in vitro and in vivo experimental approaches, we are determining if manipulation of genes known to play an important role in feeding also influence the development of the pathways that mediate hypothalamic responses to changes in energy balance. Recent findings indicate that these neural pathways develop during discrete temporal domains suggesting that there are region specific mechanisms governing assembly of homeostatic circuits. Thus, the central goal of the laboratory is to identify signalling mechanisms that control the development and differentiation of forebrain pathways mediating neuroendocrine function, which may provide insight into the causes of hormone sensitive developmental abnormalities and neurological disorders.

Hutton LA, Gu GB, Simerly RB. (1998) Development of a sexually dimorphic projection from the bed nuclei of the stria terminalis to the anteroventral periventricular nucleus in the rat.

J . Neurosci 18:3003-3013.

Simerly, R.B. (2000) Development of sexually dimorphic forebrain pathways. In: Sexual Differentiation of the Brain. A. Matsumoto, ed. CRC Press, Boca Raton pp 175-202.

Ibanez, M. A., G. Gu and R.B. Simerly. (2001) Target dependent sexual differentiation of a limbic-hypothalamic neural pathway. J. Neurosci., 21(15):5652-5659.

To contact Dr. Simerly directly: simerlyr@ohsu.edu