Opioid-induced dysregulation of cortico-striatal circuits

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Project Summary/Abstract Opioid-based drugs are mainstays for pain management despite the risk of dependence, addiction, and cognitive impairments, even when taken as directed. Yet, the neurological underpinnings of opioid addiction remain relatively under-investigated, thereby limiting our understanding of the neural and associated psychological basis of addiction to opioids. Impaired decision-making, strong perseverance and an extraordinary motivation to obtain drug are widely seen as core aspects of addiction. These behaviors are expressed only by a fraction of those exposed to the drug – highlighting a significant degree of individual variability and a need to identify largely unknown factors that convey risk or resilience. Hypofunction of prefrontal circuits has emerged as a primary mechanism by which this transition occurs, however evidence regarding the nature, sub-circuit(s) locus, and development of this hypofunction is lacking. Our published data find that self-administration (SA) of the potent opioid, remifentanil (Rem), promotes a progressive hypoactive state in prelimbic cortex (PrL) pyramidal neurons that underlies impairments in cognitive flexibility, and that this phenomenon occurs on a faster timeline in females. Pilot data indicate inflexibility aligns with increased perseverative drug seeking and motivation for drug that is more prominent in females. We predict these changes emerge as a result of changes in PL-Core circuits, as pilot data indicate that hypoactivity is more prominent in PrL-Core PN and that this plasticity aligns with sex- and cell-type specific adaptations in synaptic strength at downstream Core medium spiny neurons (MSNs) based on expression of dopamine type I (D1) versus type II (D2) receptors. This proposal will combine circuit-specific ex vivo measures of plasticity, in vivo Ca2+ imaging, and chemogenetics with a novel SA model that permits longitudinal assessment of individual variability in the development of motivated and perseverative drug-seeking and a clinically relevant operant model to assess cognitive flexibility (strategy shifting) to identify changes from synapse to function to behavior. Aim1 of this proposal will further investigate exposure dependent changes within PrL-Core circuits using pathway-specific ex vivo electrophysiology. Intersectional chemogenetic manipulations will assess the contribution of this circuit flexibility and drug seeking and whether dysfunction underlies deficits in flexibility and changes in perseverance/motivation. Aim2 will use Ca2+ imaging to examine the corresponding disruptive effects of opioid plasticity on PrL-Core information processing associated with decision making and measure longitudinal changes in basal states and activity encoding opioid taking with progressive SA. Aim 3 will identify synaptic modifications at PrL-Core D1- and D2- MSN synapses. Contralateral chemogenetic targeting will determine contributions of PrL-to-D1-MSN and PrL- to-D2-MSN circuits in flexibility and longitudinally determine if contributions to opioid taking and behavior shifts over time. Proposed studies will provide novel insight into progressively developing changes in function and behavior, with the potential to inform more tailored treatments based on sex and stage of addiction.