Contributions of KCNQ2/3 channels to medium spiny neuron excitability and cocaine reward

PROJECT SUMMARY Substance use disorder is a multidimensional neuropsychiatric disease increasing in prevalence across the United States despite increased awareness and substantial leaps in treatment approaches. Unfortunately, these treatments commonly fail due to strongly encoded drug-associations, often resulting in relapse. Drugs of abuse, such as cocaine, act on the mesolimbic dopamine system to increase dopaminergic transmission in the nucleus accumbens (NAc), a key brain region important for reward processing. Medium spiny neurons (MSNs) within the NAc are responsive to increases in dopamine transmission. Importantly, MSNs do not generate spontaneous action potentials so changes in excitability are dependent on dopaminergic input, in addition to input from other projecting areas. When studying MSNs in relation to substance abuse, there is substantial evidence demonstrating MSNs increase their excitability following cocaine exposure or dopamine stimulation. However, very little research has examined why this happens and how voltage-gated ion channels in the NAc are implicated in cocaine-induced physiological and behavioral plasticity. My preliminary data suggests a role for KCNQ2/3, m-current, potassium channels in MSN excitability and the rewarding effects of cocaine. Although pharmacological manipulation of KCNQ2/3 channels decreases drug seeking behaviors and KCNQ2/3 channels are important for several intrinsic properties, the role of KCNQ2/3 channels in MSN excitability and cocaine- related molecular and behavioral adaptations has never been studied. In this Proposal, I will test the overarching hypothesis that KCNQ2/3 channels in the NAc are involved in functional and behavioral plasticity associated with cocaine-seeking behaviors. Specific Aim 1 of this proposal will use multiple approaches to determine how KCNQ2/3 channels influence baseline MSN excitability and establish gene-to-function relationships between KCNQ expression and MSN physiology. Specific Aim 2 will will combine CRISPR/dCas9 tools and cocaine self- administration to target specific KCNQ2/3-mediated aspects of drug related learning and compulsive drug seeking. Together, these experiments will define how KCNQ2/3 channels regulate MSN physiology, identify the relationship between KCNQ subunits and MSN excitability, and determine if KCNQ2/3 channels in the NAc modulates cocaine-related behavioral plasticity. These studies with reveal previously unknown mechanisms by which KCNQ2/3 channels contribute to psychostimulant response, and will provide a foundation for future experiments to explore how KCNQ2/3 channels contribute to motivated behavior.