在拔毛癖的Sapap3基因敲除小鼠模型中探索伏隔核回路与催产素疗法。
Exploring the nucleus accumbens circuit and oxytocin therapy in a Sapap3 knockout mouse model of trichotillomania.
作者信息
Wang Yuan, Yu Jingjing, Ma Rui, Chen Yundong, Lu Shihao, Fang Jianqun
机构信息
Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China.
School of First Clinical, Ningxia Medical University, No.1106 South Shengli Street, Yinchuan, 750004, Ningxia, China.
出版信息
Sci Rep. 2025 Aug 5;15(1):28492. doi: 10.1038/s41598-025-14076-y.
Trichotillomania (TTM), an understudied psychiatric disorder, was investigated using Sapap3 knockout (KO) mice to elucidate nucleus accumbens (NAc) circuit dysfunction and oxytocin's therapeutic potential. Under aversive conditions, KO mice exhibited TTM-like behavioral phenotypes compared to wild-type (WT) controls: elevated anxiety-like behavior (reduced total distance 33328.45 ± 6703.97 mm vs. WT 47787.22 ± 12221.33 mm; decreased standing episodes 34.20 ± 19.41 vs. WT 58.10 ± 15.55; increased immobility duration 175.05 ± 54.46 s vs. WT 90.23 ± 70.22 s, all p < 0.05), excessive grooming duration (467.43 ± 94.98 s vs. WT 391.62 ± 86.44 s, p < 0.05), and impaired social interaction characterized by elevated aggression (70 ± 10% victory rate in tube-dominance test vs. WT, p < 0.05). Calcium imaging revealed NAc neuronal hypoactivity (peak ΔF/F: 2.44 ± 1.67% vs. WT 6.92 ± 2.08%, p < 0.05). Molecular analyses revealed: (1) Dopaminergic signaling alterations (increased dopamine: 26.95 ± 2.04 pg/mL vs. WT 22.43 ± 1.85 pg/mL, p < 0.05; D1 receptor up-regulation 1.29-fold and D2 down-regulation 0.89-fold). (2) Synaptic plasticity disruptions (CREB overexpression: 1.71-fold, p < 0.01; SHANK upregulation: 1.18-fold, p < 0.05). (3) SAPAP3-SHANK3 interaction deficits confirmed by immunofluorescence (compensatory SHANK3 up-regulation 1.46-fold). Oxytocin effects were paradoxical: acute administration exacerbated total grooming duration (550.45 ± 33.65 s vs. KO baseline 467.43 ± 94.98 s, p < 0.05) but reduced grooming bouts (50.80 ± 28.20 vs. 95.30 ± 31.92, p < 0.01) and attenuated aggression (victory rate against WT decreased to 65 ± 5%). Sex-stratified analysis revealed enhanced grooming severity in female KO mice (the grooming duration 526.59 ± 25.69 s vs. male KO 408.26 ± 104.33 s, p < 0.05). These findings highlight NAc circuit dysfunction and complex oxytocin effects in TTM, suggesting therapeutic targets while emphasizing the need for sex-stratified.
拔毛癖（TTM）是一种研究较少的精神疾病，本研究使用Sapap3基因敲除（KO）小鼠来阐明伏隔核（NAc）回路功能障碍以及催产素的治疗潜力。在厌恶条件下，与野生型（WT）对照相比，KO小鼠表现出类似TTM的行为表型：焦虑样行为增加（总移动距离减少，KO为33328.45±6703.97毫米，WT为47787.22±12221.33毫米；站立次数减少，KO为34.20±19.41次，WT为58.10±15.55次；不动持续时间增加，KO为175.05±54.46秒，WT为90.23±70.22秒，所有p<0.05）、过度梳理持续时间增加（KO为467.43±94.98秒，WT为391.62±86.44秒，p<0.05），以及以攻击性增加为特征的社交互动受损（在试管优势测试中的胜率为70±10%，而WT为p<0.05）。钙成像显示NAc神经元活动减退（峰值ΔF/F：KO为2.44±1.67%，WT为6.92±2.08%，p<0.05）。分子分析显示：（1）多巴胺能信号改变（多巴胺增加：KO为26.95±2.04皮克/毫升，WT为22.43±1.85皮克/毫升，p<0.05；D1受体上调1.29倍，D2受体下调0.89倍）。（2）突触可塑性破坏（CREB过表达：1.71倍，p<0.01；SHANK上调：1.18倍，p<0.05）。（3）免疫荧光证实SAPAP3 - SHANK3相互作用缺陷（补偿性SHANK3上调：1.46倍）。催产素的作用自相矛盾：急性给药加剧了总梳理持续时间（KO为550.45±33.65秒，而KO基线为467.43±94.98秒，p<0.05），但减少了梳理次数（KO为50.80±28.20次，而KO基线为95.30±31.92次，p<0.01）并减轻了攻击性（对WT的胜率降至65±5%）。性别分层分析显示雌性KO小鼠的梳理严重程度增加（梳理持续时间为526.59±25.69秒，而雄性KO为408.26±104.33秒，p<0.05）。这些发现突出了TTM中NAc回路功能障碍和催产素的复杂作用，提示了治疗靶点，同时强调了性别分层研究的必要性。
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