青少年灵长类动物和啮齿动物的杏仁核选择性地发生星形胶质细胞增生，每日Δ9-Tetrahydrocannabinol，由大麻二酚共同治疗预防

IF 3.7 Q2 NEUROSCIENCES

Biological psychiatry global open science Pub Date : 2025-03-29 DOI:10.1016/j.bpsgos.2025.100496

Yalin Sun , Meenalochani Sivasubramanian , Marija Milenkovic , Andrew Gumbert , Jack Bergman , Preston Ge , Myriam Heiman , Marie-Eve Di Raddo , Sarah L. Withey , Bertha K. Madras , Susan R. George

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引用次数: 0

摘要

背景：青少年开始使用大麻会增加神经精神疾病的风险，包括杏仁核功能障碍。然而，在成熟的杏仁核中介导Δ9-tetrahydrocannabinol （THC）触发的神经适应性变化的机制尚不清楚。方法对长期服用四氢大麻酚的雄性青春期波利维猴灵长类动物的杏仁核组织进行蛋白质组学分析，为第二种雄性青春期（出生后）和成年（P70） Sprague-Dawley大鼠的胶质纤维酸性蛋白（GFAP）、stathmin-1和神经元细胞粘附分子（NrCAM）的靶向分析提供了基础。灵长类动物活动监测和大鼠行为测试分别揭示了四氢大麻酚干扰睡眠结构和焦虑相关行为。原代大鼠星形胶质细胞培养提供了四氢大麻酚激活星形胶质细胞炎症功能的机制。结果四氢大麻酚诱导的GFAP和补体因子- b （CF-B）上调仅在青少年杏仁核中引起促炎胶质细胞激活，而在其他脑区和成人中没有这种作用。四氢大麻酚减弱突触可塑性增强剂，镇静素-1和NrCAM，影响未在成人中重现。共同施用大麻二酚（CBD）可以预防星形胶质细胞增生，但不能恢复突触可塑性标志物水平。星形胶质细胞增生与睡眠片段化相关，可塑性减弱与焦虑相关。四氢大麻酚诱导的GFAP和CF-B的上调与CBD的衰减在培养的星形胶质细胞中被复制，这需要大麻素1型受体（CB1R）激活的钙信号。成熟脑CB1R表达的升高是星形细胞定位于杏仁核，但在皮层和纹状体神经元。结论星形胶质细胞中CB1R的脑区域和年龄特异性调节与四氢大麻酚和青少年杏仁核对炎性胶质瘤的易感性密切相关，损害与神经精神疾病有关的行为。减轻CBD引起的THC特异性变化为减轻THC的某些不良影响提供了线索。

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Astrogliosis Occurs Selectively in Amygdala of Adolescent Primate and Rodent Following Daily Δ9-Tetrahydrocannabinol, Prevented by Cannabidiol Co-Treatment

Background

Adolescent-onset cannabis use confers higher risk for neuropsychiatric disorders, implicating amygdala dysfunction. However, the mechanisms that mediate Δ⁹-tetrahydrocannabinol (THC)–triggered neuroadaptive changes in the maturing amygdala remain unclear.

Methods

Proteomic analysis of amygdala tissue from male adolescent Saimiri boliviensis nonhuman primates chronically treated with THC provided leads for targeted analyses of glial fibrillary acidic protein (GFAP), stathmin-1, and neuronal cell adhesion molecule (NrCAM) in a second species of male adolescent (postnatal day [P]35) and adult (P70) Sprague-Dawley rats. Primate activity monitoring and rat behavioral testing revealed THC-disrupted sleep architecture and anxiety-related behavior, respectively. Primary rat astrocyte cultures provided mechanistic insight into THC activation of astrocyte inflammatory function.

Results

THC-induced upregulation of GFAP and complement factor-B (CF-B) signified proinflammatory glial activation exclusively in the adolescent amygdala, an effect absent in other brain regions and in adults. THC attenuated synaptic plasticity enhancers, stathmin-1 and NrCAM, effects not recapitulated in adults. Co-administered cannabidiol (CBD) prevented astrogliosis but did not restore synaptic plasticity marker levels. Astrogliosis was correlated with fragmented sleep, and attenuated plasticity markers were correlated with anxiety. THC-induced GFAP and CF-B upregulation with attenuation by CBD were replicated in cultured astrocytes, requiring cannabinoid type 1 receptor (CB1R)-activated calcium signaling. Elevated CB1R expression in the maturing brain was astrocyte-localized in the amygdala, but neuronal in the cortex and striatum.

Conclusions

Brain region- and age-specific regulation of CB1R in astrocytes critically links THC and unique adolescent amygdala vulnerability to inflammatory gliosis, impairing behaviors implicated in neuropsychiatric disorders. Mitigation of specific THC-induced changes by CBD offers leads for attenuating some adverse effects of THC.

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来源期刊

Biological psychiatry global open science Psychiatry and Mental Health

CiteScore

4.00

自引率

0.00%

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审稿时长

91 days