The incidence of affective disorders including depression and anxiety disorders in women is twice that of men. This gender difference, which emerges during puberty, suggests a potential role of estradiol. Interestingly, the severity of affective symptoms is negatively correlated with the endogenous estradiol levels. However, the mechanism by which endogenous estradiol modulates synaptic circuits relevant to affective behaviors is not well understood. We propose to investigate whether and how variations in estradiol levels modulate synapses in the medial prefrontal cortex (mPFC), a brain region critical for the regulation of affective behaviors. We will also test whether pharmacological activation of estrogen receptors improves affective behaviors during periods of low endogenous estradiol. Preliminary results indicate that the effects of estradiol on the mPFC synapses require brain derived neurotrophic factor (BDNF), a secreted trophic protein involved in affective behaviors. Experiments will be carried out to elucidate the mechanism by which estradiol and BDNF interact at mPFC synapses. These experiments are likely to shed light on the mechanism of sex differences in affective behaviors and the vulnerability of periods of low estradiol levels to environmental and genetic challenges. In addition, our studies will provide insights into possible therapeutic targets and windows of opportunity to modulate the mPFC synapses for the management of affective disorders.

Public Health Relevance

An important question in psychiatry today is what accounts for the profound gender difference in affective disorders, in which women are affected at a significantly higher rate than men. Given the crucial role of the medial prefrontal cortex in the regulation of affective behaviors, we propose to investigate how changes in endogenous estradiol levels modulate medial prefrontal cortical synapses, which might provide insights into the basis of sex difference and potential management strategies in affective disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56MH096899-02
Application #
8802056
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Desmond, Nancy L
Project Start
2014-03-01
Project End
2016-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
2
Fiscal Year
2014
Total Cost
$414,715
Indirect Cost
$164,715
Name
New York University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016