Electrochemical assessment of behaviorally relevant circuit function after TBI

TBI 后行为相关电路功能的电化学评估

• 批准号: 10296678
• 负责人: Theresa Currier Thomas
• 金额: $ 33.58万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10296678
• 关键词: 3-Dimensional; Address; Adult; Age; Anesthesia procedures; Attenuated; Behavior; Behavior assessment; Behavioral; Behavioral Symptoms; Biological Markers; Brain; Collection; Coupling; Curiosities; Data Reporting; Dendrites; Development; Diffuse; Diffuse Brain Injury; Effectiveness; Esthesia; Evaluation; Female; Functional disorder; Glutamates; Goals; Human; Hypersensitivity; Injury; Light; Liquid substance; Maintenance; Maps; Measures; Microelectrodes; Modality; Modeling; Monitor; Morbidity - disease rate; Morphology; Neurologic; Neurologic Deficit; Neurons; Noise; Patient Care; Percussion; Phase; Phonophobias; Photophobia; Potassium; Public Health; Publishing; Rattus; Rehabilitation therapy; Reporting; Research; Rodent; Rodent Model; Sensory; Sex Differences; Source; Technology; Testing; Thalamic structure; Therapeutic; Time; Translations; Traumatic Brain Injury; Vibrissae; Vision; awake; behavioral response; effective therapy; experimental study; fluid percussion injury; glutamatergic signaling; in vivo; in vivo Model; injured; male; neurotransmission; omega-Conotoxins; presynaptic; prevent; reconstruction; response; sensory system; sex; somatosensory; temporal measurement; therapeutic evaluation

Project Summary/Abstract Traumatic brain injuries (TBI) frequently result in persisting post-traumatic neurological consequences, including hypersensitivity to light, with limited effective treatments. Vision is a primary sensory modality in humans, similar to whisker sensation in rodents. Primary sensory modalities incorporate a large portion of the brain for processing, making them susceptible to diffuse TBI. The goal of this proposal is to employ an experimental rodent model of diffuse TBI that highlights sensory deficits to evaluate delayed alterations in glutamate signaling as a universal consequence of TBI and its potential for modulation. Using this model in preliminary results the PI has demonstrated that TBI induces late-onset sensory hypersensitivity to whisker stimulation by post-injury day (PID) 28 that persists to PID 56. This injury-induced sensory hypersensitivity is measured using the established Whisker Nuisance Task (WNT), where whisker stimulation results in active evasion and aberrant responses in injured rats compared to ambivalence or curiosity in uninjured rats. Since the whisker circuit is glutamatergic, this research team implemented electrochemical microelectrode array technology, capable of real-time measurements of glutamate neurotransmission in vivo, for recordings within the relays of the whisker circuit in anesthetized rats. The PI reported that WNT scores positively correlate to the magnitude of potassium (KCl)-evoked glutamate release in the somatosensory thalamus and cortex. Evoked-glutamate release was sensitive to Ω-conotoxin, indicating hypersensitive presynaptic glutamate release as a potential mechanism for whisker hypersensitivity. Also, 3D reconstruction of neuron morphology shows increased numbers of terminating dendrites within the thalamus at PID 28, providing a potential source for increased glutamate release. KCl-evoked glutamate responses are required in anesthetized studies since whisker stimulation-evoked glutamate responses are suppressed by anesthesia. Thus, real-time recordings of glutamate neurotransmission in the awake, freely-moving rat permits the evaluation of whisker stimulation- evoked glutamate responses during the WNT. This has led to the central hypotheses that TBI-induced sensory hypersensitivity arises from altered glutamate signaling in sensory circuits and that early rehabilitation will restore circuit function and alleviate behavioral symptoms. To test these hypotheses adult male and female rats will be subjected to diffuse TBI by midline fluid percussion and evaluated for: 1) the influence of sex on late-onset sensory hypersensitivity to whisker stimulation and glutamate neurotransmission; 2) whisker stimulated-evoked glutamate release in awake, freely-moving rats, with respect to time post-diffuse TBI, and 3) evidence that circuit-directed rehabilitation, focused on the whiskers, can mitigate hypersensitive glutamate release and concurrent behavioral sensory hypersensitivity. Impact: Coupling this model of circuit disruption with electrochemical recordings in awake, freely-moving rats allows for evaluation of glutamate signaling as a biomarker for injury-induced persisting neurological deficits for evaluation of therapeutic approaches.

项目总结/摘要 创伤性脑损伤（TBI）经常导致持续的创伤后神经系统后果， 包括对光过敏，有效治疗有限。视觉是一种主要的感觉方式， 人类，类似于啮齿动物的胡须感觉。初级感觉模态包含了大部分的 大脑进行处理，使他们容易受到弥漫性创伤性脑损伤。该提案的目的是雇用一名 弥漫性TBI的实验啮齿动物模型，突出感觉缺陷，以评估 谷氨酸信号传导作为TBI的普遍结果及其调节潜力。使用此模型 初步结果PI已经证明，TBI诱导迟发性感觉过敏晶须 持续至PID 56的损伤后第28天（PID）的刺激。这种损伤诱导的感觉超敏反应是 使用已建立的胡须营养任务（WNT）进行测量，其中胡须刺激导致活跃的 与未受伤大鼠的矛盾心理或好奇心相比，受伤大鼠的逃避和异常反应。以来 该晶须电路是电化学的，该研究小组实现了电化学微电极阵列 技术，能够实时测量体内谷氨酸神经传递，用于记录 在麻醉大鼠的触须电路的继电器。PI报告称，WNT评分与以下各项呈正相关 钾（KCl）诱发的丘脑和皮层释放谷氨酸的幅度。 诱发的谷氨酸释放对芋螺毒素敏感，表明突触前谷氨酸超敏 释放作为一个潜在的机制，晶须过敏。此外，神经元形态的3D重建 显示在PID 28丘脑内终止树突的数量增加，提供了一个潜在的来源， 来增加谷氨酸的释放KCl诱发的谷氨酸反应在麻醉研究中是必需的， 胡须刺激诱发的谷氨酸反应被麻醉抑制。因此，实时记录 清醒、自由活动的大鼠的谷氨酸神经传递允许评估胡须刺激- 在WNT期间诱发谷氨酸反应。这导致了TBI诱导的中心假设 感觉超敏反应是由感觉回路中谷氨酸信号的改变引起的， 会恢复电路功能减轻行为症状为了验证这些假设， 通过中线流体冲击使大鼠经受弥漫性TBI，并评价：1）性别对 对触须刺激和谷氨酸神经传递迟发型感觉超敏反应; 2）触须 相对于弥漫性TBI后时间，清醒、自由移动大鼠中刺激诱发的谷氨酸释放，以及3） 证据表明，电路定向康复，重点是胡须，可以减轻过敏性谷氨酸盐 释放和并发的行为感觉超敏反应。影响：耦合这种电路中断模型 在清醒的自由移动的大鼠中进行电化学记录，可以评估谷氨酸信号传导作为一种 用于评估治疗方法的损伤诱导的持续性神经功能缺损的生物标志物。

项目成果

Evidence for the induction of analgesic cross-tolerance between opioid and apelin/APJ systems in male rats.

在雄性大鼠中诱导阿片类药物和 apelin/APJ 系统之间镇痛交叉耐受的证据。

• DOI: 10.15288/jsad.23-00377
• 发表时间: 2024
• 期刊: Journal of studies on alcohol and drugs
• 影响因子: 3.4
• 作者: Abbasloo,Elham;Esmaeili-Mahani,Saeed;Kobeissy,Firas;Thomas,TheresaCurrier
• 通讯作者: Thomas,TheresaCurrier

Sex-Dependent Pathology in the HPA Axis at a Sub-acute Period After Experimental Traumatic Brain Injury.

• DOI: 10.3389/fneur.2020.00946
• 发表时间: 2020
• 期刊: Frontiers in neurology
• 影响因子: 3.4
• 作者: Bromberg CE;Condon AM;Ridgway SW;Krishna G;Garcia-Filion PC;Adelson PD;Rowe RK;Thomas TC
• 通讯作者: Thomas TC

Mild and Moderate Traumatic Brain Injury and Repeated Stress Affect Corticosterone in the Rat.

轻度和中度创伤性脑损伤和反复压力会影响大鼠的皮质酮。

• DOI: 10.1089/neur.2020.0019
• 发表时间: 2020
• 期刊: Neurotrauma reports
• 影响因子: 2.4
• 作者: Rowe RK;Ortiz JB;Thomas TC
• 通讯作者: Thomas TC

Case report: Lingering post-concussive symptoms in a pediatric patient with presumed Ehlers-Danlos syndrome.

• DOI: 10.3389/fped.2022.937223
• 发表时间: 2022
• 期刊: FRONTIERS IN PEDIATRICS
• 影响因子: 2.6
• 作者: Curry, Tala Maris;Esfandiarei, Mitra;Thomas, Theresa Currier;Rastogi, Reena Gogia
• 通讯作者: Rastogi, Reena Gogia

Satureja khuzistanica Jamzad essential oil and pure carvacrol attenuate TBI-induced inflammation and apoptosis via NF-κB and caspase-3 regulation in the male rat brain.

• DOI: 10.1038/s41598-023-31891-3
• 发表时间: 2023-03-23
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Abbasloo, Elham;Amiresmaili, Sedigheh;Shirazpour, Sara;Khaksari, Mohammad;Kobeissy, Firas;Thomas, Theresa Currier
• 通讯作者: Thomas, Theresa Currier