Hippocampal Demyelination and Cognitive Dysfunction

描述（由申请人提供）：多发性硬化症（MS）是一种人类中枢神经系统（CNS）的炎性脱髓鞘疾病，是美国年轻人非创伤性神经功能障碍的主要原因。MS作为一种白色疾病的经典观点最近已经扩展到包括灰质脱髓鞘。灰质脱髓鞘的临床影响可以解释为什么在MS患者中，脑成像检测到的白色病变与神经功能障碍的相关性很低。超过50%的MS患者存在认知障碍，他们的认知功能障碍对生活质量的影响大于身体残疾。最近对死后MS脑的研究已经确定，海马脱髓鞘破坏了兴奋性突触的维持和调节记忆和学习的神经元信号级联的激活。海马脱髓鞘是MS患者认知能力下降的可能原因。为了证实和扩展这一假设，我们已经成功地开发了海马脱髓鞘的小鼠模型，并确定这些小鼠具有降低的记忆/学习、降低的突触密度、降低的调节记忆/学习的神经元蛋白和降低的长时程增强（LTP）。再髓鞘化逆转了这些变化。本提案中概述的研究旨在阐明脱髓鞘脊髓中导致神经元功能障碍和记忆障碍的神经元变化序列。我们利用多学科的方法来关联行为，电生理，生物化学，形态学和体内成像变化脱髓鞘campi，并将确定是否髓鞘再生逆转记录的变化。我们的研究是转化的，应该确定潜在的治疗靶点，可以减少或延迟MS患者的认知功能下降。我们的小鼠模型还应该为旨在改善MS患者认知的疗法的“原理证明”测试提供平台。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an inflammatory demyelinating disease of the human central nervous system (CNS) and the major cause of non-traumatic neurological disability in young adults in the USA. The classical view of MS as a white matter disease has recently been extended to include gray matter demyelination. The clinical impact of gray matter demyelination may explain why white matter lesions detected by brain imaging poorly correlate with neurological disability in MS patients. Greater than 50% of MS patients are cognitively impaired and their cognitive dysfunction has a greater impact on quality of life than physical disability. Recent studies of postmortem MS brains have established that hippocampal demyelination disrupts the maintenance of excitatory synapses and activation of neuronal signaling cascades that modulate memory and learning. Hippocampal demyelination is a likely cause of cognitive decline in MS patients. To confirm and extend this hypothesis, we have successfully developed a mouse model of hippocampal demyelination and established that these mice have reduced memory/learning, reduced synaptic densities, reduced neuronal proteins that modulate memory/learning and reduced long term potentiation (LTP). Remyelination reversed these changes. The studies outlined in this proposal are designed to unravel the sequence of neuronal changes in demyelinated hippocampi that contribute to neuronal dysfunction and memory impairment. We utilize a multidisciplinary approach to correlate behavioral, electrophysiological, biochemical, morphological, and in vivo imaging changes in demyelinated hippocampi and will determine if remyelination reverses documented changes. Our studies are translational and should identify potential therapeutic targets that could reduce or delay cognitive decline in MS patients. Our mouse model should also provide a platform for "proof of principle" testing of therapies designed to improve cognition in MS patients.