Chronic alcohol exposure disrupts top-down control over basal ganglia action selection to produce habits

Abstract

Addiction involves a predominance of habitual control mediated through action selection processes in dorsal striatum. Research has largely focused on neural mechanisms mediating a proposed progression from ventral to dorsal lateral striatal control in addiction. However, over reliance on habit striatal processes may also arise from reduced cortical input to striatum, thereby disrupting executive control over action selection. Here, we identify novel mechanisms through which chronic intermittent ethanol exposure and withdrawal (CIE) disrupts top-down control over goal-directed action selection processes to produce habits. We find CIE results in decreased excitability of orbital frontal cortex (OFC) excitatory circuits supporting goal-directed control, and, strikingly, selectively reduces OFC output to the direct output pathway in dorsal medial striatum. Increasing the activity of OFC circuits restores goal-directed control in CIE-exposed mice. Our findings show habitual control in alcohol dependence can arise through disrupted communication between top-down, goal-directed processes onto basal ganglia pathways controlling action selection.

Fig. 1

Chronic ethanol exposure and repeated withdrawal biases towards habitual control over actions. a Experimental timeline of CIE and the following operant training and subsequent outcome devaluation testing (DV). b Mice (3 cohorts, Air n = 15, CIE n = 19) are trained to press the same lever (left or right) for the same food outcome (food pellet or sucrose) in two distinct contexts under RI or RR schedules of reinforcement. c, d Response rate of lever pressing during acquisition under RI (c) or RR (d) schedules. e Schematic of the outcome devaluation procedures. On the devalued day, mice receive 1 h free access to the outcome previously produced by lever pressing, immediately followed by a 5 min extinction test in each context. To control for effects of general satiety on responding, on the valued day mice receive 1 h free access to the remaining outcome, immediately followed by a 5 min extinction test in each context. f Normalized lever presses showing the distribution of lever pressing between the valued and devalued day in each training context. g Devaluation index (see Methods) for each group in the previously trained RI and RR contexts. Data are represented as mean ± SEM. ****p < 0.001, *p < 0.05 reflect one-sample t tests against 0.5 and 0, respectively

Fig. 2

CIE induces long-lasting disruptions to orbitostriatal circuits. a Experimental timeline used for electrophysiological recordings. Mice were given viral injections and allowed 2–4 weeks to recover before exposure to the CIE procedure. b Schematic of OFC recording site. c The number of spikes plotted against current injected (left) and representative traces of action potential firing at 200 pA (right) (3 cohorts, Air n = 8, CIE n = 11). d Schematic of OFC injection site and DMS recording site for optically induced currents. e Cre-dependent ChR2-YFP expression at the OFC injection site (left) and OFC terminals in the DMS (right). f Paired pulse ratio (PPR) of optically induced currents of OFC input to D1 SPNs. Scale bars represent 25 ms (horizontal) and 50 pA (vertical) (3 cohorts, Air n = 7, CIE n = 15). g Representative current traces of asynchronous release to D1 SPNS recorded in 2 mM Sr²⁺. Scale bars represent 250 ms (horizontal) and 50 pA (vertical). h Average frequency of asynchronous release to D1 SPNs (Air n = 8, CIE n = 12). i Average amplitude of asynchronous release to D1 SPNs. j PPR of optically induced currents of OFC input to D2 SPNs (3 cohorts, Air n = 7, CIE n = 9). k Representative current traces of asynchronous release to D2 SPNs recorded in 2 mM Sr²⁺. l Average frequency of asynchronous release to D2 SPNs (Air n = 7, CIE n = 7). m Average amplitude of asynchronous release to D2 SPNs. Data points and bar graphs represent the average ± SEM. ****p < 0.0001, **p < 0.01, *p < 0.05

Fig. 3

CIE does not alter all excitatory input into striatal circuits. a Experimental timeline for cohorts of mice used for electrophysiological recordings. Mice were injected with AAV ChR2 in the OFC and allowed 2–4 weeks to recover before exposure to the CIE procedure. Data collected in which currents were evoked electrically were done in the same brain slices used for optically evoked currents. b Schematic of DMS recording site and placement of stimulating electrode within striatum. c, d Paired pulse ratio (PPR) of electrically induced currents onto D1 SPNs (Air n = 6, CIE n = 6) (c) and D2 SPNS (Air n = 7, CIE n = 11) (d) in Air or CIE-exposed mice. Scale bars represent 25 ms (horizontal) and 50 pA (vertical). e Representative traces of spontaneous EPSCs (sEPSCs) in D1 SPNs in Air and CIE mice. Scale bars represent 1 s (horizontal) and 20 pA (vertical). f, d Frequency (f) and amplitude (g) of sEPSCs in D1 SPNs from Air and CIE mice. h Representative traces of spontaneous EPSCs (sEPSCs) in D2 SPNs in Air and CIE mice. i, j Frequency (i) and amplitude (j) of sEPSCs in D2 SPNs from Air and CIE mice. Data points and bar graphs represent the average ± SEM

Fig. 4

Activation of OFC neurons restores control by goal-directed processes. a Experimental outline. Mice were injected with an activating DREADD (hM3Dq) in the OFC. After recovery, mice underwent CIE procedures followed by operant training and outcome devaluation testing. CNO was administered to hM3Dq expressing CIE-exposed mice (CIE H3), control CIE-exposed mice (CIE), and Air-exposed mice (Air) 30 min prior to prefeeding on both valued and devalued testing days. b Schematic of OFC injection site with hM3D-mCherry (left) and subsequent expression of mCherry in the OFC (middle). Schematic of maximum (pink) and minimum (red) boundaries of viral spread in the OFC (right). c The number of spikes plotted against the current injected (left). Representative traces of action potential firing at 200 pA (right) (n = 6 cells). d Normalized lever presses for each group (three cohorts, Air n = 16, CIE control n = 14, CIE H3 n = 19) showing the distribution of lever presses between valued and devalued days in random interval (RI) and random ratio (RR) trained contexts. e Devaluation index for each group in the previously trained RI and RR contexts. Data are represented as mean ± SEM. **p < 0.01 and ***p < 0.001 reflect one-sample t tests against 0.5 and *p < 0.05 and #p = 0.09 reflect one-sample t tests against 0