CB1R blockade unmasks TRPV1-mediated contextual fear generalization in female, but not male rats.
CB1R blockade unmasks TRPV1-mediated contextual fear generalization in female, but not male rats.
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DOI：
10.1038/s41386-023-01650-z
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发表时间：
2023-09
影响因子：
7.6
通讯作者：
Shansky, Rebecca M.
中科院分区：
文献类型：
--
作者：
Huckleberry, Kylie A.;Calitri, Roberto;Li, Anna J.;Mejdell, Mackenna;Singh, Ashna;Bhutani, Vasvi;Laine, Mikaela A.;Nastase, Andrei S.;Morena, Maria;Hill, Matthew N.;Shansky, Rebecca M.
越来越多的证据表明，支配学习和记忆的神经生物学过程在男性和女性中可能是不同的，但这些性别差异背后的许多具体机制尚未完全确定。在这里，我们调查了潜在的性别差异内源性大麻素（eCB）调制巴甫洛夫恐惧条件反射和灭绝，检查多种防御行为，包括休克反应，条件冻结，和条件飞镖。我们发现，虽然作用于eCB受体的药物的全身给药不会影响飞镖的发生，但被归类为飞镖的女性对药物给药的反应与被归类为非飞镖的女性不同。最值得注意的是，CB 1 R拮抗剂AM 251产生的线索引起的冻结和上下文泛化选择性增加，在女性非镖，持续在灭绝和灭绝检索测试，但阻止了TRPV 1 R拮抗剂辣椒平的共同管理。为了确定这些性别差异的潜在突触机制，我们接下来采用生物化学和神经解剖学追踪技术来量化花生四烯酸（AEA），TRPV 1 R和体周CB 1 R的表达，重点放在腹侧海马（vHip），因为它在介导情境恐惧泛化中具有已知的作用。这些试验确定了恐惧条件诱发的AEA释放和vHip-BLA电路结构的性别特异性效应。总之，我们的数据支持一个模型，其中vHip-BLA电路中的性二态性促进了女性对CB 1 R的上下文处理依赖，当CB 1 R被阻断时，CB 1 R对TRPV 1介导的中断敏感。
Increasing evidence suggests that the neurobiological processes that govern learning and memory can be different in males and females, but many of the specific mechanisms underlying these sex differences have not been fully defined. Here we investigated potential sex differences in endocannabinoid (eCB) modulation of Pavlovian fear conditioning and extinction, examining multiple defensive behaviors, including shock responsivity, conditioned freezing, and conditioned darting. We found that while systemic administration of drugs acting on eCB receptors did not influence the occurrence of darting, females that were classified as Darters responded differently to the drug administration than those classified as Non-darters. Most notably, CB1R antagonist AM251 produced an increase in cue-elicited freezing and context generalization selectively in female Non-darters that persisted across extinction and extinction retrieval tests but was prevented by co-administration of TRPV1R antagonist Capsazepine. To identify a potential synaptic mechanism for these sex differences, we next employed biochemical and neuroanatomical tracing techniques to quantify anandamide (AEA), TRPV1R, and perisomatic CB1R expression, focusing on the ventral hippocampus (vHip) given its known role in mediating contextual fear generalization. These assays identified sex-specific effects of both fear conditioning-elicited AEA release and vHip-BLA circuit structure. Together, our data support a model in which sexual dimorphism in vHip-BLA circuitry promotes a female-specific dependence on CB1Rs for context processing that is sensitive to TRPV1-mediated disruption when CB1Rs are blocked.
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