Investigating the role of striatal direct and indirect pathway spiny projection neurons in a cocaine-induced impairment of goal-directed behavioural control

Substance use disorder (SUD) is a debilitating disorder characterized by disruption of flexible decision-making, resulting in the persistence of drug-seeking and taking behaviours despite negative consequences. This impairment of goal-directed action control is thought to occur in response to repeated drug exposure, which induce neuroplastic changes within the dorsal striatum. The dorsal striatum is comprised of two functionally distinct regions with the prevailing view being that dorsomedial (DMS) and dorsolateral (DLS) striatum mediates goal-directed and habit-based action selection, respectively. However, recent evidence points to a more nuanced role of direct pathway (dSPNs) and indirect pathway spiny projection neurons (iSPNs) in mediating such functions within each of these subregions. Therefore, in the present thesis, we aim to characterise SPN activity within the DMS and DLS under more purposeful or more automatic behavioural control. Furthermore, we aim to examine how drug exposure may alter SPN activity in the DMS and DLS, resulting in an accelerated transition to more automatic action control. To achieve this, we injected male and female Drd1a-iCre rats with Cre-dependent GCaMP8f virus and implanted fibre optic probes targeting the DMS (n=18) or DLS (n=10) to record from isolated dSPNs. Recovered rats were treated with cocaine (30mg/kg, intraperitoneal injection) or saline for 6 days prior to behavioural testing. Rats were trained according to a random interval schedule for pellets and assessed during early and late phases of instrumental behaviour using the outcome-devaluation test. Aligned with previous literature, we have shown that cocaine animals are less purposefully after extended training, even for natural rewards. From our studies, this increase is accompanied by dSPN changes in DLS but not DMS neural response to lever press and magazine entry. Interestingly, cocaine reduced neural responses to lever presses but increased neural responses to magazine entries, which could point to cocaine-driven aberrant changes in appetitive-consummatory action-sequences related to the drug seeking-taking chain. Overall, DLS dSPNs are more sensitive to cocaine exposure - a finding that might have relevance for understanding the development of inflexible behaviour in neuropsychiatric conditions.