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Decoding Secondary Motor Cortex Neuronal Activity During Cocaine Self-Administration: Insights From Longitudinal In
Yingying Chen1, Haoying Fu1, Amith Korada1
1Department of Biochemistry, Molecular Biology, and Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana.
Background:
We recently reported that cocaine relapse risk is linked to hyperexcitability in the secondary motor cortex (M2) after prolonged withdrawal following intravenous self-administration (IVSA). However, the neuronal mechanisms underlying drug-taking behaviors and the response of M2 neurons to contingent drug delivery remain poorly understood.
Methods:
Mice received cocaine as reinforcement (reinforcers [RNFs]) following active lever presses (ALPs) but not inactive lever presses (ILPs). Using miniScopes for in vivo calcium imaging during cocaine IVSA, we tracked M2 neuronal activity with single-cell resolution. Then we analyzed Ca2+ transients in the M2 at the early versus late stages during the 1-hour daily sessions on day 1 and day 5.
Results:
M2 neurons adapted to both operant behaviors and drug exposure history. Specifically, saline mice showed a reduction in both saline-taking behaviors and Ca2+ transient frequency with the 1-hour session. In contrast, cocaine mice maintained high ALP and RNF counts, with increased Ca2+ transient frequency and amplitude on day 1, persisting through day 5. Compared with saline control mice, cocaine mice exhibited a lower percentage of positively responsive neurons and a higher percentage of negatively responsive neurons before ALPs and after RNFs, a difference not seen before ILPs. Furthermore, as drug-taking behaviors progressed during the daily session, cocaine mice showed greater neuronal engagement with a larger population, particularly linked to ALPs and RNFs, with reduced overlap in neurons associated with ILPs.
Conclusions:
The M2 undergoes dynamic neuronal adaptations during drug-taking behaviors, supporting its role as a potential substrate mediating the persistence of drug-seeking behaviors in cocaine relapse.
