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.

哺乳动物新皮层的一个显著特征是其在一生中不断变化的非凡能力， 尤其是在早期发展阶段。皮层区域及其连接的发展是高度相关的。 取决于他们从各种感觉器官（如眼睛）接收的传入感觉输入， 皮肤这种输入，连同环境中可用的感官信息的独特组合， 塑造大脑皮层以产生最佳行为。我们从我们自己实验室以前的研究中得知， 早期失去眼睛的输入会导致大脑发生巨大变化， 正常情况下，初级视觉皮层（V1）包含对躯体感觉和听觉做出反应的神经元。 刺激.这个重组的V1接受来自丘脑核团和皮层区域的异位输入， 体感和听觉处理。目前的建议涉及几个基本问题 这些先前的发现提出：1）失明的发病年龄如何不同地影响皮质 连通性？2)在重组的V1和S1中，单神经元反应特性是什么？ 失明会影响这些特性吗3)功能和解剖之间的关系是什么 V1和S1的变化以及由备用感觉系统介导的代偿行为？我们的动物 模型，短尾负鼠，在出生时是高度成熟的（相当于小鼠胚胎的第11天）， 允许在发育时间点对神经系统进行子宫外操作， 其他哺乳动物在这些实验中，将在特定的发育阶段进行双侧去核。 里程碑：1）在视网膜中自发活动开始之前，在视网膜神经节细胞具有自发活动之前， 到达他们的皮层下目标，并在丘脑皮层轴突已经支配新皮层; 2）当 视网膜中存在自发活动，视网膜膝状体和丘脑皮质轴突受到神经支配 3）刚睁眼后，当视网膜中的感觉驱动活动存在时，丘脑皮质 和皮质连接已经形成。摘除后，将在几个时间点评估动物 不同的时间点。这些研究在范围上是新颖的，因为他们询问了视力丧失的年龄是如何变化的。 影响大脑回路和行为的重组，如果功能和解剖结构发生变化， 新皮层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治疗后的行为结果。 针对不同年龄段进行的针对性治疗。