Mobilization of endocannabinoids by midbrain dopamine neurons is required for the encoding of reward prediction

Miguel Á. Luján, Dan P. Covey, Reana Young-Morrison, LanYuan Zhang, Andrew Kim, Fiorella Morgado, Sachin Patel, Caroline E. Bass, Carlos Paladini and Joseph F. Cheer ()
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Miguel Á. Luján: University of Maryland School of Medicine
Dan P. Covey: University of Maryland School of Medicine
Reana Young-Morrison: University of Maryland School of Medicine
LanYuan Zhang: University of Maryland School of Medicine
Andrew Kim: University of Maryland School of Medicine
Fiorella Morgado: University of Maryland School of Medicine
Sachin Patel: Northwestern University Feinberg School of Medicine
Caroline E. Bass: University at Buffalo, State University of New York
Carlos Paladini: University of Texas at San Antonio
Joseph F. Cheer: University of Maryland School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Brain levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) shape motivated behavior and nucleus accumbens (NAc) dopamine release. However, it is not clear whether mobilization of 2-AG specifically from midbrain dopamine neurons is necessary for dopaminergic responses to external stimuli predicting forthcoming reward. Here, we use a viral-genetic strategy to prevent the expression of the 2-AG-synthesizing enzyme diacylglycerol lipase α (DGLα) from ventral tegmental area (VTA) dopamine cells in adult mice. We find that DGLα deletion from VTA dopamine neurons prevents depolarization-induced suppression of excitation (DSE), a form of 2-AG-mediated synaptic plasticity, in dopamine neurons. DGLα deletion also decreases effortful, cue-driven reward-seeking but has no effect on non-cued or low-effort operant tasks and other behaviors. Moreover, dopamine recording in the NAc reveals that deletion of DGLα impairs the transfer of accumbal dopamine signaling from a reward to its earliest predictors. These results demonstrate that 2-AG mobilization from VTA dopamine neurons is a necessary step for the generation of dopamine-based predictive associations that are required to direct and energize reward-oriented behavior.

Date: 2023
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DOI: 10.1038/s41467-023-43131-3

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