Interneuron Precursors and the induction of cortical plasticity

中间神经元前体和皮质可塑性的诱导

• 批准号: 9179634
• 负责人: Arturo Alvarez-Buylla
• 金额: $ 43.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-02 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9179634
• 关键词: Activities of Daily Living; Adolescent; Adult; Age; Amblyopia; Amygdaloid structure; Animal Model; Anxiety Disorders; Brain; Brain Diseases; Cell Therapy; Cells; Clinical; Collection; Corpus striatum structure; Data; Development; Embryo; Embryonic Development; Epilepsy; Eye; Ganglia; Genetic; Heterotopic Transplantation; Hippocampus (Brain); Human; Impairment; In Situ Hybridization; Infant; Injury; Interneurons; Laboratories; Life; Maps; Medial; Methods; Modification; Mus; Neonatal; Neuraxis; Neurons; Ocular Dominance; Optics; Parkinson Disease; Parvalbumins; Pattern; Phencyclidine; Phenotype; Physiology; Play; Population; Process; Prosencephalon; Recovery of Function; Recruitment Activity; Research; Role; Sampling; Seizures; Somatostatin; Source; Spinal cord injury; Staining method; Stains; Techniques; Testing; Therapeutic Uses; Tissue Banks; Transplantation; Vision; Visual Cortex; Work; base; brain repair; brain tissue; cell type; critical period; embryonic stem cell; excitatory neuron; experience; experimental study; immunocytochemistry; induced pluripotent stem cell; juvenile animal; mature animal; migration; monocular deprivation; neonatal hypoxic-ischemic brain injury; neural circuit; novel; pleasure; postnatal; programs; public health relevance; response; tool; visual plasticity

DESCRIPTION (provided by applicant): Most forebrain interneurons originate in the developing medial ganglionic eminence (MGE), from where they migrate into cortex, hippocampus, striatum, and amygdala to form local inhibitory circuits. When transplanted into the juvenile or adult mouse cortex, MGE cells retain the ability for migration, functional integration, and differentiation primarily into parvalbumin (PV) and somatostatin (SOM) expressing GABAergic cells. Previous work has shown that GABAergic inhibition is required for the induction of cortical plasticity and brain repair. Recent work from our laboratories has shown that transplantation of MGE cells into the neonatal or juvenile mouse visual cortex can induce a new period of ocular dominance plasticity (ODP). The transplantation of MGE cells can also enhance the brain's capacity for functional recovery and is being developed as a possible cell therapy for several brain disorders. The ability of these cells to induce plasticity de novo also offers a powerful tool to study the mechanisms and limits of cortical plasticity. The present proposal has three Aims. Aim (1) will determine which type of cortical interneuron is responsible for the induction of cortical plasticity. We have developed and validated genetic tools to ablate PV, SOM, or both cell types from the MGE grafts. Previous research suggests that PV cells may be responsible for the induction of ODP, but this hypothesis has not been formally tested. Our preliminary studies suggest that ODP can still be rekindled, even when most PV cells are eliminated from MGE grafts. We will determine if SOM interneuron depletion is sufficient for the elimination of ODP, or whether both these populations have the capacity to induce ODP. This ODP is induced in young animals weeks after the end of the critical period, but it remains unknown if the adult brain is similarly receptive to interneuron-induced plasticity. Aim (2) will determine if the transplantation of cortical interneurons in the adult brain can induce ODP and contribute to recovery of function. We have developed and validated optical recording techniques to study ODP induction in adult mice. We also have preliminary evidence that MGE cells grafted into the adult mouse cortex migrate and integrate, suggesting that they could also modify cortical circuits and possibly induce ODP. Aim (3) will determine the normal pattern of interneuron maturation in the human visual cortex. If cortical interneurons are key to the induction of critical period plasticity in humans, what is normal pattern of interneuron maturation in infants? Studies from our labs suggest that interneurons continue to be recruited into some regions in the infant brain and this could underlie extended periods of plasticity. Using a collection of brain samples from our developmental tissue bank, we have validated staining and stereological methods to quantify and map PV, SOM, and other markers of immature and mature interneurons. Identification of cortical interneurons responsible for the induction of plasticity, the age range when plasticity can be induced, and the normal patterns of human interneuron maturation will provide new information for the use of MGE cells in brain repair.

描述（申请人提供）：大多数前脑中间神经元起源于发育中的内侧神经节隆起（MGE），从那里迁移到皮层、海马、纹状体和杏仁核，形成局部抑制回路。当移植到幼年或成年小鼠皮层时，MGE细胞保留了迁移、功能整合和主要分化为表达gaba能细胞的小白蛋白（PV）和生长抑素（SOM）的能力。先前的研究表明，gaba能抑制是诱导皮质可塑性和大脑修复所必需的。我们实验室最近的工作表明，将MGE细胞移植到新生或幼年小鼠视觉皮层可以诱导一个新的眼优势可塑性（ODP）时期。MGE细胞的移植还可以增强大脑功能恢复的能力，并且正在开发作为几种脑部疾病的可能细胞疗法。这些细胞诱导新生可塑性的能力也为研究皮质可塑性的机制和限制提供了有力的工具。目前的建议有三个目的。目的(1)将确定哪一种皮层中间神经元负责皮层可塑性的诱导。我们已经开发并验证了从MGE移植物中切除PV、SOM或两种细胞类型的遗传工具。先前的研究表明，PV电池可能对ODP的诱导负责，但这一假设尚未得到正式验证。我们的初步研究表明，即使从MGE移植物中消除了大多数PV电池，ODP仍然可以重新点燃。我们将确定SOM中间神经元的损耗是否足以消除ODP，或者这两个种群是否都有能力诱导ODP。这种ODP是在临界期结束几周后在幼龄动物中诱导的，但尚不清楚成年大脑是否同样能接受中间神经元诱导的可塑性。目的(2)将确定成人大脑皮层中间神经元移植是否可以诱导ODP并有助于功能恢复。我们已经开发并验证了光学记录技术来研究成年小鼠的ODP诱导。我们也有初步证据表明，移植到成年小鼠皮层的MGE细胞可以迁移和整合，这表明它们也可以改变皮层回路，并可能诱发ODP。目的(3)将确定人类视觉皮层中间神经元成熟的正常模式。如果皮层中间神经元是诱导人类关键期可塑性的关键，那么中间神经元成熟的正常模式是什么