Interneuron Precursors and the induction of cortical plasticity

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)，它们从那里迁移到皮质、海马体、纹状体和杏仁核形成局部抑制电路。当MGE细胞移植到幼年或成年小鼠的皮质中时，MGE细胞保留了迁移、功能整合和分化的能力，主要是分化为表达GABA能细胞的小白蛋白(PV)和生长抑素(SOM)。以前的工作表明，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皮质可以诱导新的眼优势可塑性(ODP)时期。MGE细胞的移植也可以增强大脑的功能恢复能力，并正在被开发为一种可能的脑部疾病的细胞疗法。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度提供了一个强有力的工具。目前的建议有三个目标。目的(1)将确定哪种类型的皮质中间神经元负责皮质可塑性的诱导。我们已经开发和验证了基因工具来去除MGE移植物中的PV和/或SOM细胞类型。以前的研究表明，光伏细胞可能是诱导ODP值的原因，但这一假说尚未得到正式检验。我们的初步研究表明，即使大多数光伏细胞从MGE移植物中消失，ODP值仍然可以重新点燃。我们将确定SOM神经元间的耗竭是否足以消除ODP值，或者这两个群体是否都有能力诱导ODP值。在关键期结束后的几周内，幼年动物就会诱导这种ODP值，但成人大脑是否同样能接受神经元间诱导的可塑性仍是未知的。目的(2)将确定成人大脑皮质中间神经元移植是否能诱导ODP并有助于功能的恢复。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，移植到成年小鼠大脑皮质的MGE细胞可以迁移和整合，这表明它们也可以改变皮质回路，并可能诱导ODP。目的(3)将确定人眼视皮层神经元成熟的正常模式。如果皮质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 在婴儿身上？我们实验室的研究表明，中间神经元继续被招募到婴儿大脑的某些区域，这可能是延长可塑性时期的基础。使用从我们的发育组织库收集的大脑样本，我们已经验证了染色和体视学方法来量化和绘制未成熟和成熟中间神经元的PV、SOM和其他标记。识别负责诱导可塑性的皮质中间神经元、可诱导可塑性的年龄范围以及人类中间神经元成熟的正常模式将为MGE细胞在脑修复中的应用提供新的信息。

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.