The long range goal of this work is to clarify the cellular and molecular events that underlie the hormonal control of neural development in the mammalian central nervous system. Central to this goal is a clear understanding of how individual subpopulations of neurons in limbic regions acquire hormone sensitivity, and how circulating hormones influence neuronal proliferation, survival and differentiation. Both sex steroid and thyroid hormones exert profound neurotrophic effects on developing neurons, and the expression of sex steroid and thyroid hormone receptors by discrete populations of neurons during critical periods of development is thought to be the primary molecular event underlying the hormonal control of neuronal development and neurotransmitter plasticity. The proposed project will use the media nucleus of the amygdala (MeAp) as a model system to study the development of a sexually dimorphic population of preprocholecystokinin (PCCK)-containing neurons that appears to develop under the influence of perinatal steroid hormones. Moreover, the MeAp contains high densities of cells that express sex steroid and thyroid hormone receptors, and has been implicated in a variety of neuroendocrine functions including the control of ovulation, sexual and aggressive behavior, and salt appetite. Experiments are proposed that will (1) define the ontogeny of the sexual dimorphism in PCCK cells in the MeAp, and (2) evaluate the role of hormone receptors in mediating the sexual differentiation of these cells. These broad goals will be accomplished as follows: (Specific Aim 1) Thymidine """"""""birth dating"""""""" will be used in combination with in situ hybridization to examine the hypothesis that exposure to sex steroids during the neonatal period enhances the expression of PCCK mRNA within MeAp neurons, or preferentially promotes the survival of cells in the MeAp that express the PCCK phenotype. In addition, in situ and solution hybridization techniques will be used to test the following hypotheses: (Specific Aim 2) the expression patterns of sex steroid and thyroid hormone receptor mRNAs during the neonatal period are sexually dimorphic and dependent on neonatal sex steroids; (Specific Aim 3) circulating thyroid hormones influence the ability of sex steroids to induce sexual differentiation of PCCK mRNA-containing cells in the MeAp. (Specific Aim 4) A double in situ hybridization technique will be used to test the hypothesis that AR, ER, and TR receptor mRNAs are differentially expressed in PCCK containing neurons in the MeAp during critical periods for sexual differentiation. The results of these studies will make a significant contribution to our emerging understanding of cellular mechanisms underlying the hormonal control of neuronal development, and may provide clues about mechanisms responsible for sex- related aberrations in neurotransmitter expression that may contribute to major depression, schizophrenia, and other hormone-sensitive mental disorders that occur during childhood and adolescence.
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| Simerly, R B; Zee, M C; Pendleton, J W et al. (1997) Estrogen receptor-dependent sexual differentiation of dopaminergic neurons in the preoptic region of the mouse. Proc Natl Acad Sci U S A 94:14077-82 |
