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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Special Emphasis Panel (ZMH1-ERB-L (04))
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Vicentic, Aleksandra
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University of Washington
Schools of Medicine
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Locke, Timothy M; Soden, Marta E; Miller, Samara M et al. (2018) Dopamine D1 Receptor-Positive Neurons in the Lateral Nucleus of the Cerebellum Contribute to Cognitive Behavior. Biol Psychiatry 84:401-412
Jo, Yong S; Heymann, Gabriel; Zweifel, Larry S (2018) Dopamine Neurons Reflect the Uncertainty in Fear Generalization. Neuron 100:916-925.e3
Chung, Amanda S; Miller, Samara M; Sun, Yanjun et al. (2017) Sexual congruency in the connectome and translatome of VTA dopamine neurons. Sci Rep 7:11120
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Soden, Marta E; Miller, Samara M; Burgeno, Lauren M et al. (2016) Genetic Isolation of Hypothalamic Neurons that Regulate Context-Specific Male Social Behavior. Cell Rep 16:304-313
Padilla, Stephanie L; Qiu, Jian; Soden, Marta E et al. (2016) Agouti-related peptide neural circuits mediate adaptive behaviors in the starved state. Nat Neurosci 19:734-741
Jones, Graham L; Soden, Marta E; Knakal, Cerise R et al. (2015) A genetic link between discriminative fear coding by the lateral amygdala, dopamine, and fear generalization. Elife 4:
Samelson, Bret K; Gore, Bryan B; Whiting, Jennifer L et al. (2015) A-kinase Anchoring Protein 79/150 Recruits Protein Kinase C to Phosphorylate Roundabout Receptors. J Biol Chem 290:14107-19

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