Addiction Research Group, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada.
Department of Anatomy and Cell Biology, Western University, London, Ontario, N6A 3K7, Canada.
Mol Psychiatry. 2023 Oct;28(10):4234-4250. doi: 10.1038/s41380-023-02190-0. Epub 2023 Aug 1.
With increasing maternal cannabis use, there is a need to investigate the lasting impact of prenatal exposure to Δ9-tetrahydrocannabinol (THC), the main psychotropic compound in cannabis, on cognitive/memory function. The endocannabinoid system (ECS), which relies on polyunsaturated fatty acids (PUFAs) to function, plays a crucial role in regulating prefrontal cortical (PFC) and hippocampal network-dependent behaviors essential for cognition and memory. Using a rodent model of prenatal cannabis exposure (PCE), we report that male and female offspring display long-term deficits in various cognitive domains. However, these phenotypes were associated with highly divergent, sex-dependent mechanisms. Electrophysiological recordings revealed hyperactive PFC pyramidal neuron activity in both males and females, but hypoactivity in the ventral hippocampus (vHIPP) in males, and hyperactivity in females. Further, cortical oscillatory activity states of theta, alpha, delta, beta, and gamma bandwidths were strongly sex divergent. Moreover, protein expression analyses at postnatal day (PD)21 and PD120 revealed primarily PD120 disturbances in dopamine D1R/D2 receptors, NMDA receptor 2B, synaptophysin, gephyrin, GAD67, and PPARα selectively in the PFC and vHIPP, in both regions in males, but only the vHIPP in females. Lastly, using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS), we identified region-, age-, and sex-specific deficiencies in specific neural PUFAs, namely docosahexaenoic acid (DHA) and arachidonic acid (ARA), and related metabolites, in the PFC and hippocampus (ventral/dorsal subiculum, and CA1 regions). This study highlights several novel, long-term and sex-specific consequences of PCE on PFC-hippocampal circuit dysfunction and the potential role of specific PUFA signaling abnormalities underlying these pathological outcomes.
随着母体大麻使用量的增加，有必要研究产前暴露于大麻中主要精神活性化合物Δ9-四氢大麻酚（THC）对认知/记忆功能的持久影响。内源性大麻素系统（ECS）依赖多不饱和脂肪酸（PUFAs）发挥作用，在调节前额叶皮层（PFC）和海马网络依赖性行为方面发挥着至关重要的作用，这些行为对认知和记忆至关重要。使用产前大麻暴露（PCE）的啮齿动物模型，我们报告说，雄性和雌性后代在各种认知领域均存在长期缺陷。但是，这些表型与高度不同的、依赖于性别的机制有关。电生理记录显示，雄性和雌性的 PFC 锥体神经元活动均过度活跃，但雄性的腹侧海马（vHIPP）活动减少，而雌性的 vHIPP 活动过度。此外，皮质θ、α、δ、β和γ频带的振荡活动状态具有强烈的性别差异。此外，在出生后第 21 天（PD21）和第 120 天（PD120）进行蛋白质表达分析显示，主要在 PD120 时，雄性的 PFC 和 vHIPP 中多巴胺 D1R/D2 受体、NMDA 受体 2B、突触小体蛋白、Gephyrin、GAD67 和 PPARα的表达发生紊乱，但在雌性中仅 vHIPP 发生紊乱。最后，使用基质辅助激光解吸/电离成像质谱（MALDI IMS），我们鉴定出在 PFC 和海马体（腹侧/背侧下托区和 CA1 区）中，特定神经 PUFAs（即二十二碳六烯酸（DHA）和花生四烯酸（ARA））和相关代谢物存在区域、年龄和性别特异性缺乏，这种缺乏存在于 PFC 和海马体中。这项研究强调了 PCE 对 PFC-海马回路功能障碍的几个新的、长期的和性别特异性的后果，以及这些病理结果潜在的特定 PUFAs 信号异常的作用。
