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bioRxiv · 10.1101/2020.12.04.411819

Mechanism for differential recruitment of orbitostriatal transmission during outcomes and actions in alcohol dependence

Gremel, C. M.·Renteria, R.·Cazares, C.·Baltz, E. T.·Schreiner, D. C.·Yalcinbas, E. A.·Steinkellner, T.·Hnasko, T. S.
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Abstract

Psychiatric disease often produces symptoms that have divergent effects on neural activity. For example, in drug dependence, dysfunctional value-based decision-making and compulsive-like actions have been linked to hypo- and hyper-activity of orbital frontal cortex (OFC)-basal ganglia circuits, respectively, however, the underlying mechanisms are unknown. Here we show that alcohol dependence enhanced activity in OFC terminals in dorsal striatum (OFC-DS) associated with actions, but reduced activity of the same terminals during periods of outcome retrieval, corresponding with a loss of outcome control over decision-making. Disrupted OFC-DS terminal activity was due to a dysfunction of dopamine-type 1 receptors on spiny projection neurons (D1R SPNs) that resulted in increased retrograde endocannabinoid (eCB) signaling at OFC-D1R SPN synapses reducing OFC-DS transmission. Blocking CB1 receptors restored OFC-DS activity in vivo and rescued outcome-based control over decision-making. These findings demonstrate a circuit-, synapse-, and computation specific mechanism gating OFC activity following the induction of alcohol dependence.

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Gremel, C. M., Renteria, R., Cazares, C., Baltz, E. T., Schreiner, D. C., Yalcinbas, E. A., Steinkellner, T., Hnasko, T. S.. 2020-12-04. Mechanism for differential recruitment of orbitostriatal transmission during outcomes and actions in alcohol dependence. https://doi.org/10.1101/2020.12.04.411819

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