Difficulty down-regulating negative affect is a prominent feature of anxiety disorders and impairment in the extinction of an aversively-conditioned response, long an important model of anxiety, is a likely mechanism underlying this form of anxiety-related emotion dysregulation. A separate line of inquiry has indicated that specific genes are associated with both extinction deficits and the functional neuroanatomy of emotion regulation. Specifically the serotonin transporter promoter gene (5-HTTLPR) is associated with greater amygdala and reduced rostral anterior cingulate activation during affective challenge and the DRD4 dopamine receptor gene has been linked with extinction learning. Imaging genetics studies of extinction will be useful for understanding the mechanisms underlying affect dysregulation in anxiety and risk for anxiety.
SPECIFIC AIMS : The proposed research project will integrate findings from these domains by assessing how the 5-HTTLPR and DRD4 genes influence neural circuitry previously implicated in emotion dysregulation and extinction learning in a sample of those at risk for anxiety. CAREER DEVELOPMENT PLAN: The candidate's long term goal is to become an independent investigator in the area of imaging genetics of emotion regulation and affective psychopathology. The proposed research and training activities will focus on building expertise in three domains: 1) conditioning as a model for anxiety, 2) genetics and imaging genetics of affect-related traits, and 3) further development of previously established neuroimaging skills. The candidate will work closely with a team of mentors and consultants with expertise spanning these three domains. In addition to the proposed research project, the candidate will complete formal coursework and lab-based training, along with advisor-directed didactics in each area. SIGNIFICANCE: This project and the candidate's subsequent work will utilize the power of the imaging genetics approach to more precisely specify the mechanisms via which genes modulate emotion dysregulation and confer risk for anxiety and affective psychopathology.

Public Health Relevance

I will examine how specific genes influence brain regions activated when attempting to down- regulate responses to previously threatening stimuli among individuals at risk for anxiety disorders. These data will further our understanding of neurobiological factors associated with vulerability to anxiety and provide an important step toward identifying appropriate prevention and intervention measures for clinical anxiety.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Scientist Development Award - Research & Training (K01)
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Adult Psychopathology and Disorders of Aging Study Section (APDA)
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Wynne, Debra K
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University of Wisconsin Milwaukee
Schools of Arts and Sciences
United States
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Pedersen, Walker S; Muftuler, L Tugan; Larson, Christine L (2017) Disentangling the effects of novelty, valence and trait anxiety in the bed nucleus of the stria terminalis, amygdala and hippocampus with high resolution 7T fMRI. Neuroimage 156:293-301
Stout, Daniel M; Shackman, Alexander J; Pedersen, Walker S et al. (2017) Neural circuitry governing anxious individuals' mis-allocation of working memory to threat. Sci Rep 7:8742
Miskovich, Tara A; Pedersen, Walker S; Belleau, Emily L et al. (2016) Cortical Gyrification Patterns Associated with Trait Anxiety. PLoS One 11:e0149434
Pedersen, Walker S; Larson, Christine L (2016) State anxiety carried over from prior threat increases late positive potential amplitude during an instructed emotion regulation task. Emotion 16:719-29
Lewis, Kimberly L; Taubitz, Lauren E; Duke, Michael W et al. (2015) State rumination enhances elaborative processing of negative material as evidenced by the late positive potential. Emotion 15:687-93
Stout, Daniel M; Shackman, Alexander J; Johnson, Jeffrey S et al. (2015) Worry is associated with impaired gating of threat from working memory. Emotion 15:6-11
Belleau, Emily L; Taubitz, Lauren E; Larson, Christine L (2015) Imbalance of default mode and regulatory networks during externally focused processing in depression. Soc Cogn Affect Neurosci 10:744-51
Taubitz, Lauren E; Robinson, Jordan S; Larson, Christine L (2013) Modulation of the startle reflex across time by unpleasant pictures distinguishes dysphoric from non-dysphoric women. Int J Psychophysiol 87:124-9
Stout, Daniel M; Shackman, Alexander J; Larson, Christine L (2013) Failure to filter: anxious individuals show inefficient gating of threat from working memory. Front Hum Neurosci 7:58
Larson, Christine L; Baskin-Sommers, Arielle R; Stout, Daniel M et al. (2013) The interplay of attention and emotion: top-down attention modulates amygdala activation in psychopathy. Cogn Affect Behav Neurosci 13:757-70

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