D1 and D2 Dopaminoceptive Ensembles in Limbic Brain Regions in Drug Addiction

Icahn School Of Medicine At Mount Sinai, New York NY

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Abstract

SUMMARY This R01 grant focused historically on neurotrophic mechanisms in the long-term actions of stimulant and opioid drugs of abuse on the brain’s reward circuitry, especially the nucleus accumbens (NAc). This effort contributed to appreciating the distinct roles played by NAc medium spiny neurons (MSNs) that express either the D1 or D2 dopamine receptor in addiction-related molecular, cellular, circuit, and behavioral abnormalities. In recent years, our work has evolved still further to focus on subpopulations of these NAc D1 and D2 MSNs – so-called “ensembles” – which are activated by acute vs. chronic drug exposure. In parallel, we have also begun to characterize neuronal ensembles in key limbic brain regions that provide glutamatergic inputs to the NAc. Dopaminoceptive neurons in these other regions are also subdivided into mostly non-overlapping populations of D1- and D2-expressing neurons. The objective of this competitive renewal application is to extend our in-depth characterization of drug-activated neuronal ensembles – both in the NAc and in key input regions – and of prominent drug-induced adaptations in those ensemble neurons that mediate aspects of addiction-like syndromes in mouse models. Aim 1 focuses on the NAc, where we will continue to use Arc- CreERT2 mice to tag cells activated in response to one stimulus (e.g., first or last cocaine or opioid exposure) and track how those cells respond over time during the course of drug self-administration and relapse. We have robust preliminary data that distinct ARC ensemble cells are recruited by initial vs. repeated drug exposure and serve different (in some cases opposite) roles in controlling behavioral responses to the drugs. Interestingly, both the initial and repeated ensembles are composed of mixtures of D1 and D2 MSNs – which display unique transcriptional patterns compared to non-ensemble D1 and D2 MSNs, which underscores the importance of moving beyond the simplified dichotomy of characterizing D1 vs. D2 NAc MSNs per se. Studies with Arc-CreERT2 mice will be complemented by single nucleus RNA-sequencing (snRNAseq) which has demonstrated much larger ensembles of NAc MSNs that are affected by initial and repeated drug exposure: in other words, as seen in other brain regions in the learning and memory field as well, ensembles defined by Arc or any other immediate early gene (e.g., Fos) represent a smaller subset of a larger population of neurons involved, which can be captured uniquely by use of snRNAseq. As we make progress with the NAc, we will focus in Aim 2 on equivalent studies of key input regions to the NAc where we have also defined ensembles, composed of mixtures of D1 and D2 dopaminoceptive neurons, that are activated in response to cocaine or opioid exposure. We already have considerable preliminary data for such drug-activated ensembles in ventral hippocampus and the paraventricular nucleus of the thalamus. Together, this work will contribute to an improved understanding of the biological basis of drug addiction and provide new pathways for identifying molecular and cellular targets suitable for future therapeutic discovery efforts.