Dose mediates the protracted effects of adolescent THC exposure on reward and stress reactivity in males relevant to perturbation of the basolateral amygdala transcriptome

基底外侧杏仁核 扁桃形结构 星形胶质细胞 神经科学 转录组 心理学 谷氨酸受体 内分泌学 生理学 内科学 医学 中枢神经系统 生物 基因表达 遗传学 基因 受体
作者
Jacqueline‐Marie N. Ferland,Randall J. Ellis,Gregory Rompala,Joseph A. Landry,James E. Callens,Annie Ly,Micah D. Frier,Teddy O. Uzamere,Yasmin L. Hurd
出处
期刊:Molecular Psychiatry [Springer Nature]
卷期号:28 (6): 2583-2593 被引量:10
标识
DOI:10.1038/s41380-022-01467-0
摘要

Despite the belief that cannabis is relatively harmless, exposure during adolescence is associated with increased risk of developing several psychopathologies in adulthood. In addition to the high levels of use amongst teenagers, the potency of ∆-9-tetrahydrocannabinol (THC) has increased more than fourfold compared to even twenty years ago, and it is unclear whether potency influences the presentation of THC-induced behaviors. Expanded knowledge about the impact of adolescent THC exposure, especially high dose, is important to delineating neural networks and molecular mechanisms underlying psychiatric risk. Here, we observed that repeated exposure to low (1.5 mg/kg) and high (5 mg/kg) doses of THC during adolescence in male rats produced divergent effects on behavior in adulthood. Whereas low dose rats showed greater sensitivity to reward devaluation and also self-administered more heroin, high dose animals were significantly more reactive to social isolation stress. RNA sequencing of the basolateral amygdala, a region linked to reward processing and stress, revealed significant perturbations in transcripts and gene networks related to synaptic plasticity and HPA axis that were distinct to THC dose as well as stress. In silico single-cell deconvolution of the RNAseq data revealed a significant reduction of astrocyte-specific genes related to glutamate regulation in stressed high dose animals, a result paired anatomically with greater astrocyte-to-neuron ratios and hypotrophic astrocytes. These findings emphasize the importance of dose and behavioral state on the presentation of THC-related behavioral phenotypes in adulthood and dysregulation of astrocytes as an interface for the protracted effects of high dose THC and subsequent stress sensitivity.
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