Biological psychiatry · 2026
Sirtuin 2 Regulates Dorsal Hippocampal Actin Polymerization and Microtubule Acetylation-Dependent EB3 Activation to Modulate Opioid Withdrawal-Induced Aversive Memory and Associative Learning.
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Long Jian-Dong, Yao Song-Yu, Wu Wei-Wei, Zan Gui-Ying, Wang Zhi-Wen, Wei Xiang-Yan, Shu Xue-Lian, Chen Ye-Xiang, Ju Yun-Yue, Chen Jing, Chai Jing-Rui, Ye Ru-Feng, Lu Jia-Shuo, Xu Chi, Chen Zhong, Liu Jing-Gen, Wang Yu-Jun
Аннотация
BACKGROUND: Aversive memories formed during drug withdrawal can potentiate compulsive drug-seeking behavior. Dynamic rearrangement of the actin cytoskeleton in dendritic spines is crucial for aversive memory formation. We previously discovered that actin polymerization in the dorsal hippocampus plays a key role in this process, but the molecular mechanisms governing this reorganization remain unclear.
METHODS: Conditioned morphine withdrawal-induced conditioned place aversion behavior in male Sprague Dawley rats was developed to evaluate aversive memory associated with opioid withdrawal. Contextual fear conditioning and appetitive conditioning paradigms were used to assess the behavioral specificity of the identified mechanisms. Western blots and dendritic spine imaging detected actin rearrangement and spine density. Co-immunoprecipitation, genetic manipulation, and pharmacological approaches were used to investigate sirtuin 2 (Sirt 2) and its downstream signaling.
RESULTS: We demonstrate that Sirt 2, an NAD+-dependent deacetylase, critically regulates dorsal hippocampal actin polymerization and opioid withdrawal-associated aversive memory through modification of microtubules (MTs). Sirt 2-induced tubulin deacetylation triggers EB3 dephosphorylation by promoting translocation of Ca2+-dependent phosphatase calcineurin to MTs. This enhances EB3-drebrin interaction, driving actin remodeling through the p140Cap/Src/cortactin/cofilin pathway. Furthermore, pharmacological inhibition of Sirt 2 also attenuated contextual fear conditioning and showed a trend toward reducing appetitive conditioning, indicating a shared role across multiple memory processes.
CONCLUSIONS: The current study elucidates the molecular mechanisms by which Sirt 2 regulates dorsal hippocampal actin dynamics and drives opioid withdrawal memory and associative learning. Our findings reveal a broader role for Sirt 2 in multiple forms of associative memory, offering potential therapeutic insights for withdrawal-induced compulsive behaviors and other memory-related disorders.
METHODS: Conditioned morphine withdrawal-induced conditioned place aversion behavior in male Sprague Dawley rats was developed to evaluate aversive memory associated with opioid withdrawal. Contextual fear conditioning and appetitive conditioning paradigms were used to assess the behavioral specificity of the identified mechanisms. Western blots and dendritic spine imaging detected actin rearrangement and spine density. Co-immunoprecipitation, genetic manipulation, and pharmacological approaches were used to investigate sirtuin 2 (Sirt 2) and its downstream signaling.
RESULTS: We demonstrate that Sirt 2, an NAD+-dependent deacetylase, critically regulates dorsal hippocampal actin polymerization and opioid withdrawal-associated aversive memory through modification of microtubules (MTs). Sirt 2-induced tubulin deacetylation triggers EB3 dephosphorylation by promoting translocation of Ca2+-dependent phosphatase calcineurin to MTs. This enhances EB3-drebrin interaction, driving actin remodeling through the p140Cap/Src/cortactin/cofilin pathway. Furthermore, pharmacological inhibition of Sirt 2 also attenuated contextual fear conditioning and showed a trend toward reducing appetitive conditioning, indicating a shared role across multiple memory processes.
CONCLUSIONS: The current study elucidates the molecular mechanisms by which Sirt 2 regulates dorsal hippocampal actin dynamics and drives opioid withdrawal memory and associative learning. Our findings reveal a broader role for Sirt 2 in multiple forms of associative memory, offering potential therapeutic insights for withdrawal-induced compulsive behaviors and other memory-related disorders.