2. Academic Validation
  3. A ventral hippocampus-basolateral amygdala circuit regulates the unconditioned stimulus retrieval-induced reconsolidation of remote fear memory

A ventral hippocampus-basolateral amygdala circuit regulates the unconditioned stimulus retrieval-induced reconsolidation of remote fear memory

  • J Adv Res. 2025 Oct 12:S2090-1232(25)00782-9. doi: 10.1016/j.jare.2025.10.015.
Dan Guo 1,  Zhong Wang 2,  Fanglin Liu 1,  Wenhao Chen 3,  Xuejiao Gao 2,  Shihao Huang 1,  Serik Tabarak 4,  Yuan Yao 1,  Shiya Zhang 1,  Jie Shi 5,  Lin Lu 6,  Ying Han 7
Affiliations

Affiliations

  • 1 Department of Neurobiology, School of Basic Medical Sciences, National Institute on Drug Dependence, Peking University, Beijing 100191, China; Beijing Key Laboratory of Drug Dependence Research, Peking University, Beijing 100191, China.
  • 2 Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing 100191, China.
  • 3 Department of Psychiatry, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
  • 4 Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China.
  • 5 Department of Neurobiology, School of Basic Medical Sciences, National Institute on Drug Dependence, Peking University, Beijing 100191, China; Beijing Key Laboratory of Drug Dependence Research, Peking University, Beijing 100191, China. Electronic address: shijie@bjmu.edu.cn.
  • 6 Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing 100191, China; Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China; Research Unit of Diagnosis and Treatment of Mood Cognitive Disorder, Chinese Academy of Medical Sciences (No.2018RU006), China. Electronic address: linlu@bjmu.edu.cn.
  • 7 Department of Neurobiology, School of Basic Medical Sciences, National Institute on Drug Dependence, Peking University, Beijing 100191, China; Beijing Key Laboratory of Drug Dependence Research, Peking University, Beijing 100191, China. Electronic address: yinghan@bjmu.edu.cn.
PMID: 41086982 DOI: 10.1016/j.jare.2025.10.015
Abstract

Introduction: Memory is retrieved and updated during reconsolidation, which provides a potential target for therapeutic intervention. Reconsolidation blockade following unconditioned stimulus (US) retrieval has shown increasing promise in disrupting persistent remote fear memory, yet the underlying neural mechanisms remain poorly understood.

Objectives: This study aims to elucidate the neural mechanisms involved in US retrieval-induced reconsolidation of remote fear memory.

Methods: We established a rat model of contextual fear conditioning to investigate recent and remote fear memory with reconsolidation induced by US or conditioned stimulus (CS) retrieval. Pharmacological intervention, retrograde tracing, immunofluorescence, fiber photometry, as well as chemogenetic manipulation were employed to identify and manipulate key circuits involved in reconsolidation of fear memory.

Results: In this study, we show that pharmacological disruption of the US retrieval-induced reconsolidation of fear memory had a relatively long-lasting effect and was also effective for remote fear memory. We further reveal that activity of ventral hippocampal CA1 (vCA1)-basolateral amygdala (BLA) circuit specially contributes to US retrieval-induced reconsolidation of remote fear memory. Specifically, pharmacological interventions and inhibition of this circuit after US retrieval effectively disrupted remote fear memory, which showed long-term efficacy and resistance to reinstatement. Conversely, activating this circuit blocked the disruptive effect of propranolol on the remote fear memory reconsolidation.

Conclusion: Our findings suggest that the vCA1-BLA circuit becomes increasingly important for remote fear memory reconsolidation, particularly induced by US retrieval. This study highlights the potential for targeting specific circuits involved in reconsolidation of remote fear memory for therapeutic interventions in fear-related disorders.

Keywords

Basolateral amygdala; PTSD; Reconsolidation; Remote fear memory; Unconditioned stimulus retrieval; Ventral hippocampus.

Figures
Products