Microglia Dysregulation and Altered Responses to Stress after Traumatic Brain Injury
创伤性脑损伤后小胶质细胞失调和对压力的反应改变
基本信息
- 批准号:10388892
- 负责人:
- 金额:$ 3.5万
- 依托单位:
- 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:2022-02-01 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAnimalsAnti-Inflammatory AgentsAreaAttenuatedBehaviorBehavioralBindingBiologicalCSF1R geneCellsChronicChronic stressClinicalCognitionCognitiveCognitive deficitsCorticosteroneDataElectrophysiology (science)EnsureFunctional disorderGene Expression ProfileGenesGlucocorticoid ReceptorGlucocorticoidsGoalsHippocampus (Brain)HormonesHumanHydrocortisoneImmuneImmune System DiseasesImmunohistochemistryImpaired cognitionImpairmentIndividualInflammationInflammatoryInjuryIpsilateralKnock-outLateralLearningLesionLifeLightLiquid substanceLong-Term PotentiationMediatingMental disordersMicrogliaMusNR3C1 geneNeuraxisNeuronsOutcomePathologyPathway interactionsPercussionPersonsProductionQuality of lifeRNAReceptor ActivationRecoveryReporterReportingRodentRoleSignal TransductionSleep FragmentationsSleep disturbancesStressSurvivorsTestingTraumatic Brain InjuryUnited Statesantagonistbiological adaptation to stresscomorbiditycytotoxicitydisabilityexperimental studyhypothalamic-pituitary-adrenal axisimprovedinjury stressorinsightneuroinflammationneuron lossneuroprotectionneurotransmissionresponsestressortranscriptome sequencing
项目摘要
PROJECT SUMMARY
More than 5.3 million individuals suffer from a traumatic brain injury (TBI) related disability in the United States.
Mounting clinical and experimental evidence shows a common co-morbidity of TBI is hypothalamic-pituitary-
adrenal (HPA) axis dysfunction that results in the suppression of the stress hormone - cortisol in humans or the
equivalent corticosterone (CORT) in rodents. Suppressed CORT is associated with aberrant neuronal responses
in stress circuitry and can exacerbate post-TBI impairments, including cognitive and behavioral deficits. Sleep
fragmentation is a frequent consequence of stress, thus we predict that post-injury sleep fragmentation engages
a vulnerable biological pathway that substantially influences outcome by modulating neuroinflammation. For
example, increasing data demonstrates that microglia mediate chronic TBI-induced recovery by perpetuating
maladaptive inflammation, cytotoxicity, and altering neuronal viability and plasticity. Importantly, this microglial
response may be worsened by post-TBI stressors. For example, microglia highly express glucocorticoid receptor
(GR), which binds CORT to induce potent anti-inflammatory signaling. We hypothesize that TBI-induced
suppression of CORT may compromise the anti-inflammatory action of GR in microglia, thus CORT production
in response to stressors after TBI is vital to ensure control of inflammation. Due to the interplay of the stress and
immune axes, the effect of chronic stress on TBI outcome must be better understood. This proposal aims to
determine how neuronal activation and stress circuitry is altered in response to post-TBI sleep fragmentation,
and how microglial GR may influence inflammation, neuronal activation, and cognition with post-TBI sleep
fragmentation. Aim 1 will determine how microglia influence stress circuitry and hippocampal neuronal function
with post-TBI sleep fragmentation. To do this, Pt. 3 we will rapidly deplete microglia through CSF1R antagonism
and expose animals with and without microglia to post-TBI sleep fragmentation to define the cell specific role of
microglia on neuronal activation in stress circuitry. We will further determine the RNA profile of the hippocampus
following microglia depletion with post-TBI sleep fragmentation and perform electrophysiology to distinguish
whether differences in hippocampal activity are due to changes in neuronal function and viability or microglial
signaling. Aim 2 will test if microglial GR activation mediates inflammation, neuronal activation, and behavior
following post-TBI sleep fragmentation. To do this, we will use Pt. 3 an inducible knockout of GR in microglia
and determine differences in RNA sequencing profile, immunohistochemistry, and hippocampal-dependent
behavioral tasks with sleep fragmentation after TBI. We hypothesize that reactive microglia mediate neuronal
deficits in response to post-TBI sleep fragmentation through suppressed GR anti-inflammatory action. Ultimately,
this proposed study will shed light on stress-immune dysfunction after TBI and better understand how to improve
long-term quality of life and outcome for TBI survivors.
项目摘要
在美国,超过530万人患有创伤性脑损伤(TBI)相关的残疾。
越来越多的临床和实验证据表明,TBI的常见并发症是下丘脑-垂体-肾上腺皮质功能障碍。
肾上腺(HPA)轴功能障碍,导致人类或哺乳动物的应激激素-皮质醇的抑制。
当量皮质酮(CORT)。CORT抑制与异常神经元反应有关
在应激回路中,可加重TBI后的损伤,包括认知和行为缺陷。睡眠
碎片化是压力的常见后果,因此我们预测,受伤后的睡眠碎片化
一种脆弱的生物学途径,通过调节神经炎症而显著影响结果。为
例如,越来越多的数据表明,小胶质细胞介导慢性TBI诱导的恢复,
适应不良炎症、细胞毒性以及改变神经元活力和可塑性。重要的是,
TBI后应激源可能会使反应恶化。例如,小胶质细胞高表达糖皮质激素受体,
(GR),其结合CORT以诱导有效的抗炎信号传导。我们假设TBI诱导的
CORT的抑制可能会损害GR在小胶质细胞中的抗炎作用,因此CORT的产生
对TBI后应激源的反应对于确保炎症的控制至关重要。由于压力的相互作用,
免疫轴,慢性应激对TBI结果的影响必须得到更好的理解。这项建议旨在
确定神经元激活和应激回路如何响应TBI后睡眠片段而改变,
以及小胶质细胞GR如何影响TBI后睡眠的炎症、神经元激活和认知
碎片化目的1将确定小胶质细胞如何影响应激回路和海马神经元功能
脑外伤后的睡眠碎片为了做到这一点,PT。3.我们将通过CSF 1 R拮抗作用快速耗尽小胶质细胞
并将有和没有小胶质细胞的动物暴露于TBI后的睡眠片段,以确定
小胶质细胞对应激回路中神经元活化的影响。我们将进一步确定海马体的RNA图谱
在小胶质细胞耗竭与TBI后睡眠片段化之后,进行电生理学以区分
海马活动的差异是否是由于神经元功能和活力的变化,
发信号。目标2将测试小胶质细胞GR激活是否介导炎症、神经元激活和行为
脑外伤后的睡眠碎片为此,我们将使用Pt。3小胶质细胞中GR的可诱导敲除
并确定RNA测序谱、免疫组织化学和细胞周期依赖性
行为任务与TBI后睡眠碎片。我们假设反应性小胶质细胞介导神经元
通过抑制GR抗炎作用,减少对TBI后睡眠片段化的反应。最后,
这项拟议中的研究将阐明创伤性脑损伤后的应激免疫功能障碍,并更好地了解如何改善
TBI幸存者的长期生活质量和结局。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Zoe M. Tapp其他文献
Mechanistic insights into chemotherapy-induced circadian disruption using rodent models
利用啮齿动物模型对化疗引起的昼夜节律紊乱的机制研究
- DOI:
10.1016/j.tins.2024.12.011 - 发表时间:
2025-04-01 - 期刊:
- 影响因子:15.100
- 作者:
Zoe M. Tapp;Amiya K. Ghosh;Karl H. Obrietan;Leah M. Pyter - 通讯作者:
Leah M. Pyter
Zoe M. Tapp的其他文献
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{{ truncateString('Zoe M. Tapp', 18)}}的其他基金
Microglia Dysregulation and Altered Responses to Stress after Traumatic Brain Injury
创伤性脑损伤后小胶质细胞失调和对压力的反应改变
- 批准号:
10756431 - 财政年份:2022
- 资助金额:
$ 3.5万 - 项目类别:
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