The genome of brain cells is continually active during development, in adulthood and during senescence,and the nature of the gene products is regulated by internal and external chemical signals. The large environmental influence on gene expression in brain is evident from the fact that the concordance of inherited diseases such as schizophrenia and Alzheimer's disease between identical twins is not even as high as 50%. Environmental influences on neural gene expression play an important role in cyclic and seasonal changes in reproductive behaviors and the adaption of emotional and cognitive behaviors to stress and reproductive status; they are also important in the response to brain injury,to psychoactive drugs and to toxic substances. The goal of our research for more than 20 years has been to elucidate cellular,molecular and neurochemical mechanisms by which the external environmental,acting through the endocrine system and neurally-produced neuroactive substances,modifies gene expression in the nervous system and results in long-term changes in brain structure and function. The hormones of the gonads,adrenals and thyroid enter the brain, bind to specific intracellular receptors which bind to the genome,and alter gene expression underlying developmental and adult processes that determine specific neural and behavioral states.
The aim of our project is to examine the interactions between steroid hormones and neuroactive substances in a brain area,namely,the ventromedial nuclei of the hypothalamus (VMN),which is essential for the control of a specific behavior and where there is a hormonally-mediated developmental influence. In the VMN, where estradiol (E) and progesterone (P) act sequentially to govern sexual behavior(lordosis) in female,but not in males,rats. The sex difference is the result of actions of testosterone (T) during development to suppress development of lordosis capability in males. Our past work indicates that E and P actions on lordosis and developmental effects of T result in genomically-mediated changes in VMN. The VMN represents a """"""""simplified""""""""system in which to study the role of hormonally-regulated gene expression in determining the structural and functional interactions between neuroactive substances that subserves a developmentally-programmed and genomically activated behavioral response. Specific experiments explore E and P regulation of receptors for oxytocin,GABA and serotonin in males and females;E and P regulation of synaptic and dendritic plasticity;and search for cell nuclear proteins other than steroid hormone receptors which regulate tissue and sex-specific expression of E and P regulated gene products. Results obtained in this system should be applicable to other hormone-neurotransmitter interactions in other brain areas and should also be representative of many effects of transcriptional promotors and enhancers,of which steroid receptors are only one class,on neural gene expression which relates to synaptic and dendritic plasticity and neurotransmission.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurology B Subcommittee 2 (NEUB)
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Rockefeller University
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New York
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Newell, Andrew J; Lalitsasivimol, Diana; Willing, Jari et al. (2018) Progesterone receptor expression in cajal-retzius cells of the developing rat dentate gyrus: Potential role in hippocampus-dependent memory. J Comp Neurol 526:2285-2300
McEwen, Bruce S; Milner, Teresa A (2017) Understanding the broad influence of sex hormones and sex differences in the brain. J Neurosci Res 95:24-39
Waters, Elizabeth M; Thompson, Louisa I; Patel, Parth et al. (2015) G-protein-coupled estrogen receptor 1 is anatomically positioned to modulate synaptic plasticity in the mouse hippocampus. J Neurosci 35:2384-97
McEwen, Bruce S; Gray, Jason D; Nasca, Carla (2015) 60 YEARS OF NEUROENDOCRINOLOGY: Redefining neuroendocrinology: stress, sex and cognitive and emotional regulation. J Endocrinol 226:T67-83
Pierce, Joseph P; Kelter, David T; McEwen, Bruce S et al. (2014) Hippocampal mossy fiber leu-enkephalin immunoreactivity in female rats is significantly altered following both acute and chronic stress. J Chem Neuroanat 55:9-17
Milner, Teresa A; Burstein, Suzanne R; Marrone, Gina F et al. (2013) Stress differentially alters mu opioid receptor density and trafficking in parvalbumin-containing interneurons in the female and male rat hippocampus. Synapse 67:757-72
Van Kempen, Tracey A; Kahlid, Sana; Gonzalez, Andreina D et al. (2013) Sex and estrogen receptor expression influence opioid peptide levels in the mouse hippocampal mossy fiber pathway. Neurosci Lett 552:66-70
Burstein, Suzanne R; Williams, Tanya J; Lane, Diane A et al. (2013) The influences of reproductive status and acute stress on the levels of phosphorylated delta opioid receptor immunoreactivity in rat hippocampus. Brain Res 1518:71-81
Akama, Keith T; Thompson, Louisa I; Milner, Teresa A et al. (2013) Post-synaptic density-95 (PSD-95) binding capacity of G-protein-coupled receptor 30 (GPR30), an estrogen receptor that can be identified in hippocampal dendritic spines. J Biol Chem 288:6438-50
McEwen, Bruce S (2012) The ever-changing brain: cellular and molecular mechanisms for the effects of stressful experiences. Dev Neurobiol 72:878-90

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