The long-term goal of the proposed research is to elucidate the mechanisms by which estradiol enhances hippocampal dendritic spine and synapse density and performance of hippocampus-dependent behaviors in female rodents. This proposal addresses the hypothesis that the neurotrophin, brain-derived neurotrophic factor (BDNF), mediates estradiol's actions in the hippocampus. In the first specific aim, I will to characterize the response of the mouse hippocampus to physiologic levels of ovarian hormones, using endpoints previously demonstrated to be increased by estradiol in vitro and/or in vivo rat hippocampus: activation of the mediator of protein translation Akt, activation of the mediator of actin depolymerization LIMK, and expression of the presynaptic vesicle protein synaptophysin. To do this, I will use quantitative immunocytochemistry to examine these endpoints in the mouse hippocampus at high- and low- estradiol phases of the mouse estrous cycle. In the second specific aim, I will determine whether BDNF mediates the effects of ovarian hormones on these endpoints using a mouse model of BDNF deficiency. Using the same quantitative immunocytochemical techniques as in the first aim, I will determine whether the effects of ovarian hormones on the above endpoints are preserved in BDNF-deficient mice compared to wild-type mice. Finally, in the third specific aim, I will determine whether BDNF is important for the effects of ovarian hormones on hippocampal function. To assess the contribution of BDNF to previously reported estrus cycle fluctuations in hippocampus-dependent memory, object placement memory will be performed on wild-type mice and BDNF-deficient mice at high- and low- estradiol phases of the estrus cycle. The influence of estrogens on mental health in women is suggested by gender differences in susceptibility to mental disorders, short-term modulation of mood and cognition by ovarian hormones, and increased risk of depression and cognitive decline after menopause. The proposed studies will investigate the effects of ovarian hormones on the female mouse hippocampus, a part of the brain implicated in psychiatric disorders including depression and dementia. The studies will examine the role of the BDNF molecule in the effects of ovarian hormones, as this molecule has previously been linked to psychiatric disorders including depression. The findings will reveal possible mechanisms by which natural and pharmacological ovarian hormones modulate brain function, influencing susceptibility to psychiatric disorders and dementia across the menstrual cycle and lifespan. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30MH082528-02
Application #
7502656
Study Section
Special Emphasis Panel (ZRG1-F02A-A (20))
Program Officer
Curvey, Mary F
Project Start
2007-09-20
Project End
2010-09-19
Budget Start
2008-09-20
Budget End
2009-09-19
Support Year
2
Fiscal Year
2008
Total Cost
$45,972
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Type
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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
Bath, Kevin G; Chuang, Jocelyn; Spencer-Segal, Joanna L et al. (2012) Variant brain-derived neurotrophic factor (Valine66Methionine) polymorphism contributes to developmental and estrous stage-specific expression of anxiety-like behavior in female mice. Biol Psychiatry 72:499-504
Spencer-Segal, J L; Tsuda, M C; Mattei, L et al. (2012) Estradiol acts via estrogen receptors alpha and beta on pathways important for synaptic plasticity in the mouse hippocampal formation. Neuroscience 202:131-46
Spencer-Segal, Joanna L; Waters, Elizabeth M; Bath, Kevin G et al. (2011) Distribution of phosphorylated TrkB receptor in the mouse hippocampal formation depends on sex and estrous cycle stage. J Neurosci 31:6780-90
Spencer, Joanna L; Waters, Elizabeth M; Milner, Teresa A et al. (2010) BDNF variant Val66Met interacts with estrous cycle in the control of hippocampal function. Proc Natl Acad Sci U S A 107:4395-400
Mitterling, Katherine L; Spencer, Joanna L; Dziedzic, Noelle et al. (2010) Cellular and subcellular localization of estrogen and progestin receptor immunoreactivities in the mouse hippocampus. J Comp Neurol 518:2729-43
Spencer, J L; Waters, E M; Milner, T A et al. (2008) Estrous cycle regulates activation of hippocampal Akt, LIM kinase, and neurotrophin receptors in C57BL/6 mice. Neuroscience 155:1106-19