Interneuron Precursors and the induction of cortical plasticity

描述（由申请人提供）：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），从那里它们迁移到皮质、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质中时，MGE细胞保留迁移、功能整合和分化的能力，主要分化为表达GABA能细胞的小清蛋白（PV）和生长抑素（SOM）。先前的工作表明，GABA能抑制是诱导皮质可塑性和脑修复所必需的。本实验室最近的工作表明，将MGE细胞移植到新生或幼年小鼠的视皮层中可以诱导一个新的眼优势可塑性（ODP）时期。MGE细胞的移植也可以增强大脑功能恢复的能力，并且正在开发作为几种大脑疾病的可能细胞疗法。这些细胞重新诱导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标。目的（1）确定哪种类型的皮层中间神经元负责诱导皮层可塑性。我们已经开发并验证了遗传工具，以消融PV，SOM，或两种细胞类型的MGE移植物。以前的研究表明，光伏电池可能是负责诱导ODP，但这一假设尚未得到正式验证。我们的初步研究表明，ODP仍然可以重新点燃，即使大多数PV细胞从MGE移植物中消除。我们将确定SOM中间神经元耗竭是否足以消除ODP，或者这两个群体是否有能力诱导ODP。这种ODP在关键期结束后的几周内在年轻动物中诱导，但成年大脑是否同样接受中间神经元诱导的可塑性仍然未知。目的（2）研究皮层中间神经元移植是否能诱导ODP并促进功能恢复。我们已经开发并验证了光学记录技术，以研究ODP诱导成年小鼠。我们也有初步的证据表明，移植到成年小鼠皮层的MGE细胞迁移和整合，这表明他们也可以修改皮层电路，并可能诱导ODP。目的（3）探讨人视皮层中间神经元成熟的正常模式。如果皮质中间神经元是人类关键期可塑性诱导的关键，那么中间神经元成熟的正常模式是什么 在婴儿中？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，这可能是可塑性延长的基础。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映射PV，SOM和其他标记的不成熟和成熟的中间神经元。鉴定负责诱导可塑性的皮层中间神经元，可塑性可以被诱导的年龄范围，以及人类中间神经元成熟的正常模式将为MGE细胞在脑修复中的使用提供新的信息。

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.