The long-range goal of this work is to clarify cellular mechanisms that underlie development of sexually dimorphic neural pathways in the mammalian forebrain. The proposed project will use a sexually dimorphic limbic-hypothalamic pathway as a model system to study how sex steroid hormones specify patterns of forebrain connections. During the second week of life, the anteroventral periventricular nucleus of the preoptic region (AVPV) receives a sexually dimorphic input from the principal nucleus of the bed nuclei of the stria terminalis (BSTp) that develops according to a directed mechanism. During the past project period we developed an organotypic co-culture model to demonstrate that sexual differentiation of this pathway is due to a target dependent, estrogen receptor alpha (ERalpha)-mediated, action of estrogen on the AVPV. Preliminary evidence presented in the body of this application indicates that the estrogen-regulated neurotrophin BDNF (brain derived neurotrophic factor), and the class 3 semaphorin Sema 3C, are expressed in the AVPV in sexually dimorphic patterns and appear to play important roles in promoting BSTp-AVPV projections. Our Overall Hypothesis is that E2 acts on the AVPV during the first few days of life to alter expression of neurotrophic and chemotropic factors that promote its innervation by BSTp neurons. Both in vitro and in vivo experimental models will be used to test two specific hypotheses:
Specific Aim 1. During postnatal development, ERalpha mediates increased expression of BDNF in the AVPV, which acts on BSTp axons via TrkB receptors to promote neurite extension.
Specific Aim 2. ERalpha dependent expression of semaphorin in the AVPV influences development of sexually dimorphic projections from the BSTp to the AVPV. In addition to characterizing expression of these molecules during development of the BSTp-AVPV pathway, we will utilize a loss of function/gain of function strategy to explore their role during growth and guidance of BSTp projections. The results of these studies will make a significant contribution to our emerging understanding of molecular events that mediate hormonal control of brain development, and will add to what is known about developmental regulation of axon guidance generally. These studies may also provide clues about mechanisms responsible for sex-linked aberrations in neural connectivity that contribute to a variety of hormone-sensitive neurological disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037952-08
Application #
7354747
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Gnadt, James W
Project Start
1999-09-01
Project End
2010-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
8
Fiscal Year
2008
Total Cost
$318,290
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
052277936
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
Cooke, Bradley M; Simerly, Richard B (2005) Ontogeny of bidirectional connections between the medial nucleus of the amygdala and the principal bed nucleus of the stria terminalis in the rat. J Comp Neurol 489:42-58
Forger, Nancy G; Rosen, Greta J; Waters, Elizabeth M et al. (2004) Deletion of Bax eliminates sex differences in the mouse forebrain. Proc Natl Acad Sci U S A 101:13666-71
Polston, E K; Gu, G; Simerly, R B (2004) Neurons in the principal nucleus of the bed nuclei of the stria terminalis provide a sexually dimorphic GABAergic input to the anteroventral periventricular nucleus of the hypothalamus. Neuroscience 123:793-803
Bouret, Sebastien G; Draper, Shin J; Simerly, Richard B (2004) Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice. J Neurosci 24:2797-805
Bouret, Sebastien G; Draper, Shin J; Simerly, Richard B (2004) Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 304:108-10
Bouret, Sebastien G; Simerly, Richard B (2004) Minireview: Leptin and development of hypothalamic feeding circuits. Endocrinology 145:2621-6
Polston, Eva K; Simerly, Richard B (2003) Sex-specific patterns of galanin, cholecystokinin, and substance P expression in neurons of the principal bed nucleus of the stria terminalis are differentially reflected within three efferent preoptic pathways in the juvenile rat. J Comp Neurol 465:551-9
Zup, Susan L; Carrier, Heather; Waters, Elizabeth M et al. (2003) Overexpression of bcl-2 reduces sex differences in neuron number in the brain and spinal cord. J Neurosci 23:2357-62
Gu, Guibao; Cornea, Anda; Simerly, Richard B (2003) Sexual differentiation of projections from the principal nucleus of the bed nuclei of the stria terminalis. J Comp Neurol 460:542-62
Simerly, Richard B (2002) Wired for reproduction: organization and development of sexually dimorphic circuits in the mammalian forebrain. Annu Rev Neurosci 25:507-36

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