The inflammatory mechanisms underlying olfactory dysfunction in prognosis of TBI progression to dementia

项目摘要 20%-68%的创伤性脑损伤(TBI)患者表现出与创伤相关的嗅觉缺陷(OD)，这可能 不仅影响生活质量，还影响认知和神经精神功能。尽管后- 创伤性嗅觉障碍在一个多世纪的医学文献中已经有了记录，无论是 潜在的机制和治疗方法仍不清楚。此外，颅脑损伤的发生率显著增加 罹患阿尔茨海默病(AD)或非AD形式的痴呆症的风险。最近对OD的研究已经 重点关注其作为早期生物标志物诊断神经退行性疾病及其疾病的潜力 进步。因此，患有OD的脑外伤幸存者可能是其进展为痴呆症的早期征兆。广告 发病机制表明，包括嗅球在内的外周嗅觉通路是潜在的 负责前驱AD中OD的结构候选者。新出现的研究表明，过量服药与 OB炎症反应的存在，表明OB病理可能提供了OB之间的机制联系 脑外伤和阿尔茨海默病或痴呆。最近的数据表明，脑损伤诱导的快速和持久的促炎作用 OB的反应伴随着磷酸化tau的增加和OB的萎缩，导致早期 以及持续的嗅觉缺陷。新数据表明，小胶质细胞介导的炎症在 一种新发现的小胶质细胞Hv1的缺失可减轻OB的神经元过度兴奋 NADPH氧化酶依赖的活性氧物种的产生所需的离子通道。基于这些 我们的研究结果和我们的初步数据，我们假设在脑损伤后早期，小胶质细胞Hv1介导的炎症在 OB有助于局部神经元的过度兴奋导致嗅觉功能障碍，从而预示着其 进展为迟发性神经变性。 多学科的方法，包括由设计师独家激活的设计师受体 药物(DREADD)对OB小胶质细胞、小胶质细胞特异性和诱导性Hv1 KO的化学发生抑制作用 老鼠结合显微镜和生化方法，以及全面的神经行为测试，我们 将在建立良好的对照皮质中检查OB的神经炎症和神经退行性变 冲击性小鼠脑损伤模型及其与OD和迟发性痴呆样行为的相关性(AIM 1)。 此外，强大的体内和体外电生理方法将被用于表征 颅脑损伤引起的炎症对OB的网络和突触功能的不利影响(AIM 2)。最后， 我们将确定是否通过遗传或药物抑制OB中的炎症途径 鼻腔给药减轻颅脑损伤引起的炎症和神经变性，从而改善功能 结果(目标3)。 我们的研究将首次将嗅觉功能障碍与脑外伤后的痴呆症和神经变性联系起来。 我们的发现将可能有助于开发有效的方法来早期和准确地诊断 脑损伤相关的OD与神经退行性变和痴呆的发展

Project Summary 20–68% of traumatic brain injury (TBI) patients exhibit trauma-associated olfactory deficits (OD) which can compromise not only the quality of life but also cognitive and neuropsychiatric functions. Although post- traumatic anosmia has been documented in the medical literature for more than a century, neither the underlying mechanisms nor treatment remain clear. Moreover, the occurrence of TBI significantly increases risk for the development of Alzheimer’s disease (AD) or non-AD forms of dementia. Recent studies of OD have focused its potential as an early biomarker for the diagnosis of neurodegenerative disorders and their disease progression. Thus, TBI survivors with OD may be an early sign heralding its progression to dementia. AD pathogenesis revealed that the peripheral olfactory pathways including the olfactory bulb (OB) are the potential structural candidates responsible for OD in prodromal AD. Emerging studies have associated OD with the presence of OB inflammatory response, suggesting that OB pathology may provide a mechanistic link between TBI and AD or dementia. Recent data indicate that TBI-induced rapid and persistent pro-inflammatory responses in the OB were accompanied by increased phosphorylated tau and OB atrophy, resulting in early and persistent olfactory deficits. New data indicate that microglia-mediated inflammation contributed to neuronal hyperexcitation in the OB which was mitigated in the absence of Hv1, a newly discovered microglial ion channel required for NADPH oxidase-dependent generation of reactive oxygen species. Based on these findings and our preliminary data, we hypothesize that early after TBI microglial Hv1-mediated inflammation in the OB contributes to hyperexcitation of local neurons leading to olfactory dysfunction, thus heralding its progression to late-onset neurodegeneration. With multidisciplinary approaches including the Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic inhibition of OB microglia, microglia-specific and inducible Hv1 KO mice combined with microscopy and biochemical approaches, and comprehensive neurobehavioral testing, we will examine neuroinflammation and neurodegeneration in the OB in a well-established controlled cortical impact mouse TBI model and their correlation with OD and late-onset dementia-like behaviors (AIM 1). Furthermore, powerful in vivo and in vitro electrophysiological approaches will be applied to characterize detrimental effects of TBI-induced inflammation on network and synaptic functions in the OB (AIM 2). Lastly, we will determine whether genetic or pharmacological inhibition of inflammatory pathways in the OB through intranasal delivery mitigates TBI-induced inflammation and neurodegeneration thus improves functional outcomes (AIM 3). Our study will be the first to link olfactory dysfunction to dementia and neurodegeneration following TBI. Our findings will potentially shed light on developing effective approaches for early and accurate diagnosis of TBI-associated OD in the development of neurodegeneration and dementia.