Anxiety disorders, such as post-traumatic stress disorder (PTSD) are hypothesized to result from a failure of fear processing centers in the brain to form appropriate associative memories during a traumatic event. Emerging evidence suggests that the dopamine neurotransmitter system is important for associative fear learning, raising the intriguing possibility that disregulation of this system during a fearful experience could be a contributing factor in the development of some anxiety disorders. Consistent with this hypothesis, we recently discovered that genetic disruption of the phasic activation of dopamine neurons impairs Pavlovian fear conditioning in mice, resulting the manifestation of generalized anxiety- like behavior. To date, very little is known about the neural circuitry regulating, or regulated by phasic dopamine signaling. Our hypothesis is that a select excitatory input to dopamine neurons facilitates the phasic activation of a subset of these cells during a fearful experience. Subsequent phasic dopamine release into discrete brain regions engages the dopamine D1 receptor to facilitates the formation of memories related to the fearful event. To test this hypothesis, we will utilize a multidisciplinary approach involving mouse behavior, genetics, molecular biology, viral-mediated gene transfer, and in vivo fiber- optic imaging of dopamine neuron activity in freely behaving mice. We are innovating a technique that will allow for fibered fluorescence microscopy of real-time activity-dependent calcium dynamics within dopamine neurons projecting to specific targets during Pavlovian fear conditioning in mice that will allow us to generate a map of phasic dopamine neuron activation. Additionally, we are establishing a combinatorial viral vector based approach for the conditional inactivation of specific genes in neurons projecting to select targets that will allow us to map the critical inputs to dopamine neurons for fear conditioning. Finally, we have developed a method for conditional gene reconstitution that will allow us to generate a map of the minimal essential brain regions requiring D1R expression for fear conditioning. Together these techniques will help us to establish the precise neural circuitry of dopamine-dependent fear processing and will provide broadly useful tools for the dissection of behaviorally relevant circuits throughout the brain.

Public Health Relevance

Anxiety disorders, such as post-traumatic stress disorder (PTSD) that manifest following a traumatic life experience result from the disregulation of fear processing centers in the brain. Little is known about the specific connections in the brain that are critical for normal fear processing and the prevention of generalized anxiety. We will use state of the art techniques in viral-mediated gene transfer and fiber-optic imaging of deep brain tissue in mice to precisely map connections of the dopamine neurotransmitter system in the brain that are critical for fear processing. By understanding how dopamine interfaces with other transmitter systems in the brain, we can develop better therapies to treat these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
3R01MH094536-02S1
Application #
8691185
Study Section
Special Emphasis Panel (ZMH1-ERB-L (04))
Program Officer
Vicentic, Aleksandra
Project Start
2011-09-16
Project End
2016-08-31
Budget Start
2013-07-10
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$75,598
Indirect Cost
$26,667
Name
University of Washington
Department
Pharmacology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Gore, Bryan B; Soden, Marta E; Zweifel, Larry S (2014) Visualization of plasticity in fear-evoked calcium signals in midbrain dopamine neurons. Learn Mem 21:575-9
Soden, M E; Gore, B B; Zweifel, L S (2014) Defining functional gene-circuit interfaces in the mouse nervous system. Genes Brain Behav 13:2-12
Gore, Bryan B; Zweifel, Larry S (2013) Genetic reconstruction of dopamine D1 receptor signaling in the nucleus accumbens facilitates natural and drug reward responses. J Neurosci 33:8640-9
Hollon, Nick G; Soden, Marta E; Wanat, Matthew J (2013) Dopaminergic prediction errors persevere in the nucleus accumbens core during negative reinforcement. J Neurosci 33:3253-5
Soden, Marta E; Jones, Graham L; Sanford, Christina A et al. (2013) Disruption of dopamine neuron activity pattern regulation through selective expression of a human KCNN3 mutation. Neuron 80:997-1009
Carter, Matthew E; Soden, Marta E; Zweifel, Larry S et al. (2013) Genetic identification of a neural circuit that suppresses appetite. Nature 503:111-4