# Regulation of glial markers expression in the rat basolateral amygdala and hippocampus during morphine aversive memory retrieval and its extinction

## TL;DR

This study explores how glial cells in the rat brain change during morphine withdrawal and extinction therapy, suggesting they may play a role in relapse prevention.

## Contribution

The study reveals microglial activity in the hippocampus during morphine aversive memory retrieval and extinction.

## Key findings

- Microglial markers in the CA1 region were downregulated during aversive memory retrieval and restored after extinction.
- The microglial marker klf4 was reduced during extinction memory retrieval in the dentate gyrus.
- Negative correlations were found between microglial markers and aversive memory strength.

## Abstract

Opioid use disorder is driven by neurobehavioral adaptations where environmental cues trigger relapse. Consequently, extinction therapy (ET) aims to modify drug-associated memories but has limited long-term efficacy. Recently, evidence suggested that glial cells may contribute to neuroplasticity phenomena in addiction. In this sense, this study examined whether aversive memories of morphine withdrawal and their extinction induce transcriptional changes in glial markers (gfap, aif1, itgam, klf4) in key memory-related regions: the basolateral amygdala (BLA) and hippocampus (dentate gyrus [DG] and CA1).

Using the conditioned place aversion (CPA) paradigm in rats, we assessed avoidance behavior after naloxone-precipitated withdrawal and its extinction. Transcriptional analyses did not reveal major changes in the BLA. However, in CA1, downregulation of microglial markers cooccurred with aversive memory retrieval and restored after extinction. Moreover, one of the microglial markers, klf4, was reduced concomitantly with extinction memory retrieval in the DG. Correlation analyses showed negative associations between microglial markers and aversive memory strength, suggesting glial involvement in withdrawal-related learning.

These findings might indicate that microglial activity in CA1 plays a role in opioid withdrawal-associated memories, and extinction training might be returning these effects to basal levels. Therefore, targeting glial responses could provide new therapeutic strategies to prevent relapse.

The online version contains supplementary material available at 10.1186/s12993-025-00313-x.