Infralimbic projections and the extinction of cocaine seeking
Creators: name: Nett, Kelle Elayne
Publisher: name: University of Iowa
Year: 2025
Subjects: amygdala
cocaine seeking
dendritic spines
extinction
infralimbic
nucleus accumbens
public abstract

description: The infralimbic cortex (IL) mediates the extinction and ongoing inhibition of cocaine seeking. Evidence suggests that IL activity immediately following an unreinforced lever press during extinction learning is necessary for encoding the change in contingency that occurs during extinction (i.e., that a lever press no longer produces an outcome). However, the larger circuitry, temporal nature, and structural alterations of such encoding is unclear. The present experiments utilized closed-loop optogenetics and iontophoretic cell-loading to probe the larger circuitry involved in extinction encoding and characterize dendritic spine morphology associated with cocaine exposure and extinction learning. Lastly, the present work analyzed cocaine self-administration patterns of female and male rats used in these experiments to determine whether sex differences in cocaine taking emerge. To assess the circuitry and temporal nature of extinction encoding, female and male Sprague-Dawley rats received optogenetic inhibition of IL afferents immediately following an unreinforced lever press, or after a 20 s delay. To characterize structural alterations, dendritic spine morphology of IL pyramidal neurons in female Sprague-Dawley rats was quantified after cocaine self-administration, cocaine self-administration followed by homecage withdrawal, and cocaine self-administration followed by extinction training. To assess cocaine self-administration between sexes, female and male self-administration data was pooled within each experiment and analyzed.
description: Results indicate that optogenetic inhibition of IL projections to the nucleus accumbens (NA) shell and IL projections to the amygdala immediately following an unreinforced lever press during extinction impaired extinction encoding. Importantly, when post-lever press inhibition was given following a 20 s delay, there was no effect in either pathway, suggesting that extinction encoding in both the IL-NAshell and IL-amygdala pathways is restricted to the 20 s period immediately following an unreinforced lever press. Dendritic spine analysis results indicated that cocaine self-administration and withdrawal do not alter dendritic spine morphology of IL pyramidal neurons of female rats. However, extinction training led to decreased spine volume and more dispersed spines. Interestingly, the rate of extinction for each rat was negatively correlated with the clustering of spines on IL neurons with non-specific projection targets and was not significantly correlated with IL neurons that projection to the NAshell. Lastly, female and male self-administration data indicate that opposing sex differences emerge depending upon the length of self-administration procedures used. Together, the present findings suggest that the IL mediates cocaine extinction through separate downstream projections and that structural alterations within the IL appear to reflect such learning in a pathway-dependent manner.