The prevalence of anxiety disorders is twice as high in women. The reason for this eleveated prevalence is unclear, partly because most animal research has used only males, and most human research has not considered sex as a variable of interest. This proposal will begin to examine the neurobiological basis for these differences by first studying how natural fluctuations of estrogen in healthy women may influence the resting-state activity and the extinction-induced reactivity of the fear extinction network, including the amygdala, hippocampus, and the ventromedial prefrontal cortex (vmPFC). Additional experiments will involve exogenous manipulations of estrogen in naturally cycling women to see how these manipulations may interact with the functional activation of the fear extinction network. Healthy women will participate in a well-established fear conditioning and extinction protocol at different points of their menstrual cycle. Functional MRI and psychophysiological tools wil be employed to test two overall hypotheses: 1) Naturally elevated estrogen levels during the menstrual cycle will facilitate the resting-state activity and extinction-induced functional reactivity of the fear extinction network, and will be associated with enhanced extinction retention, and 2) Exogenous administration of estrogen to women will enhance extinction retention, which will be associated with enahnced resting-state activity and extinction-induced functional reactivity of this extinction circuitry during extinction recall. Findings from his proposal may help develop sex-specific treatments for anxiety disorders, for example by using hormonal-based pharmacological adjuncts to facilitate the processes of safety learning during therapy.

Public Health Relevance

The incidence of most anxiety and mood disorders is twice as high in women. This proposal will begin to examine the role of endogenous and exogenous estrogen levels on the functional activity and reactivity of the fear extinction network in healthy women. If successful, this approach could lead to developing sex-specific treatments to enhance the outcome of extinction-based therapies using estrogen as an adjunct to such therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH097880-03
Application #
8701400
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Vicentic, Aleksandra
Project Start
2012-08-01
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
$580,445
Indirect Cost
$246,856
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Graham, Bronwyn M; Milad, Mohammed R (2014) Inhibition of estradiol synthesis impairs fear extinction in male rats. Learn Mem 21:347-50
Cover, K K; Maeng, L Y; Lebrón-Milad, K et al. (2014) Mechanisms of estradiol in fear circuitry: implications for sex differences in psychopathology. Transl Psychiatry 4:e422
Graham, Bronwyn M; Milad, Mohammed R (2013) Blockade of estrogen by hormonal contraceptives impairs fear extinction in female rats and women. Biol Psychiatry 73:371-8
Lebron-Milad, K; Tsareva, A; Ahmed, N et al. (2013) Sex differences and estrous cycle in female rats interact with the effects of fluoxetine treatment on fear extinction. Behav Brain Res 253:217-22