Optogenetic Testing of Mechanims of Dopamine Action in Pavlovian Learning

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DESCRIPTION (provided by applicant): Mesolimbic dopamine is considered to have a major role in Pavlovian reward learning. Pavlovian reward learning processes underlie many aspects of drug seeking behavior and may play a critical role in drug relapse. Hence our overall goal is to better understand the basic neurobehavioral mechanisms of reward learning. Here we seek to better define that role using optogenetic tools that will allow precise control of dopamine neuron activity during behavior. We will use the Th:Cre rat, a transgenic rat expressing Cre recombinase under control of a tyrosine hydroxylase (Th) promoter that allows for gene expression limited to dopamine neurons in the VTA following infusion of cre-dependent viruses expressing either channelrhodopsin or halorhodopsin. We can then deliver light through optical fibers surgically implanted into the VTA in the behaving rat to activate or inhibit activity of DA neurons. The proposed studies are based upon the notion that 1) dopamine neuron activity during the receipt of unexpected reward drives new learning about cues that predict the availability that reward, and that 2) decreases in dopamine neuron activity during expected reward may contribute to extinction of responding to reward-predictive cues. Thus we propose to extend preliminary findings to show that increases in dopamine neuron activity induced by optical stimulation functions as a positive prediction error and can cause learning. We also will test the hypothesis that suppression of dopamine neuron activity by optical stimulation functions as a negative prediction error and decreases learned responding. Additionally, we will test the hypothesis that these effects are mediated by dopamine neurons that project to the nucleus accumbens. Hence, using well-characterized Pavlovian conditioning procedures in combination with state-of- the-art behavioral optogenetics, the current aims are designed to expand our understanding of causal roles for VTA DA neuron activity in reward learning.