Separate vmPFC Ensembles Control Cocaine Self-Administration Versus Extinction in Rats

Area of Science:

• Neuroscience
• Behavioral Neuroscience
• Addiction Research

Background:

• The ventral medial prefrontal cortex (vmPFC) is implicated in encoding both drug-seeking behaviors and the extinction of these memories.
• Understanding the neural circuitry underlying opposing memories, such as drug self-administration and extinction, is crucial for addiction research.

Purpose of the Study:

• To investigate whether distinct neuronal ensembles within the vmPFC encode cocaine self-administration and extinction memories.
• To determine the projection targets of these distinct vmPFC ensembles within the nucleus accumbens (NAc) in male and female rats.
• To elucidate the roles of these distinct vmPFC-NAc pathways in regulating cocaine seeking and extinction.

Main Methods:

• Utilized cocaine self-administration and extinction paradigms in male and female rats.
• Employed Fos immunohistochemistry to identify activated neuronal ensembles in the vmPFC.
• Used Daun02 chemogenetic inactivation to selectively lesion self-administration and extinction ensembles.
• Applied retrograde tracing (fluorescent cholera toxin subunit B) to map vmPFC projections to NAc core and shell.
• Conducted functional disconnection experiments involving vmPFC inactivation and NAc dopamine D1-receptor blockade.

Main Results:

• vmPFC activation (Fos) was observed during cocaine-seeking tests after both no-extinction and extinction sessions.
• Lesioning the self-administration ensemble decreased cocaine seeking, while lesioning the extinction ensemble increased it.
• vmPFC self-administration ensembles project to the NAc core, whereas extinction ensembles project to the NAc shell.
• Functional disconnection confirmed distinct roles for vmPFC-NAc core and shell pathways in self-administration versus extinction.

Conclusions:

• Neuronal ensembles for cocaine self-administration and extinction memories coexist within the vmPFC.
• These ensembles possess distinct output pathways to the nucleus accumbens core and shell, respectively.
• This segregation of outputs allows for differential regulation of cocaine seeking and extinction behaviors.