MECHANISMS OF FUNCTIONAL AND BEHAVIORAL RECOVERY FOLLOWING ISCHEMIC STROKE

描述(申请人提供)：这个K25指导职业发展奖的目标是为候选人(实验物理学博士)提供必要的神经科学培训，以及脑损伤和修复机制方面的培训，以开始独立的职业生涯，研究中风的恢复。华盛顿大学医学院将为候选人的培训提供一个理想的环境，使他们能够接触到脑功能、功能成像、中风和中风康复领域的一些领先的医疗和生物医学合作者。这项拟议的研究将在李振武博士和约瑟夫·卡尔弗博士的共同指导下进行，将使用缺血性中风的小鼠模型来研究网络连接和周围活动对皮质可塑性和行为恢复的作用。目前的研究表明，复杂的行为依赖于分布式网络交互；这些神经网络的中断，例如中风，因此被证明会改变大脑功能和行为结果。然而，不太清楚的是，改变的网络对脑损伤后行为和功能恢复的影响。越来越多的证据表明，生理活动(通过使用受损的通道)可以促进恢复；由此得出的结论是，大脑中(或缺乏)网络连接可能对中风恢复机制产生深远影响。了解网络结构和活动对卒中康复的影响，然后是潜在的治疗方法，将需要在恢复期将功能连通性(FC)措施与网络操作联系起来的机械性研究。为了实现这一目标，这笔赠款建议利用两项新技术，即功能连接光学固有信号成像(fcOIS，由候选者共同开发)，它首次允许在小鼠中进行FC成像，以及个体发育。本研究将通过以下几个目标来验证这一假说：局部或远端脑回路的慢性间歇性激活或抑制调节局灶性脑缺血损伤后的网络可塑性：1)评估前爪躯体感觉皮层光性血栓性脑梗塞后网络功能障碍、功能重新定位和行为恢复的时程和演变。2)确定S1fp光凝后周围抑制神经元间活动对FC、重定位和行为恢复的选择性影响。3)确定对侧同位输入对S1fp光凝后Fc、重定位和行为恢复的选择性影响。拟议研究的结果可能会对促进人类中风后康复的干预措施的设计产生影响：通过直接的非侵入性脑刺激或通过优化生理治疗操作(例如，旨在通过刺激大脑的自然恢复机制来增强可塑性的“强制使用”疗法)。

DESCRIPTION (provided by applicant): The goal of this K25 Mentored Career Development Award is to provide the candidate (a Ph.D. in experimental physics) with the necessary training in neuroscience, and mechanisms of brain injury and repair to launch an independent career studying stroke recovery. Washington University School of Medicine will provide an ideal setting for the candidate's training by providing them access to some of the leading medical and biomedical collaborators in the fields of brain function, functional imaging, stroke, and stroke recovery. The proposed research, which will be conducted under the co-mentorship of Drs. Jin-Moo Lee and Joseph Culver, will examine the role of network connectivity and perilesional activity on cortical plasticity and behavioral recovery using a mouse model of ischemic stroke. Current research suggests that complex behaviors rely on distributed network interaction; disruption in these neural networks, for example by stroke, has consequently been shown to alter brain function and behavioral outcome. However, what is much less clear is the impact of altered networks on behavioral and functional recovery after brain injury. There is accumulating evidence that physiological activity (through use of the impaired modality) enhances recovery; it follows that network connectivity in the brain (or lack of) may have profound influences on stroke recovery mechanisms. Understanding the implications of network structure and activity on stroke recovery, and then potential therapeutic approaches, will require mechanistic studies linking functional connectivity (fc) measures to network manipulations during the recovery period. Towards this goal, this grant proposes to take advantage of two novel technologies, functional connectivity optical intrinsic signal imaging (fcOIS, co-developed by the candidate), which for the first time allows fc imaging in mice, and ontogenetic. This proposal will test the hypothesis that chronic, intermittent activation or inhibition of local or distant brain circuits modulates network plasticity following focal ischemic injury through the following Aims: 1) Evaluate the time-course and evolution of network fc, functional remapping, and behavioral recovery following photothrombotic infarction of the forepaw somatosensory cortex (S1fp). 2) Determine the selective influence of perilesional inhibitory interneuronal activity on fc, remapping, and behavioral recovery after S1fp photothrombosis. 3) Determine the selective influence of contralesional homotopic input to perilesional cortex on fc, remapping and behavioral recovery after S1fp photothrombosis. Results from the proposed studies could have implications for the design of interventions to promote recovery following human stroke: either through direct non-invasive brain stimulation or through optimization of physiologic therapeutic maneuvers (e.g. "forced-use" therapies designed to enhance plasticity through stimulation of the brain's natural recovery mechanisms.