Structural and Functional Dysconnectivity in Dopamine/Acetylcholine Circuitry in Repetitive Mild TBI

重复性轻度 TBI 中多巴胺/乙酰胆碱回路的结构和功能脱节

• 批准号: 9916055
• 负责人: C EDWARD DIXON
• 金额: $ 43.04万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916055
• 关键词: Acetylcholine; Affect; Behavioral; Brain Injuries; Cell Nucleus; Chronic; Diagonal Band of Broca; Diffusion Magnetic Resonance Imaging; Dopamine; Electric Stimulation; Fiber; Fluorescence; Goals; Grant; Hippocampus (Brain); Human; Image; Immunohistochemistry; Impaired cognition; Liquid substance; Measures; Medial; Methods; Microdialysis; Neurologic Deficit; Neurons; Neurotransmitters; Pathway Analysis; Pathway interactions; Percussion; Physical Function; Process; Rattus; Septal Area; Severities; Sorting - Cell Movement; Specificity; Structure; Substantia nigra structure; Synaptosomes; System; Transgenic Organisms; Traumatic Brain Injury; Tyrosine 3-Monooxygenase; Ventral Tegmental Area; basal forebrain; cholinergic; cholinergic neuron; cognitive function; cognitive recovery; emotional functioning; enhanced green fluorescent protein; median forebrain bundle; mild traumatic brain injury; nerve supply; neurotransmission; neurotransmitter release; nigrostriatal pathway; novel; tool; tractography; white matter

Traumatic brain injury (TBI) of all severities can result in chronic disturbances of cognitive, behavioral, emotional, and physical functioning. Recovery of cognitive function after TBI is a dynamic process in which alterations in neurotransmitter systems do not likely occur in isolation. Numerous studies have demonstrated that the dopaminergic (DA) innervation of medial septum and diagonal band of broca (medial septal area [MSA]) regions that are dense with cholinergic neurons can affect hippocampal acetylcholine (ACh) release. The goal of this R21 grant is to evaluate mild repetitive TBI-induced changes in the integrity of dopaminergic/cholinergic connectivity using contemporary tools including diffusion MRI tractography with network analysis, transgenic human tyrosine hydroxylase GFP expressing rats, and Fluorescence activated synaptosomal sorting (FASS) analysis. The overall hypothesis is that TBI produces a loss of DA fiber connectivity, including DAergic innervation of the MSA, which contributes to cholinergic deficits. Aim 1 will determine the effects of repeated mild fluid percussion TBI (rmTBI) on the connectivity of the nigrostriatal pathway using high-definition fiber tracking in conjunction with network topology analysis. Complimentary immunohistochemistry in hTH-GFP rats will be compared to the imaging tractography to enhance specificity to DA circuits. Aim 2 will determine if rmTBI results in a loss of DAergic innervation in the MSA, which is a region of cholinergic nuclei that project to the hippocampus. Changes in DA innervation will be determined by a novel florescence-activated synaptosome sorting (FASS) process to quantitate hTH-GFP-positive synaptosomes in the MSA. To determine if the loss of DAergic innervation of cholinergic systems is functionally significant, we will use microdialysis to measure hippocampal ACh levels evoked by electrical stimulation of the medial forebrain bundle. If successful, this project will demonstrate the use of contemporary and novel methods to evaluate the degree and consequences of DAergic dysconnectivity after TBI.

所有严重程度的创伤性脑损伤（TBI）可导致认知、行为、情绪、 和身体机能。脑外伤后认知功能的恢复是一个动态的过程， 神经递质系统不可能孤立地发生。许多研究表明， 内侧隔和Broca斜角带（内侧隔区[MSA]）区域的多巴胺能（DA）神经支配 胆碱能神经元密集的海马神经元可以影响海马乙酰胆碱（ACh）的释放。这个目标 R21赠款旨在评价轻度重复TBI诱导的多巴胺能/胆碱能神经元完整性的变化。 使用现代工具的连接性，包括扩散MRI纤维束成像与网络分析，转基因 人酪氨酸羟化酶GFP表达大鼠和荧光激活突触体分选（FASS） 分析.总体假设是TBI导致DA纤维连接丧失，包括DA能神经连接丧失。 神经支配的MSA，这有助于胆碱能缺陷。目标1将确定反复轻度 使用高清纤维追踪对黑质纹状体通路的连接性进行液压冲击TBI（rmTBI） 结合网络拓扑分析。在hTH-GFP大鼠中的互补免疫组织化学将是 与成像纤维束描记术相比，以增强对DA回路的特异性。目标2将确定rmTBI结果是否 在MSA中DA能神经支配的丧失中，MSA是一个胆碱能核的区域，其投射到 海马体。DA神经支配的变化将由一种新的荧光激活的突触体决定 在一个实施方案中，使用FASS分选（FASS）过程来定量MSA中的hTH-GFP阳性突触体。以确定是否失去了 DA能神经支配胆碱能系统具有重要的功能意义，我们将使用微透析来测量 通过电刺激内侧前脑束诱发的海马ACh水平。如果成功，这个项目 将展示使用当代和新颖的方法来评估的程度和后果， TBI后DA能神经连接障碍。