Investigating the lasting effects of adolescent cannabinoid exposure on mesocortical development

项目摘要 青春期是一个重要的神经发育时期，也是许多人开始 使用大麻Delta-9-tetrahydrocannabinol（THC）是大麻中发现的主要精神活性成分之一， 大麻和THC暴露在青春期以前与持久的认知缺陷有关。 在这个建议中，我将研究如何在青春期自我管理的THC影响GABA能 大脑中皮层区域的活动，以及这些变化如何有助于成年后的执行功能。 使用静脉内THC自我给药的啮齿动物模型，我的初步数据表明，有一个剂量- 和性别依赖的影响THC自我管理的性能的一个复杂的工作记忆任务。四氢大麻酚 暴露的动物也表现出大麻素和GABA能受体的表达减少，主要是在 前边缘皮层和腹侧被盖区。一个主要的问题仍然是关于细胞类型特异性， 这些变化，以及它们如何与药物暴露和性相互作用，影响成年后的行为结果。 在拟议的研究中，我将调查分子，神经递质和电路水平的变化， 由THC自身给药引起。在本项目的K99辅导阶段，我将开发新的技能， 边缘前区GABA能突触的高级多标记荧光免疫组织化学和成像 雄性和雌性大鼠的皮质。我会评估突触前和突触后的变化 四氢大麻酚自我管理和认知训练然后，我将获得使用光纤测光的培训， 光遗传学，以了解GABA能神经传递如何有助于前额叶的表现 皮层依赖的认知任务，以及THC自我管理如何影响这种神经元激活模式 和神经递质活动。在独立R 00阶段，我将研究 腹侧被盖区和前额叶皮层在这些行为中的同步活动，并评估如何 THC自我管理可以使用电生理学改变这种活动。我还将确定THC如何自我- 给药有助于前边缘皮层中多巴胺能突触输入的发展。我有 聚集了一个多元化和经验丰富的专家教师指导团队，提供技术和专业 在我的训练和向独立过渡的过程中给予指导。总的来说，这个奖项的研究将揭示 在分子和电路水平上，与暴露于自我相关的中皮层大脑区域的变化， 在青少年时期服用过四氢大麻酚该项目还将提供必要的技能培训， 建立一个独立的职业生涯，利用桥接细胞和电路级调查的技术， 药物使用和滥用的影响。

Project Abstract Adolescence is a period of significant neuronal development as well as the time when many individuals initiate cannabis use. Delta-9-tetrahydrocannabinol (THC) is one of the main psychoactive components found in cannabis, and THC exposure during adolescence has previously been associated with lasting cognitive deficits. In this proposal, I will investigate how self-administration of THC during adolescence influences GABAergic activity in mesocortical brain regions, and how these changes contribute to executive function in adulthood. Using a rodent model of intravenous THC self-administration, my preliminary data indicate that there is a dose- and sex-dependent effect of THC self-administration on performance of a complex working memory task. THC- exposed animals also exhibit reduced expression of cannabinoid and GABAergic receptors, primarily in the prelimbic cortex and ventral tegmental area. A major question remains concerning the cell type-specificity of these changes, and how they may interact drug exposure and sex to influence behavioral outcomes in adulthood. In the proposed studies, I will investigate the molecular, neurotransmitter, and circuit-level changes that are induced by THC self-administration. During the mentored K99 phase of this project, I will develop new skills in advanced multi-label fluorescent immunohistochemistry and imaging of GABAergic synapses in the prelimbic cortex of male and female rats. I will assess the presynaptic and postsynaptic alterations that are associated with THC self-administration and cognitive training. I will then acquire training using fiber photometry and optogenetics to understand how GABAergic neurotransmission contributes to the performance of prefrontal cortex-dependent cognitive tasks, and how THC self-administration influences this pattern of neuronal activation and neurotransmitter activity. During the independent R00 phase, I will investigate circuit-level contributions of the ventral tegmental area and prefrontal cortex to synchronous activity during these behaviors and assess how THC self-administration may modify this activity using electrophysiology. I will also determine how THC self- administration contributes to the development of dopaminergic synaptic inputs in the prelimbic cortex. I have gathered a diverse and experienced mentoring team of expert faculty to provide technical and professional guidance throughout my training and transition to independence. In total, the studies for this award will shed light on the molecular and circuit level changes to mesocortical brain regions associated with exposure to self- administered doses of THC during adolescence. This project will also provide training in the skills necessary to establish an independent career that utilizes techniques that bridge cellular and circuit-level investigation of the effects of drug use and abuse.