Investigating the lasting effects of adolescent cannabinoid exposure on mesocortical development

项目摘要 青春期是神经元发育的重要时期，也是许多个体启动的时期 吸食大麻。三角洲-9-四氢大麻酚(THC)是发现的主要精神活性成分之一 以前，青春期接触大麻和THC与持久的认知缺陷有关。 在这项提案中，我将调查青春期自我管理如何影响GABA能 大脑中皮质区域的活动，以及这些变化如何对成年后的执行功能做出贡献。 使用静脉注射THC的啮齿动物模型，我的初步数据表明，有一个剂量- 自我管理对复杂工作记忆任务绩效的性别依赖效应。THC- 暴露的动物也表现出大麻素和GABA能受体表达减少，主要是在 前皮质和腹侧被盖区。一个主要的问题仍然是关于细胞类型的特异性 这些变化，以及它们可能如何相互作用，影响药物暴露和性行为，从而影响成年后的行为结果。 在拟议的研究中，我将研究分子、神经递质和电路水平的变化 由自我给药引起的。在这个项目的K99指导阶段，我将在以下方面培养新技能 前部GABA能突触的先进多标记荧光免疫组织化学和成像 雄性和雌性大鼠的大脑皮质。我将评估相关的突触前和突触后改变 进行自我管理和认知训练。然后，我将使用光纤光度学进行培训，并 光遗传学研究GABA能神经传递对前额叶功能的影响 皮质依赖的认知任务，以及自我管理如何影响这种神经元激活模式 和神经递质活性。在独立的R00阶段，我将调查电路级的贡献 腹侧被盖区和前额叶皮质在这些行为中的同步活动并评估如何 自我给药可以利用电生理学改变这一活动。我还将决定如何让自己 给药有助于大脑皮层多巴胺能突触输入的发育。我有过 汇聚了一支多元化和经验丰富的专家教师指导团队，为您提供技术和专业 在我的训练和向独立过渡的过程中，我一直在指导我。总而言之，该奖项的研究将揭示 与自我暴露相关的中皮质脑区分子和电路水平的变化 在青春期使用剂量的THC。该项目还将提供必要的技能培训，以 建立一个独立的职业生涯，利用技术在细胞和电路层面的研究之间架起桥梁 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.