Research advances in role of histone deacetylase 4/5 in anxiety disorders

doi:10.3969/j.issn.1674-8115.2026.09.014

Abstract

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

CLC Number:

R749.7

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.

Figures/Tables 2

TrendMD

References 52

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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]