A disinhibitory microcircuit of the orbitofrontal cortex mediates cocaine preference in mice.
Mol Psychiatry
National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Research, Peking University, Beijing, 100191, China.
Published: October 2024
AI Article Synopsis
- Research indicates that the impaired orbitofrontal cortex (OFC) is linked to compulsive drug-seeking behaviors in addiction, but the detailed mechanisms are not fully understood.
- A study using a cocaine-induced model revealed that after withdrawal, dysfunction in the OFC's microcircuit leads to disinhibition.
- Key findings show that the strength of SST-PV inhibitory synapses affects OFC microcircuit function, with specific roles for SST and PV neurons in influencing cocaine preference, and Brevican plays a role in regulating this synaptic strength.
Article Abstract
Both clinical and animal studies showed that the impaired functions of the orbitofrontal cortex (OFC) underlie the compulsive drug-seeking behavior of drug addiction. However, the functional changes of the microcircuit in the OFC and the underlying molecular mechanisms in drug addiction remain elusive, and little is known for whether microcircuits in the OFC contributed to drug addiction-related behaviors. Utilizing the cocaine-induced conditioned-place preference model, we found that the malfunction of the microcircuit led to disinhibition in the OFC after cocaine withdrawal. We further showed that enhanced Somatostatin-Parvalbumin (SST-PV) inhibitory synapse strength changed microcircuit function, and SST and PV inhibitory neurons showed opposite contributions to the drug addiction-related behavior of mice. Brevican of the perineuronal nets of PV neurons regulated SST-PV synapse strength, and the knockdown of Brevican alleviated cocaine preference. These results reveal a novel molecular mechanism of the regulation of microcircuit function and a novel circuit mechanism of the OFC in gating cocaine preference.
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