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.

项目概要/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，有效的治疗方法有限，视觉是主要的感觉方式。 人类，类似于啮齿类动物的胡须感觉，主要感觉方式包含了很大一部分。 大脑进行处理，使他们容易受到弥漫性 TBI 本提案的目标是采用一种 弥漫性 TBI 的实验啮齿动物模型，突出感觉缺陷以评估延迟的改变 谷氨酸信号传导作为 TBI 的普遍结果及其在调节中的潜力。 初步结果 PI 已证明 TBI 会诱发对晶须的迟发性感觉超敏反应 损伤后第 28 天的刺激持续到 PID 56。这种损伤引起的感觉超敏反应是 使用已建立的胡须滋扰任务（WNT）进行测量，其中胡须刺激会导致活跃 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。 晶须电路是谷氨酸能的，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 PI 报告说，WNT 分数与麻醉大鼠的胡须回路的继电器呈正相关。 体感丘脑和皮质中钾 (KCl) 诱发的谷氨酸释放量。 诱发谷氨酸释放对 Ω-芋螺毒素敏感，表明突触前谷氨酸过敏 释放作为晶须过敏的潜在机制此外，神经元形态的 3D 重建。 显示 PID 28 时丘脑内终止树突数量增加，提供了潜在的来源 因为麻醉研究中需要 KCl 诱发的谷氨酸反应。 胡须刺激引起的谷氨酸反应被麻醉所抑制。 清醒、自由活动的大鼠中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，并且早期康复 会恢复回路功能并减轻行为症状来测试成年男性和女性的这些假设。 通过中线液体冲击对大鼠进行弥漫性 TBI，并评估：1) 性别对 对晶须刺激和谷氨酸神经传递的迟发性感觉过敏；2）晶须； 清醒、自由活动的大鼠中刺激诱发的谷氨酸释放，相对于弥散性 TBI 后的时间，以及 3) 有证据表明，针对胡须的电路定向康复可以减轻谷氨酸过敏 释放和并发行为感觉超敏反应：耦合这种电路中断模型。 通过对清醒、自由活动的大鼠进行电化学记录，可以评估谷氨酸信号传导 损伤引起的持续性神经功能缺陷的生物标志物，用于评估治疗方法。

项目成果

Female sex in experimental traumatic brain injury research: forging a path forward.

实验性脑外伤研究中的女性：开辟前进之路。

• 发表时间: 2022-03
• 影响因子: 6.1
• 作者: Currier Thomas, Theresa;Bromberg, Caitlin E;Krishna, Gokul
• 通讯作者: Krishna, Gokul

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

病例报告：一名疑似患有埃勒斯-当洛斯综合征的儿科患者出现挥之不去的脑震荡后症状。

• 发表时间: 2022
• 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.

Satureja khuzistanica Jamzad 精油和纯香芹酚通过 NF-κB 和 caspase-3 调节雄性大鼠大脑来减轻 TBI 诱导的炎症和细胞凋亡。

• 发表时间: 2023-03-23
• 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

Effects of isoflurane and urethane anesthetics on glutamate neurotransmission in rat brain using in vivo amperometry.

使用体内电流分析法观察异氟烷和聚氨酯麻醉剂对大鼠脑谷氨酸神经传递的影响。

• 发表时间: 2023-10-10
• 影响因子: 2.4
• 作者: Beitchman, Joshua A;Krishna, Gokul;Bromberg, Caitlin E;Thomas, Theresa Currier
• 通讯作者: Thomas, Theresa Currier

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。

• 发表时间: 2020
• 影响因子: 2.4
• 作者: Rowe, Rachel K;Ortiz, J Bryce;Thomas, Theresa Currier
• 通讯作者: Thomas, Theresa Currier