Investigating the lasting effects of adolescent cannabinoid exposure on mesocortical development

研究青少年大麻素暴露对中皮层发育的持久影响

• 批准号: 10661804
• 负责人: SIERRA STRINGFIELD
• 金额: $ 14.19万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10661804
• 关键词: Adolescence; Adolescent; Adult; Animals; Applied Skills; Award; Behavior; Behavioral; Biosensor; Brain region; CNR1 gene; Cannabinoids; Cannabis; Clinical Research; Cognitive; Cognitive deficits; Complex; Confocal Microscopy; Data; Development; Dopaminergic Cell; Dose; Drug Exposure; Drug abuse; Drug usage; Electrophysiology (science); Exhibits; Exposure to; Faculty; Female; Fiber; Foundations; Future; Grant; Image; Immunohistochemistry; Impairment; Individual; Interneurons; Intravenous; Investigation; Label; Learning; Long-Term Effects; Measures; Mentors; Methods; Microscopy; Molecular; Neurotransmitters; Performance; Phase; Photometry; Prefrontal Cortex; Preparation; Psychological reinforcement; Rattus; Recording of previous events; Research Project Grants; Rodent Model; Role; Sampling; Schedule; Self Administration; Series; Sex Differences; Short-Term Memory; Signal Transduction; Specificity; Structure; Synapses; System; THC exposure; Techniques; Testing; Tetrahydrocannabinol; Time; Training; Ventral Tegmental Area; behavior influence; behavioral outcome; cannabinoid receptor; career; cell type; cognitive function; cognitive task; cognitive training; density; dopaminergic neuron; executive function; experience; experimental study; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; improved; in vivo; indexing; insight; male; marijuana use; neuron development; neuronal patterning; neurotransmission; optogenetics; postsynaptic; pre-clinical research; presynaptic; receptor; receptor expression; response; sex; skills

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.

项目摘要 青春期是一个重要的神经元发展的时期，以及许多人启动的时间 大麻使用。 Delta-9-四氢大麻酚（THC）是发现的主要精神活性成分之一 大麻和青春期期间的THC暴露与持久的认知缺陷有关。 在此提案中，我将研究青春期THC的自我管理如何影响Gabaergic 中皮层大脑区域的活性以及这些变化在成年期间如何促进执行功能。 使用静脉内THC自我给药的啮齿动物模型，我的初步数据表明存在剂量 - THC自我管理对复杂工作记忆任务的性能的性别依赖性效果。 thc- 暴露的动物还表现出大麻素和GABA能受体的表达降低，主要在 前皮层和腹侧对盖区域。关于细胞类型特异性仍然是一个主要问题 这些变化以及它们如何相互作用的药物暴露和性别影响成年后的行为结果。 在拟议的研究中，我将研究分子，神经递质和电路级别的变化 由THC自我管理引起。在该项目的指导K99阶段，我将发展新技能 先进的多标签荧光免疫组织化学和GABA能突触的成像 雄性和雌性大鼠的皮质。我将评估关联的突触前和突触后变化 通过THC自我管理和认知培训。然后，我将使用纤维光度法获得训练，然后 光遗传学了解GABA能神经传递如何有助于前额叶的表现 依赖皮质的认知任务，以及THC自我给药如何影响这种神经元激活的模式 和神经递质活性。在独立R00阶段，我将研究电路级的贡献 在这些行为期间，腹侧对段区域和前额叶皮层同步活动，并评估如何评估 THC自我给药可以使用电生理学来改变这一活性。我还将确定如何自我 给药有助于发展前皮层中多巴胺能突触输入。我有 聚集了一支多样化且经验丰富的指导团队，以提供技术和专业人士 整个培训和过渡到独立性的指导。总的来说，该奖项的研究将阐明 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 在青春期服用THC的剂量。该项目还将提供有关必要技能的培训 建立一个独立的职业，该职业利用了桥接细胞和电路级调查的技术 吸毒和滥用的影响。