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: 10504252
• 负责人: LEAH ANN KRUBITZER
• 金额: $ 37.18万
• 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/10504252
• 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 structure; Neurons; Organ; Pathway interactions; Performance; Play; Property; Retina; Retinal Ganglion Cells; Role; Sensory; Shapes; Skin; Somatosensory Cortex; Stimulus; Tactile; Task Performances; Texture; Thalamic Nuclei; Therapeutic Intervention; Time; Tracer; Training; Vibrissae; Vision; Visual; Walking; area V1; area striata; auditory processing; auditory stimulus; base; behavior prediction; behavior test; behavioral outcome; blind; experimental study; extrastriate visual cortex; fluorophore; grasp; in utero; kinematics; machine learning algorithm; mature animal; multimodality; new growth; novel; premature; relating to nervous system; 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.

哺乳动物新大脑皮层的一个显著特征是其一生中发生变化的非凡能力， 尤其是在早期发育阶段。大脑皮层的发育和它们之间的联系是非常重要的 依赖于它们从各种感觉器官接收到的传入感觉输入，例如眼睛和 皮肤。这种输入，连同环境中可用的感觉信息的独特组合 塑造新大脑皮层以生成最佳行为。我们从我们自己实验室以前的研究中了解到 很早就失去了眼睛的输入会导致大脑的巨大变化，这样所有将 正常情况下，初级视觉皮质(V1)含有对躯体感觉和听觉做出反应的神经元 刺激。重组后的V1接受来自丘脑核团和皮质区域的异位输入 躯体感觉和听觉处理。目前的提案涉及几个基本问题 这些先前的发现提出：1)失明的发病年龄如何不同地影响大脑皮质 连通性？2)重组的V1和S1中的单神经元反应特性是什么，年龄 失明对这些特性有影响吗？3)功能和解剖之间的关系是什么？ 备用感觉系统介导的V1和S1的变化和代偿行为？我们的动物 模型，短尾负鼠，出生时高度奇异(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，双侧眼球摘除将在特定发育阶段进行。 里程碑：1)在视网膜自发活动开始之前，视网膜神经节细胞之前 到达其皮质下目标，并在丘脑皮质轴突神经支配新皮质之前；2)当 视网膜存在自发活动，视网膜原细胞和丘脑皮质轴突已被支配 他们的目标；3)就在睁开眼睛之后，当视网膜和丘脑皮质中存在感觉驱动的活动时 大脑皮层连接已经形成。在摘除眼球后，动物将在几个地方接受评估 不同的时间点。这些研究在范围上是新颖的，因为它们询问了视力丧失的年龄 影响大脑回路和行为的重组，如果功能和解剖学上的变化 新皮质与代偿行为有关。这些数据可以指导治疗干预(例如触觉 基于训练的行为)，甚至允许预测视网膜植入或基因后的行为结果 针对不同年龄段的患者进行靶向治疗。