Different lines of evidence support the notion that psychiatric disorders result from the interaction of vulnerability genes and environmental factors. The incomplete penetrance (discordance) of psychiatric disorders in identical twins has been hypothesized to be the result of environmental influences. Likewise, genetic differences have been postulated to be responsible for the seeming resilience or vulnerability to psychiatric symptoms seen in subjects exposed to similar environmental situations. Although this gene- environment diathesis of psychiatric disorders has intuitive appeal, neither the genes conferring susceptibility nor the environmental factors that increase the risk of psychiatric morbidity are well understood. Recently some progress has been made in identifying both susceptibility genes and environmental factors that may influence the outcome in major depression, the most common psychiatric disorder that takes an enormous toll on individuals, their families, and society. A highly influential study by Caspi demonstrated that certain promoter variants of the serotonin transporter gene (5HTT) interact with either early life stress (childhood maltreatment) or adult stresses (job loss, divorce, etc.) to modulate the likelihood of depressive symptoms, diagnosed major depression, and suicidal behavior in the study subjects. Specifically, the study found that promoter variants that reduce transcriptional efficiency of the 5HTT increase depression-related phenotypes whereas variants that have higher expression confer resilience to childhood or adult stresses. The availability of a mouse model of a 5HTT-environment interaction allows us to ask several specific questions regarding the positive and negative ways that the environment may be manipulated to reduce or increase the expression of depression-related behaviors. In addition, a mouse model offers the possibility to investigate the neural substrates that mediate the environmental impact on behavior. This line of investigation offers the possibility of gaining new understanding regarding the pathogenesis of depressive disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH076026-05
Application #
7767712
Study Section
Biobehavioral Mechanisms of Emotion, Stress and Health Study Section (MESH)
Program Officer
Winsky, Lois M
Project Start
2006-03-10
Project End
2012-02-29
Budget Start
2010-03-01
Budget End
2012-02-29
Support Year
5
Fiscal Year
2010
Total Cost
$335,384
Indirect Cost
Name
New York State Psychiatric Institute
Department
Type
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Gingrich, Jay A; Malm, Heli; Ansorge, Mark S et al. (2017) New Insights into How Serotonin Selective Reuptake Inhibitors Shape the Developing Brain. Birth Defects Res 109:924-932
Muller, J M; Morelli, E; Ansorge, M et al. (2011) Serotonin transporter deficient mice are vulnerable to escape deficits following inescapable shocks. Genes Brain Behav 10:166-75