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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要青春期是神经元显着发育的时期，也是许多人开始大麻的使用。 Delta-9-四氢大麻酚 (THC) 是大麻中发现的主要精神活性成分之一青春期期间接触大麻和四氢大麻酚此前已被认为与持久的认知缺陷有关。在本提案中，我将研究青春期自我施用 THC 如何影响 GABAergic 中皮层大脑区域的活动，以及这些变化如何影响成年后的执行功能。使用静脉注射 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表现的性别依赖性影响。 THC- 暴露的动物也表现出大麻素和 GABA 受体的表达减少，主要是在前边缘皮质和腹侧被盖区。一个主要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，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 THC 自我给药引起。在该项目的 K99 指导阶段，我将开发以下方面的新技能：边缘前 GABA 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皮质。我将评估相关的突触前和突触后改变 THC 自我管理和认知训练。然后我将接受使用光纤光度测量的培训光遗传学了解 GABA 能神经传递如何促进前额叶的表现皮质依赖性认知任务，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性。在独立R00阶段，我将研究电路级贡献腹侧被盖区和前额皮质在这些行为期间同步活动并评估如何 THC 自我给药可以利用电生理学改变这种活性。我还将确定 THC 如何自我给药有助于前边缘皮层多巴胺能突触输入的发育。我有聚集了一支多元化且经验丰富的专家导师团队，为您提供技术和专业指导在我的整个培训和向独立过渡的过程中提供指导。总的来说，该奖项的研究将揭示与暴露于自我相关的大脑中皮层区域的分子和电路水平变化在青春期期间施用一定剂量的 THC。该项目还将提供必要技能的培训建立一个独立的职业生涯，利用连接细胞和电路级研究的技术使用和滥用药物的影响。