Cross modal plasticity following loss of vision at different developmental stages: Cortical function, connections and compensatory behavior

不同发育阶段视力丧失后的跨模式可塑性：皮质功能、连接和补偿行为

• 批准号: 10666604
• 负责人: LEAH ANN KRUBITZER
• 金额: $ 37.09万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666604
• 关键词: Acoustic Stimulation; Acute; Address; Adult; Affect; Age; Age of Onset; Anatomy; Animal Model; Animals; Area; Auditory; Axon; Behavior; Behavioral; Bilateral; Birth; Blindness; Body part; Brain; Cannulas; Child; Complex; Data; Development; Didelphidae; Discrimination; Electrophysiology (science); Embryo; Environment; Eye; Failure; Forelimb; Gene Targeting; Impairment; Implant; Injections; Laboratories; Life; Link; Mammals; Mediating; Microinjections; Modality; Monodelphis; Monodelphis Domestica; Movement; Mus; Muscimol; Neocortex; Nervous System; Neuroanatomy; Neurons; Organ; Pathway interactions; Performance; Property; Retina; Retinal Ganglion Cells; Sensory; Shapes; Skin; Somatosensory Cortex; Stimulus; Tactile; Task Performances; Texture; Thalamic Nuclei; Therapeutic Intervention; Time; Tracer; Training; Vibrissae; Vision; Visual; Walking; area striata; auditory processing; auditory stimulus; behavior prediction; behavior test; behavioral outcome; blind; experimental study; extrastriate visual cortex; fluorophore; grasp; in utero; kinematics; machine learning algorithm; mature animal; multimodality; neocortical; neural; new growth; novel; premature; response; retina implantation; retinogeniculate; sensory input; sensory system; somatosensory; targeted treatment

A distinguishing feature of the mammalian neocortex is its remarkable ability to change over a lifetime, particularly during early development. The development of cortical fields and their connections is highly dependent on the incoming sensory inputs they receive from the various sensory organs, such as the eyes and the skin. This input, together with the unique combinations of sensory information available in the environment shapes the neocortex to generate optimal behavior. We know from previous studies in our own laboratory that very early loss of input from the eyes leads to massive changes in the brain, such that all of what would normally be the primary visual cortex (V1) contains neurons that respond to somatosensory and auditory stimulation. This reorganized V1 receives ectopic input from thalamic nuclei and cortical fields associated with somatosensory and auditory processing. The current proposal addresses several fundamental questions raised by these previous findings: 1) How does the age of onset of blindness differentially impact cortical connectivity? 2) What are single-neuron response properties in reorganized V1 and S1, and does age of blindness onset impact these properties? 3) What is the relationship between functional and anatomical changes in V1 and S1 and compensatory behaviors mediated by the spared sensory systems? Our animal model, the short-tailed opossum, is highly altricial at birth (equivalent to embryonic day 11 in the mouse), allowing ex utero manipulations to the nervous system at developmental time points that would be in utero in other mammals. In these experiments, bilateral enucleations will be made at specific developmental milestones: 1) Prior to the onset of spontaneous activity in the retina, before retinal ganglion cells have reached their subcortical targets, and before thalamocortical axons have innervated the neocortex; 2) When spontaneous activity in the retina is present and retinogeniculate and thalamocortical axons have innervated their targets; 3) Just after eye opening, when sensory driven activity in the retina is present and thalamocortical and corticocortical connections have formed. Following enucleations, animals will be assessed at several different time points. These studies are novel in scope in that they interrogate how the of age of vision loss affects the reorganization of brain circuits and behavior, and if functional and anatomical changes to the neocortex are linked to compensatory behavior. These data can direct therapeutic interventions (e.g. tactile training based behavior), and even allow predictions for behavioral outcomes following retinal implants or gene targeted therapies performed at different ages.

哺乳动物新皮质的一个显着特征是其在一生中具有显着的变化能力， 特别是在早期发展过程中。皮质区及其连接的发展高度 依赖于从各种感觉器官（例如眼睛和眼睛）接收到的传入感觉输入 皮肤。该输入以及环境中可用的感官信息的独特组合 塑造新皮质以产生最佳行为。从我们自己实验室之前的研究中我们知道 眼睛输入的早期丧失会导致大脑发生巨大变化，从而导致所有可能发生的变化。 通常是初级视觉皮层（V1）包含对体感和听觉做出反应的神经元 刺激。这个重组的 V1 接收来自与相关的丘脑核和皮质区的异位输入 体感和听觉处理。当前的提案解决了几个基本问​​题 先前的研究结果提出：1）失明的发病年龄如何对皮质产生不同的影响 连接性？ 2) 重组后的 V1 和 S1 中的单神经元反应特性是什么？ 失明发作影响这些特性吗？ 3）功能性和解剖性之间的关系是什么？ V1 和 S1 的变化以及由幸存的感觉系统介导的补偿行为？我们的动物 短尾负鼠模型在出生时处于高度晚熟状态（相当于小鼠胚胎第 11 天）， 允许在子宫内的发育时间点对神经系统进行宫外操作 其他哺乳动物。在这些实验中，双侧剜除术将在特定的发育阶段进行。 里程碑： 1) 在视网膜自发活动开始之前，在视网膜神经节细胞发生之前 在丘脑皮质轴突支配新皮质之前达到皮质下目标； 2) 当 视网膜存在自发活动，视网膜原化和丘脑皮质轴突受到神经支配 他们的目标； 3) 睁眼后，视网膜和丘脑皮质出现感觉驱动活动 皮质连接已经形成。摘除后，将对动物进行数次评估 不同的时间点。这些研究在范围上是新颖的，因为它们探讨了视力丧失的年龄如何影响视力。 影响大脑回路和行为的重组，如果功能和解剖学发生变化 新皮质与补偿行为有关。这些数据可以指导治疗干预（例如触觉 基于训练的行为），甚至可以预测视网膜植入或基因植入后的行为结果 不同年龄段进行针对性治疗。