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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：
10523713
负责人：
SIERRA STRINGFIELD
金额：
$ 14.14万
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/10523713
关键词：
Adolescence Adolescent Adult Animals 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 Light 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 neural circuit 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