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）可能会导致认知，行为，情感的长期干扰 和身体功能。 TBI后认知功能的恢复是一个动态过程，其中改变 神经递质系统不太可能孤立地发生。许多研究表明 内侧隔膜和对角线带（内侧间隔区[MSA]）区域的多巴胺能（DA）区域的神经 胆碱能神经元致密的会影响海马乙酰胆碱（ACH）释放。目标的目标 R21赠款是为了评估轻度重复的TBI诱导的多巴胺能/胆碱能的完整性变化 使用当代工具（包括扩散MRI拖拉机）和网络分析，转基因的连通性 人酪氨酸羟化酶GFP表达大鼠，荧光激活突触体分选（FASS） 分析。总体假设是TBI会产生DA纤维连通性的损失，包括Daergic MSA的神经，导致胆碱能缺陷。 AIM 1将确定重复轻度的影响 使用高清纤维跟踪的纹状体纹状体途径连通性的流体打击乐TBI（RMTBI） 结合网络拓扑分析。 HTH-GFP大鼠中的免费免疫组织化学将是 与成像学拖拉学相比，增强了对DA电路的特异性。 AIM 2将确定RMTBI是否结果 在MSA中失去了Daergic神经的丧失，这是一个投射到胆碱能核的区域 海马。 DA神经的变化将由新型的荧光激活突触体确定 分类（FASS）过程以定量MSA中的HTH-GFP阳性突触体。确定是否丢失 胆碱能系统的daergic神经在功能上很重要，我们将使用微透析来测量 内侧前脑束的电刺激引起的海马ACH水平。如果成功，这个项目 将证明使用当代和新颖方法来评估 TBI之后的DAERGIC DYSCONNECTINIVY。