Upper-respiratory infection, oligodendrocyte plasticity and behavior

上呼吸道感染、少突胶质细胞可塑性和行为

• 批准号: 10373328
• 负责人: Andrew Jonathan Steelman
• 金额: $ 40.57万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10373328
• 关键词: Adult; Affect; Aggressive behavior; Aging; Alzheimer' s Disease; Anxiety; Attention; Axon; Behavior; Behavior Therapy; Behavioral; Biochemistry; Brain; Cerebellum; Characteristics; Chronic; Clinical; Cognition; Cognitive; Complex; Coronavirus Infections; Corpus Callosum; Data; Decision Making; Demyelinations; Development; Disease; Environmental Risk Factor; Epidemiology; Euphoria; Exhibits; Exposure to; Face; Fatigue; Future; Gene Expression; Genes; Genetic Transcription; Goals; High Prevalence; Hippocampus (Brain); Homeostasis; Hour; Immune; Impaired cognition; Infection; Inflammation; Learning; Length; Lethargies; Link; Lipids; Mental Depression; Mental Health; Mental disorders; Microglia; Microscopy; Mission; Motor; Motor Skills; Multiple Sclerosis; Mus; Myelin; National Institute of Neurological Disorders and Stroke; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neuroimmune; Neurologic; Neurons; Oligodendroglia; Pathologic; Pathway interactions; Patients; Play; Prefrontal Cortex; Process; Quality of life; Reading; Regulator Genes; Research; Respiratory Tract Infections; Role; Running; Scanning Electron Microscopy; Schizophrenia; Spinal Cord; Stress; Structure; Symptoms; Synaptic plasticity; Techniques; Testing; Therapeutic; Thick; Time; Upper Respiratory Infections; Vocabulary; White Matter Disease; behavior influence; brain cell; cholesterol biosynthesis; cognitive function; cytokine; diet and exercise; early life adversity; experimental study; genetic approach; improved; influenza infection; influenzavirus; innovation; insight; lipidomics; myelination; nervous system disorder; neural circuit; neuroinflammation; neuropsychiatry; neurotransmission; novel; relating to nervous system; response; stem; stressor; systemic inflammatory response; transcriptomics; two photon microscopy; white matter

SUMMARY Systemic inflammation causes characteristic changes to behaviors including cognitive impairment, anxiety, lethargy, fatigue and depression; collectively these behaviors are termed sickness behaviors. While the exact mechanisms whereby neuroimmune interactions facilitate changes to behavior have not been entirely elucidated, activation of microglia, the resident immune cells of the brain, are thought to play a role. Intriguingly, microglial reactivity is a prominent feature of most white matter diseases. White matter abnormalities are a feature of mental health disorders, including schizophrenia. Furthermore, patients with diseases characterized by hypomyelination or demyelination exhibit symptoms of sickness behaviors including motor, cognitive, attentional and behavioral deficits and depression. In the central nervous system (CNS) oligodendrocytes (OLs) are responsible for myelin formation. Recently, the idea that myelin remains static during adulthood has been challenged and that changes to myelin can be positively affected by learning a new task or adversely affected by stress. The purpose of this proposal is to establish a link between infection and inflammation-induced myelin plasticity and sickness behavior (i.e. behavioral changes resulting from sickness). We have found that influenza infection affects OL-specific gene transcription and likely affects myelin plasticity. Since experimental influenza infection also causes microglia reactivity and cognitive impairment we are proposing to test the novel hypothesis that systemic inflammation stimulates microglia to produce factors that affect myelin plasticity and that these effects underlie changes to behavior. Since both myelin thickness and length affect neuronal conduction velocity it is easy to envision how alterations to myelin structure might affect neurocircuitry, modulate synaptic plasticity and influence behavior. In the first aim we will determine if microglia depletion affects myelin plasticity resulting from influenza infection. In the second aim we will determine if enhancing myelination inhibits infection-induced sickness behaviors. Through these experiments we expect to uncover a novel mechanism whereby infections occurring outside the CNS can modulate brain plasticity and behavior.

摘要 全身炎症会导致行为特征的改变，包括认知障碍、焦虑、 昏昏欲睡、疲倦和抑郁；这些行为统称为疾病行为。而完全相同的 神经免疫相互作用促进行为改变的机制尚未完全阐明， 小胶质细胞是大脑的常驻免疫细胞，它的激活被认为起到了一定作用。有趣的是，小胶质细胞 反应性是大多数脑白质疾病的显著特征。脑白质异常是精神疾病的一个特征 健康障碍，包括精神分裂症。此外，以髓鞘过少为特征的疾病患者 或脱髓鞘表现出疾病行为的症状，包括运动、认知、注意力和行为 赤字和抑郁。在中枢神经系统(CNS)，少突胶质细胞(OL)负责髓鞘 队形。最近，髓鞘在成年期保持静止的观点受到了挑战，这种情况发生了变化 学习一项新任务可以对髓鞘产生积极影响，也可以受到压力的不利影响。这样做的目的是 建议在感染和炎症诱导的髓鞘可塑性和疾病行为之间建立联系。 (即疾病引起的行为变化)。我们发现，流感感染会影响OL特异性基因 转录，并可能影响髓鞘的可塑性。因为实验性流感感染也会引起小胶质细胞 反应性和认知损害我们提议用来测试新的假设，即全身炎症 刺激小胶质细胞产生影响髓鞘可塑性的因子，这些效应是改变 行为。由于髓鞘的厚度和长度都会影响神经元的传导速度，因此不难想象 髓鞘结构的改变可能会影响神经回路，调节突触可塑性，并影响行为。在……里面 第一个目标，我们将确定小胶质细胞耗尽是否会影响流感感染引起的髓鞘可塑性。在……里面 第二个目标，我们将确定增强髓鞘形成是否能抑制感染诱导的疾病行为。穿过 我们希望通过这些实验揭示一种新的机制，即发生在中枢神经系统之外的感染可以 调节大脑的可塑性和行为。