Elsevier

Biological Psychiatry

Volume 93, Issue 4, 15 February 2023, Pages 300-308
Biological Psychiatry

Priority Communication
The Recruitment of a Neuronal Ensemble in the Central Nucleus of the Amygdala During the First Extinction Episode Has Persistent Effects on Extinction Expression

https://doi.org/10.1016/j.biopsych.2022.07.021Get rights and content

Abstract

Background

Adaptive behavior depends on the delicate and dynamic balance between acquisition and extinction memories. Disruption of this balance, particularly when the extinction of memory loses control over behavior, is the root of treatment failure of maladaptive behaviors such as substance abuse or anxiety disorders. Understanding this balance requires a better understanding of the underlying neurobiology and its contribution to behavioral regulation.

Methods

We microinjected Daun02 in Fos-lacZ transgenic rats following a single extinction training episode to delete extinction-recruited neuronal ensembles in the basolateral amygdala (BLA) and central nucleus of the amygdala (CN) and examined their contribution to behavior in an appetitive Pavlovian task. In addition, we used immunohistochemistry and neuronal staining methods to identify the molecular markers of activated neurons in the BLA and CN during extinction learning or retrieval.

Results

CN neurons were preferentially engaged following extinction, and deletion of these extinction-activated ensembles in the CN but not the BLA impaired the retrieval of extinction despite additional extinction training and promoted greater levels of behavioral restoration in spontaneous recovery and reinstatement. Disrupting extinction processing in the CN in turn increased activity in the BLA. Our results also show a specific role for CN PKCδ+ neurons in behavioral inhibition but not during initial extinction learning.

Conclusions

We showed that the initial extinction-recruited CN ensemble is critical to the acquisition-extinction balance and that greater behavioral restoration does not mean weaker extinction contribution. These findings provide a novel avenue for thinking about the neural mechanisms of extinction and for developing treatments for cue-triggered appetitive behaviors.

Section snippets

Subjects

One hundred ninety-nine male Sprague Dawley Fos-LacZ transgenic rats (RRID:RRRC_00865; weight: 350–470 g) were bred in-house at Concordia University and maintained on a reverse light cycle. See the Supplement for more details. All experimental procedures were in accordance with the approval granted by the Canadian Council on Animal Care and the Concordia University Animal Care Committee.

Surgery, Drugs, and Infusion

Standard surgical and drug infusion procedures were performed as previously described (26,27), with bilateral

CN but Not BLA Neurons Are Preferentially Recruited During Extinction

We characterized BLA and CN neurons activated during extinction. Rats learned to discriminate between a reinforced target cue and a nonreinforced control cue (Figure 1A, B; see the Supplement for data). After discrimination training, half the rats received extinction of the target cue (extinction group), while the other half continued to receive nonreinforced presentations of the control cue (control group) (Figure 1B). Extinction training was followed by fluorescent immunohistochemistry to

Discussion

Here, we disrupted the balance between extinction and acquisition by deleting extinction-recruited neurons in the BLA and CN. We found that CN but not BLA extinction ensembles are critical for extinction retrieval even after further learning. In addition, deletion of these ensembles enhanced the behavioral control exerted by the initial acquisition memory following the passage of time (spontaneous recovery) and outcome re-exposure (reinstatement). Our results shed new light on the relative

Acknowledgments and Disclosures

This work was supported by Fonds de recherche du Quebec Nouveaux Chercheurs grant (Grant No. 2017-NC-198182 [to MDI]), a National Alliance for Research on Schizophrenia and Depression Young Investigator grant (Grant No. 24748 [to MDI]), a Canadian Institutes of Health Research Project Grant (Grant No. PJT-155927[to MDI]), the Canada Research Chairs Program (Grant No. 950-230456 [to MDI]), a Concordia University Horizon postdoctoral fellowship (to BPPL), and a Fonds de recherche du Quebec Sante

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