MECHANISMS OF FUNCTIONAL AND BEHAVIORAL RECOVERY FOLLOWING ISCHEMIC STROKE

缺血性中风后功能和行为恢复的机制

• 批准号: 8700071
• 负责人: ADAM Q BAUER
• 金额: $ 15.12万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700071
• 关键词: Acute; Adult; American Heart Association; Animal Model; Behavior; Behavioral; Bilateral; Biological Markers; Biological Neural Networks; Brain; Brain Injuries; Brain region; Cause of Death; Chronic; Complex; Conflict (Psychology); Contralateral; Disease; Distant; Doctor of Philosophy; Equilibrium; Evolution; Exhibits; Functional Imaging; Future; Goals; Grant; Hand; Health; Human; Image; Incidence; Infarction; Injury; Interneurons; Ischemia; Ischemic Stroke; K-Series Research Career Programs; Learning; Lesion; Life; Lighting; Link; Magnetic Resonance Imaging; Measures; Mediating; Medical; Mentors; Mentorship; Modality; Movement; Mus; Neuronal Plasticity; Neurons; Neurosciences; Noise; Optics; Outcome; Patients; Pattern; Performance; Peripheral; Physics; Physiological; Process; Recovery; Recovery of Function; Rehabilitation therapy; Reporting; Research; Resolution; Role; Signal Transduction; Somatosensory Cortex; Stroke; Structure; Survivors; Technology; Testing; Therapeutic; Time; Training; Transcranial magnetic stimulation; United States; Universities; Washington; Wild Type Mouse; Work; base; behavior influence; brain repair; career; disability; effective therapy; experience; hippocampal pyramidal neuron; medical schools; mouse model; neuroimaging; new technology; optogenetics; prognostic; promoter; public health relevance; stroke recovery; therapy design

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.

描述（由申请人提供）：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以及脑损伤和修复机制方面的培训，以开展独立的职业生涯研究中风康复。华盛顿大学医学院将为候选人的培训提供理想的环境，让他们有机会接触脑功能、功能成像、中风和中风恢复领域的一些领先的医学和生物医学合作者。拟议的研究将在博士的共同指导下进行。 Jin-Moo Lee 和 Joseph Culver 将使用缺血性中风小鼠模型研究网络连接和病变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；因此，这些神经网络的破坏（例如中风）已被证明会改变大脑功能和行为结果。然而，尚不清楚的是网络改变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（通过使用受损的方式）可以促进康复；由此可见，大脑中的网络连接（或缺乏）可能对中风恢复机制产生深远的影响。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，需要进行机制研究，将功能连接（fc）测量与恢复期间的网络操作联系起来。为了实现这一目标，这笔赠款建议利用两项新技术：功能连接光学内在信号成像（fcOIS，由候选人共同开发）和个体发育，该技术首次允许在小鼠中进行 fc 成像。该提案将测试以下假设：局部或远端脑回路的慢性、间歇性激活或抑制通过以下目标调节局灶性缺血性损伤后的网络可塑性：1）评估网络 fc 的时间过程和演变、功能重新映射和行为恢复前爪体感皮层（S1fp）光血栓性梗死后。 2)确定S1fp光血栓形成后病灶周围抑制性中间神经元活动对fc、重新映射和行为恢复的选择性影响。 3) 确定对侧同伦输入对病灶周围皮质对 S1fp 光血栓形成后的 fc、重映射和行为恢复的选择性影响。拟议研究的结果可能对促进人类中风后康复的干预措施的设计产生影响：通过直接非侵入性脑刺激或通过优化生理治疗策略（例如旨在通过刺激大脑可塑性来增强可塑性的“强制使用”疗法）。大脑的自然恢复机制。