Enhancing synaptic and structural plasticity by manipulating PirB

通过操纵 PirB 增强突触和结构可塑性

• 批准号: 8527451
• 负责人: George Vidal
• 金额: $ 3.76万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8527451
• 关键词: Acute; Adolescent; Adult; Affect; Age; Alzheimer' s Disease; Amblyopia; Autistic Disorder; Binocular Vision; Brain; Brain Injuries; Cells; Data; Dendritic Spines; Development; Disease; Dyslexia; Electrophysiology (science); Eye; Fire - disasters; Goals; Human; Immunoglobulins; Immunologic Receptors; Injury; Laboratories; Learning; Life; Link; Long-Term Depression; Long-Term Potentiation; Mediating; Microscopy; Molecular; Mus; Neurodegenerative Disorders; Neurons; Ocular Dominance; Orthologous Gene; Pathway interactions; Process; Psyche structure; Publications; Reagent; Regulation; Research Training; Role; Schizophrenia; Sensory; Slice; Stroke; Structure; Synapses; Synaptic plasticity; Testing; Vertebral column; Visual; Visual Cortex; area striata; critical developmental period; critical period; density; developmental disease; experience; hippocampal pyramidal neuron; monocular deprivation; novel; public health relevance; receptor; relating to nervous system; research study; response; transmission process; two-photon; white matter; Acute; Adolescent; Adult; Affect; Age; Alzheimer' s Disease; Amblyopia; Autistic Disorder; Binocular Vision; Brain; Brain Injuries; Cells; Data; Dendritic Spines; Development; Disease; Dyslexia; Electrophysiology (science); Eye; Fire - disasters; Goals; Human; Immunoglobulins; Immunologic Receptors; Injury; Laboratories; Learning; Life; Link; Long-Term Depression; Long-Term Potentiation; Mediating; Microscopy; Molecular; Mus; Neurodegenerative Disorders; Neurons; Ocular Dominance; Orthologous Gene; Pathway interactions; Process; Psyche structure; Publications; Reagent; Regulation; Research Training; Role; Schizophrenia; Sensory; Slice; Stroke; Structure; Synapses; Synaptic plasticity; Testing; Vertebral column; Visual; Visual Cortex; area striata; critical developmental period; critical period; density; developmental disease; experience; hippocampal pyramidal neuron; monocular deprivation; novel; public health relevance; receptor; relating to nervous system; research study; response; transmission process; two-photon; white matter

DESCRIPTION (provided by applicant): When the brain is developing, it uses specific rules to determine if two neurons should form a synapse between them or not. For example, neurons that "fire together" will often "wire together", and those that are "out of synch, lose their link" These synaptic plasticity rules are very important in determining what portion of the cortex and which cells will be devoted to certain processes, such as binocular vision. The Shatz laboratory has found that PirB (paired immunoglobulin-like receptor B), an immune receptor found normally in neurons and having a human ortholog, acts as a "brake" on plasticity in the mouse visual cortex. Removing PirB genetically in the mouse (i.e. "removing the brake") enhances plasticity in visual cortex. "Removing the brake" on cortical plasticity in the adult could be important in recovering from injury (e.g. stroke), neurodegenerative disease (e.g. Alzheimer's), or developmental disorders (e.g. autism or amblyopia). Therefore, one of the greatest priorities of the lab is to understand the cellular and molecular mechanisms that underlie the enhanced plasticity that comes from removing PirB genetically from the mouse, or when PirB is directly blocked. The first goal of this project is to understand if PirB has an effect on synaptic plasticiy rules (such as the rule "fire together, wire together") that cause plasticity to decrease in adulthood. This will be done by comparing normal brains and brains lacking PirB using cortical slice electrophysiology. The second goal of this project is to directly block the function of PirB and see if these and other plasticity rules can be changed immediately. This will be observed using cortical slice electrophysiology and live two-photon excitation microscopy. If cells do modify their structure and synaptic plasticity rules, then acutely "removing the brake" by blocking PirB could provide new ways to overcome injury, disease, or developmental disorders of the brain.

描述（由申请人提供）：当大脑开发时，它使用特定的规则来确定两个神经元是否应在它们之间形成突触。例如，“一起射击”的神经元通常会“将线”和“失去链接”的那些突触可塑性规则一起“连接”，对于确定皮质的哪一部分以及哪些细胞将用于某些过程，例如双眼视觉，非常重要。 Shatz实验室发现PIRB（配对的免疫球蛋白样受体B）是一种通常在神经元中发现并具有人类直系同源物的免疫受体，它是小鼠视觉皮层可塑性的“制动器”。在小鼠中遗传上的PIRB（即“卸下制动器”）可以增强视觉皮层的可塑性。成人皮质可塑性的“去除制动器”对于从损伤中恢复（例如中风），神经退行性疾病（例如阿尔茨海默氏症）或发育障碍（例如自闭症或弱视）可能很重要。因此，实验室的最大优先事项之一是了解细胞和分子机制，这些机制是从小鼠遗传上删除PIRB或PIRB直接阻止的piRB所带来的增强可塑性的基础。该项目的第一个目标是了解PIRB是否对突触性塑料规则（例如“射击在一起，将连接在一起”）产生影响，从而导致可塑性在成年后的降低。这将通过比较使用皮质切片电生理学缺乏PIRB的正常大脑和大脑来完成。该项目的第二个目标是直接阻止PIRB的功能，看看是否可以立即更改这些和其他可塑性规则。使用皮质切片电生理学和活两光兴奋显微镜观察到这一点。如果细胞确实改变了其结构和突触可塑性规则，则通过阻止PIRB急性“拆除制动器”可以提供克服脑部损伤，疾病或发育障碍的新方法。