Mechanism for differential recruitment of orbitostriatal transmission during actions and outcomes following chronic alcohol exposure

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 exposed mice have 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 in alcohol exposed mice.

Resting-State Functional Connectivity Differences Following Experimental Manipulation of the Orbitofrontal Cortex in Two Directions via Theta-Burst Stimulation

“…It is notable that, within the context of “gold standard” behavioral treatments (e.g., exposure with response prevention), similar opposing patterns for acute (increased urges/anxiety) versus long-term (improved CBs, anxiety relief) outcomes are fully expected, and, indeed, an enhanced acute degree of distress-inducing challenge or “exercise” for resisting compulsive urges is considered critical for enduring therapeutic outcomes. The present RSFC findings suggest that acutely down-regulating right lateral OFC-based circuitry may represent a key neural mechanism supporting the adaptive transition from habit-driven (i.e., driven by short-term anxiety/urge relief) to goal-driven adaptive function, consistent with circuit-based animal stimulation studies in which lateral OFC-striatal circuits have been implicated in expression of compulsive-like behaviors (Pascoli et al, 2015, 2018; Renteria et al, 2021).…”

Inter-individual variability amplified through breeding reveals control of reward-related action strategies by Melanocortin-4 Receptor in the dorsomedial striatum

“…MC4Rs, like D1Rs, are positively coupled to the cAMP second messenger cascade 18 , 39 , and thus can enhance D1R function 40 . D1R stimulation is necessary for learning new skills 6 , and D1R+MSNs in the DMS is involved in the development of goal-directed action strategies 10 – a process that requires inhibiting unproductive behaviors – and recalling memories linking actions and outcomes 41 . Mc4r -null mice are delayed in learning to nose poke for food, and restoration of MC4R in D1R-containing cells reinstates this capacity 25 .…”

Orbitofrontal cortex to dorsal striatum circuit is critical for incubation of oxycodone craving after forced abstinence

“…Another possibility is through retrograde signaling mediated by endocannabinoids. Supporting this hypothesis, previous studies have shown that deletion of cannabinoid type 1 receptor in OFC → DS projections disrupts the shift from goal-directed to habitual behaviors in mice (Gremel et al, 2016), and increased retrograde signaling mediated by endocannabinoid from OFC to D1R-expressing MSNs contributes to decreased OFC → DS transmission after chronic alcohol exposure (Renteria et al, 2021).…”