Decoding Secondary Motor Cortex Neuronal Activity During Cocaine Self-Administration: Insights From Longitudinal In Vivo Calcium Imaging

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.