The Mechanisms and Functional Consequences of Interhemispheric Plasticity

半球间可塑性的机制和功能后果

• 批准号: 10598822
• 负责人: Emily Rose Petrus
• 金额: $ 24.9万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598822
• 关键词: Adult; Affect; American; Amputation; Amputees; Anatomy; Animal Model; Animals; Anxiety; Area; Basic Science; Behavior; Behavioral; Bilateral; Biological Assay; Brain; Brain region; Broca' s area; Cell Nucleus; Cells; Characteristics; Chemosensitization; Clinical; Complex Regional Pain Syndromes; Corpus Callosum; Data; Denervation; Electrophysiology (science); Equilibrium; Event; Exhibits; Fiber; Foundations; Functional Magnetic Resonance Imaging; Gene Expression; Genetic; Goals; Human; Hyperactivity; Hyperalgesia; Injections; Injury; Interneurons; Intervention; Knowledge; Label; Language; Left; Life; Limb structure; Malignant Neoplasms; Mediating; Modification; Neuronal Plasticity; Neurons; Output; Pain; Patient imaging; Patients; Pattern; Peripheral nerve injury; Persons; Phantom Limb Pain; Phase; Phenotype; Prosthesis; Recovery; Recovery of Function; Rehabilitation therapy; Resolution; Rest; Rodent; Secondary to; Sensory; Slice; Stroke; Subgroup; Synapses; Synaptic plasticity; System; Therapeutic; Tissues; Training; Vascular Diseases; Vibrissae; Viral; Virus; barrel cortex; cell cortex; central nervous system injury; chronic pain; chronic painful condition; experience; experimental study; functional mimics; imaging study; in vivo; limb loss; military service; nerve damage; nerve injury; nerve transection; neural circuit; neuronal circuitry; pain reduction; peripheral nerve transection; post stroke; presynaptic; receptor; recruit; relating to nervous system; single-cell RNA sequencing; somatosensory; synaptic function; transcriptome sequencing; traumatic event

Unilateral amputation, nerve damage or stroke cause widespread and robust changes in neural activity revealed in patient imaging studies. Successful rehabilitation of affected limbs after stroke, spared senses or intact limbs after nerve injury, or incorporation of prosthetics in an amputee’s daily life relies on the brain’s ability to adapt to these changes. On the other hand, chronic pain conditions such as phantom limb pain, hyperalgesia or complex regional pain syndrome are also proposed to be a result of cortical rewiring following some of these perturbations. The mechanisms underlying these phenotypes are unknown. We have developed an animal model which displays remarkably similar neural activity phenotypes during functional magnetic resonance imaging (fMRI). I have characterized the synaptic basis of the interhemispheric plasticity that is thought to underlie either adaptive or maladaptive plasticity in patients. The goal of the K99/R00 project is to characterize the specific neurons and synapses in the cortical circuit and determine if the changes we observe have a functional output to mediate more widespread changes in the brain. The functional relevance of these changes in connectivity will help determine if the plasticity we observe is adaptive, maladaptive or both. During the K99 training phase I will use a combination of fMRI, slice electrophysiology, viral tracing, and single nucleus RNA sequencing to identify key players that mediate these changes in neural activity. These results will guide experiments in the R00 phase, where I will modulate these cells with targeted interventions to re-calibrate the system. I will also use behavior to determine if the interventions are functionally relevant in vivo. The identification of specific subsets of neurons and their functional output will enable characterization of cortical rewiring after peripheral nerve injury. I will determine which neurons may be underlying adaptive or maladaptive plasticity. By targeting these neurons for therapeutic purposes, I will enhance adaptive plasticity to mediate better recovery or reduce pain conditions caused by maladaptive plasticity. These interventions may be clinically beneficial, but in order to be most effective complete characterization of the circuit underlying these changes is required.

单侧截肢、神经损伤或中风会引起广泛而有力的神经活动变化 病人的影像研究。成功康复中风后患肢、保留感觉或神经后完整肢体 截肢者日常生活中的损伤，或假肢的融入，取决于大脑适应这些变化的能力。在……上面 另一方面，慢性疼痛状况，如幻肢痛、痛觉过敏或复杂的区域疼痛综合征 也被认为是其中一些扰动后大脑皮层重新连接的结果。这些问题背后的机制 表型尚不清楚。 我们已经开发了一种动物模型，它在 功能磁共振成像(FMRI)。我已经描述了大脑半球间可塑性的突触基础。 这被认为是患者适应性或非适应性可塑性的基础。K99/R00项目的目标是 描述皮层回路中特定的神经元和突触的特征，并确定我们观察到的变化是否具有 功能输出，以调节大脑中更广泛的变化。这些变化在功能上的相关性 连通性将有助于确定我们观察到的可塑性是适应性的、适应性的，还是两者兼而有之。在K99培训期间 第一阶段将使用功能磁共振成像、切片电生理、病毒追踪和单核RNA测序的组合来 找出调节这些神经活动变化的关键因素。这些结果将指导R00阶段的实验， 在那里，我将通过有针对性的干预来调节这些细胞，以重新校准系统。我还将利用行为来 确定干预措施在体内是否具有功能相关性。 识别特定的神经元亚群及其功能输出将使大脑皮层的特征 周围神经损伤后的重新布线。我将确定哪些神经元可能是潜在的适应性或适应性不良 可塑性。通过以这些神经元为治疗目标，我将增强适应性可塑性，以更好地调节 恢复或减轻因适应不良可塑性引起的疼痛状况。这些干预可能在临床上是有益的，但 为了最有效，需要对这些变化背后的电路进行完整的描述。