MECHANISMS OF FUNCTIONAL AND BEHAVIORAL RECOVERY FOLLOWING ISCHEMIC STROKE

描述（由申请人提供）：K25导师职业发展奖的目标是为候选人（实验物理学博士）提供神经科学，脑损伤和修复机制方面的必要培训，以开展独立的中风恢复研究职业。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，为他们提供在脑功能、功能成像、中风和中风康复领域的一些领先的医学和生物医学合作者。拟议的研究将在dr。Jin-Moo Lee和Joseph Culver将使用小鼠缺血性中风模型研究网络连通性和病变周围活动在皮质可塑性和行为恢复中的作用。目前的研究表明，复杂行为依赖于分布式网络交互；这些神经网络的破坏，例如中风，已经被证明会改变大脑功能和行为结果。然而，改变网络对脑损伤后行为和功能恢复的影响就不那么清楚了。越来越多的证据表明，生理活动（通过使用受损的模态）可以促进恢复；因此，大脑中的网络连接（或缺乏）可能对中风恢复机制有深远的影响。了解网络结构和活动对中风恢复的影响，以及潜在的治疗方法，将需要在恢复期将功能连接（fc）措施与网络操作联系起来的机制研究。为了实现这一目标，该资助建议利用两种新技术，功能连接光学固有信号成像（fcOIS，由候选人共同开发），这是第一次允许在小鼠中进行fc成像，以及个体发生。本研究将通过以下目的来验证局部或远端脑回路的慢性、间歇性激活或抑制调节局灶性缺血性损伤后网络可塑性的假设：1)评估前肢躯体感觉皮层（S1fp）光血栓性梗死后网络fc、功能重定位和行为恢复的时间过程和演变。2)确定病灶周围抑制性神经元间活动对S1fp光血栓形成后fc、重新定位和行为恢复的选择性影响。3)确定对侧同位输入对S1fp光血栓形成后的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干预措施的设计产生影响，以促进人类中风后的恢复：要么通过直接的非侵入性脑刺激，要么通过优化生理治疗操作(例如：“强制使用”疗法旨在通过刺激大脑的自然恢复机制来增强可塑性。

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.