组蛋白去乙酰化酶4/5在焦虑障碍中作用的研究进展

doi:10.3969/j.issn.1674-8115.2026.09.014

摘要/Abstract

摘要：

组蛋白去乙酰化酶4/5（histone deacetylase 4/5，HDAC4/5）在应激障碍中发挥表观遗传调控作用。Ⅱa类HDAC具有信号依赖的核质分布调控特性。HDAC4/5通过与转录因子或共抑制因子形成复合物，调控应激相关基因转录与突触可塑性，进而影响焦虑样行为，并在海马、杏仁核等关键环路中调节突触可塑性阈值。这一系列生理、生化反应与恐惧消退等可操作心理过程密切相关。HDAC4/5可作为可塑性“背景状态”调节因子，为联合暴露治疗及行为训练的时窗化干预提供理论依据，但其临床转化仍面临种属差异与病理异质性等挑战。该文围绕HDAC4/5的分子特征、信号调控、环路效应及心理学相关证据，重点整合不同焦虑障碍亚型动物模型中的因果证据与环路层面发现，总结近年基础与临床领域的研究进展。

关键词: 焦虑障碍, 表观遗传调控, 组蛋白去乙酰化酶, HDAC4, HDAC5, 神经可塑性, 恐惧消退

Abstract:

Histone deacetylase 4/5 (HDAC4/5) mediate epigenetic regulation in stress-related disorders. Class Ⅱa HDACs feature signal-dependent shuttling between the nucleus and cytoplasm. By assembling complexes with transcription factors or co-repressors, HDAC4/5 regulate the transcription of stress-responsive genes and synaptic plasticity, thereby modulating anxiety-like behaviors; they additionally regulate the threshold for synaptic plasticity within core limbic circuits including the hippocampus and amygdala. This cascade of physiological and biochemical events is closely associated with modifiable psychological processes such as fear extinction. Serving as modulators of the basal plastic state of neural circuits, HDAC4/5 lay a theoretical foundation for time-windowed interventions combining exposure therapy and behavioral training. Nevertheless, their clinical translation remains challenged by factors including interspecies differences and pathological heterogeneity. Focusing on the molecular characteristics, signal-dependent regulation, circuit-level effects, and psychology-related evidence of HDAC4/5, the present review integrates causal evidence and circuit-level findings from animal models of distinct anxiety disorder subtypes, and summarizes recent advances in basic and clinical research.

Key words: anxiety disorders, epigenetic regulation, histone deacetylase, HDAC4, HDAC5, neuroplasticity, fear extinction

中图分类号:

R749.7

霍思睿, 朱永川. 组蛋白去乙酰化酶4/5在焦虑障碍中作用的研究进展[J]. 上海交通大学学报（医学版）, 2026, 46(9): 1290-1298.

Huo Sirui, Zhu Yongchuan. Research advances in role of histone deacetylase 4/5 in anxiety disorders[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2026,(9): 1290-1298.

图/表 2

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Subtype	Model/paradigm	Behavioral readout	Circuit node	HDAC4/5 finding
GAD (persistent worry/chronic tension)	Chronic stress paradigms (e.g., social isolation or sub‑chronic stress; CUMS commonly used)	Elevated plus maze/open field; persistent avoidance	Hippocampus-PFC	Chronic stress is associated with upregulation of class Ⅱa HDACs (e.g., HDAC4/5) and reduced histone acetylation; HDAC-pathway interventions can alleviate chronic anxiety-like behaviors ^{[15, 20]}
SAD (social avoidance)	CSDS	Social interaction test; social avoidance	NAc; hippocampus; PFC-amygdala network	HDAC5 epigenetically controls behavioral adaptations to chronic social stress in NAc and modulates stress susceptibility/resilience; HDAC5 is a class Ⅱa HDAC with signal-dependent nucleocytoplasmic regulation ^{[16, 21]}
PD/specific phobia (panic/fear)	Fear conditioning & extinction (tone/context)	Freezing; extinction recall; reinstatement/renewal	Amygdala; vmPFC; hippocampus	Histone acetylation dynamics and HDAC-dependent transcriptional repression regulate fear extinction; transient HDAC-pathway disinhibition around learning windows may facilitate extinction learning and persistence ^[22-27]

Subtype	Model/paradigm	Behavioral readout	Circuit node	HDAC4/5 finding
GAD (persistent worry/chronic tension)	Chronic stress paradigms (e.g., social isolation or sub‑chronic stress; CUMS commonly used)	Elevated plus maze/open field; persistent avoidance	Hippocampus-PFC	Chronic stress is associated with upregulation of class Ⅱa HDACs (e.g., HDAC4/5) and reduced histone acetylation; HDAC-pathway interventions can alleviate chronic anxiety-like behaviors ^{[15, 20]}
SAD (social avoidance)	CSDS	Social interaction test; social avoidance	NAc; hippocampus; PFC-amygdala network	HDAC5 epigenetically controls behavioral adaptations to chronic social stress in NAc and modulates stress susceptibility/resilience; HDAC5 is a class Ⅱa HDAC with signal-dependent nucleocytoplasmic regulation ^{[16, 21]}
PD/specific phobia (panic/fear)	Fear conditioning & extinction (tone/context)	Freezing; extinction recall; reinstatement/renewal	Amygdala; vmPFC; hippocampus	Histone acetylation dynamics and HDAC-dependent transcriptional repression regulate fear extinction; transient HDAC-pathway disinhibition around learning windows may facilitate extinction learning and persistence ^[22-27]