Immune cells at the blood-brain interface driving concussion-related symptoms

脑震荡，或轻度创伤性脑损伤，每年影响全球数百万人，原因是车祸、摔倒、袭击、家庭暴力、接触性运动和战争。现在人们认识到，脑震荡病史会增加发展为长期情绪和神经认知障碍的风险。这些疾病包括焦虑和抑郁，以及阿尔茨海默氏症等神经退行性疾病。关键是，我们不知道脑震荡对大脑健康的长期负面影响背后的机制。神经免疫学领域的最新进展打开了我们对中枢神经系统和炎症之间联系的理解。下面的项目将调查在血脑界面的关键结构中渗透的免疫细胞的作用，以及它们如何导致脑震荡症状。我们假设，这些界面上的免疫反应是颅脑损伤后脑震荡症状的关键。外周和大脑之间的接口现在正受到密切关注，因为它是炎症的中心，也是脑损伤、情绪障碍和神经退行性疾病的潜在驱动因素。两个关键的血-脑界面是脑膜和脉络丛。脑膜是一套围绕大脑的保护膜，脉络丛是一种产生脑脊液的结构，对各种大脑功能是必不可少的。最近的数据显示，脑膜和脉络丛含有免疫细胞，被认为在大脑中发挥重要功能。令人惊讶的是，关于脉络丛或脑膜以及其中的免疫细胞在脑震荡中的作用，人们知之甚少。为了解决这个问题，该项目将在一个临床相关的小鼠模型中研究天然和适应性淋巴细胞在脑震荡损伤反应中的作用。T细胞和先天淋巴样细胞(ILCs)是免疫反应的强大调节者，并在神经炎症中扮演关键角色，同时存在于脑膜膜和脉络丛中。此外，已知可激活淋巴细胞(包括ILCs)的危险信号和可溶性因子也可调节脑功能和损伤后的恢复，尽管目前尚不清楚淋巴细胞如何导致脑震荡相关症状。我们预测，脑震荡症状是由脑膜和脉络丛中淋巴细胞依赖的炎症驱动的，可以靶向改善损伤后的预后。这个跨学科的项目处于神经科学和免疫学的十字路口，反映在脑损伤的建模和情绪行为和认知的评估上，同时研究驱动行为缺陷的基本免疫机制。

Concussion, or mild traumatic brain injury, affects millions world-wide each year due to motor accidents, falls, assaults, domestic violence, contact sports and war. It is now appreciated that a history of concussion increases the risk of developing long-term emotional and neurocognitive disorders. These include anxiety and depression, as well as neurodegenerative conditions such as Alzheimer's. Critically, we do not know the mechanisms behind long-term negative effects of concussion on brain health.Recent advances in the field of neuroimmunology have opened up our understanding of the connection between the central nervous system and inflammation. The following project will investigate the role of infiltrating immune cells within critical structures at the blood-brain interface and how they contribute to concussive symptoms. We hypothesise that immune responses at these interfaces are key to concussive symptoms after head injury. The interfaces between the periphery and the brain are now under intense scrutiny as hubs of inflammation and potential drivers of brain injury, mood disorders and neurodegenerative disease. Two of the key blood-brain interfaces are the meninges and the choroid plexus. The meninges are a set of protective membranes that surround the brain and the choroid plexus is a structure that produces cerebrospinal fluid and is essential for a variety of brain function. Recent data has shown that the meninges and choroid plexus contain immune cells that are proposed to play important functions in the brain. Surprisingly, little is known of the role of the choroid plexus or meninges and the immune cells within them in concussion.To address this, the project will investigate the role of innate and adaptive lymphocytes in the response to concussive injury in a clinically relevant mouse model. T cells and Innate Lymphoid Cells (ILCs) are potent regulators of the immune response, and are emerging as key players in neuroinflammation while residing in the meningeal membranes and choroid plexus. Moreover, danger signals and soluble factors known to activate lymphocytes, including ILCs, are also known to regulate brain function and recovery after injury, though it remains unknown how lymphocytes contribute to concussion-related symptoms.We predict that a concussive-symptoms are driven by lymphocyte-dependent inflammation in the meninges and choroid plexus and can be targeted to improve outcome after injury. This interdisciplinary project is at crossroads of neuroscience and immunology, reflected by the modelling of brain injury and assessment of emotional behaviour and cognition, while investigating fundamental immune mechanisms driving behavioural deficits.