Abstract:
We are interested understanding memory persistence and the ongoing modifications. As an example, we have carried out experiments to parse cellular mechanisms underlying sustained seeking behaviors that would arise after repeated usage of psychostimulants such as cocaine. We first assessed and quantified the seeking behavior of mice under progressive ratio schedule of cocaine self-administration, which enabled us to divide animals into two groups: susceptible mice that exhibited craving behaviors to cocaine infusion and resilient ones that did not. Striatal cholinergic interneurons (ChINs) are known to play critical roles in processing of reward-related information, mainly by controlling the medium spiny neurons (MSNs) of the nucleus accumbens (NAc). We found that in vivo activities of accumbal ChINs was differentially regulated by cocaine injection in drug-naïve and resilient mice vs susceptible mice. Our transcriptome and physiological analyses indicated that ChINs in the NAc displayed higher abundance of dopamine D2 receptor (DrD2) in the susceptible mice, which is necessary and sufficient for occurrence of susceptibility traits to cocaine infusion. Collectively, our data provide novel mechanistic insights into the susceptibility to cocaine addiction and ultimately contribute to the development and refinement of therapeutic interventions to these types of brain disorders.