Midbrain Dopamine Neuron Activity Predicts Impulsive Actions in Mice

Pinkhasov, Tzvia, Starosta, Sarah, Kepecs, Adam (December 2019) Midbrain Dopamine Neuron Activity Predicts Impulsive Actions in Mice. In: 58th Annual Meeting of the American-College-of-Neuropsychopharmacology (ACNP).


Background: Impulsivity, or acting without forethought or self-control despite negative consequences, increases the risk of suicidality, substance abuse, and violence. Dopamine (DA) is central to impulsivity, as posited by human neuroimaging data that highlight differences in DA-rich regions between healthy individuals and those with impulsivity-related disorders. DA is also central to reward processing, learning and motivation. While we understand that motivated behaviors are driven by phasic DA responses to reward information, we have yet to uncover how DA activity could drive the ability to suppress motivated behaviors when they are maladaptive. Methods: We developed a novel cued-reward lick-withholding task in which head-fixed mice must suppress anticipatory licking during a reward predicting cue (2s) in order to earn water reward. Three different auditory cues that predicted three different reward sizes (big, small, none) were randomly interleaved. The cue was restarted as many times as the animal licked prematurely (before the 2 second cue period was over). The total duration of the tone was used as a trial-by-trial measure of the degree of impulsivity. The task accomplishes the following: 1. It places Pavlovian cue responses in conflict with self-restraint, enabling us to study the neural substrates of action impulsivity. 2, It manipulates the degree of impulsivity by manipulating expected reward value, and 3. It provides a quantitative, trial-by-trial measure of action impulsivity that can be precisely related to neural activity. We measured DA neuron activity using fiber photometry, in which fluorescence emitted from GCaMP6f, a Calcium sensor, is used as a proxy for neural population activity. We specifically targeted DA cells by injecting GCaMP6f in the Ventral Tegmental Area (VTA) of DAT-Cre transgenic mice. An optical fiber was then implanted in the VTA to collect the bulk fluorescence signal. Results: Our behavioral results show that mice can discriminate between the three trial types and exhibit a learned waiting behavior. In addition, mice behaved more impulsively in anticipation of the larger reward, despite it resulting in a reduced rate of reward receipt. As expected, neural recordings demonstrate that phasic DA encodes expected and received reward value at reward cue and reward onset, respectively. However, when controlling for expected reward size, DA dynamically encodes the failure to suppress conditioned responses throughout the trial structure. First, cue-induced phasic DA activity is predictive of impulsivity level and may explain trial-to-trial variability in impulsivity. Second, DA ramping during the wait period predicts the onset of impulsive actions in a manner that reflects changes in reward expectation over time. Lastly, impulsive actions lead to greater DA reward responses, suggesting a mechanism for the persistence of this maladaptive behavior. Conclusions: These data suggest that phasic cue-induced DA activity may drive action impulsivity in addition to their role in learning and motivation.

Item Type: Conference or Workshop Item (Poster)
Subjects: diseases & disorders > mental disorders > impulse control disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > dopamine
organs, tissues, organelles, cell types and functions > tissues types and functions > midbrain
organs, tissues, organelles, cell types and functions > tissues types and functions > ventral tegmental area
CSHL Authors:
Communities: CSHL labs > Kepecs lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: December 2019
Date Deposited: 28 Apr 2021 14:06
Last Modified: 28 Apr 2021 14:06
Related URLs:
URI: https://repository.cshl.edu/id/eprint/39938

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