Assessing whether the adult neocortex can incorporate new projection neurons

描述(申请人提供)：评估成人大脑皮层是否能结合新的投射神经元。新大脑皮层是我们最高认知功能的所在地。由于神经退行性疾病，新皮质投射神经元可能会丢失，一旦丢失，它们通常不会被替换，导致永久性功能缺陷。有许多治疗方法正在开发中，以缓解症状并延缓神经退行性疾病的发病，例如阿尔茨海默氏症，在这种疾病中，新皮质投射神经元会丢失。然而，其他治疗，如更换皮质投射神经元，最终将是必要的，以使患者恢复到疾病前的状态。由于新皮质的复杂性和大小，开发替代丢失的投射神经元的策略是一项艰巨的任务。以前使用几种类型的移植神经干细胞或前体细胞替换新皮质中的投射神经元的尝试都没有提供可行的策略。新神经元整合有限的一个原因是，到目前为止，移植的细胞主要停留在移植部位的一团块中。为了实现将新的投射神经元在大脑皮层的广泛区域进行功能性整合的目标，需要一种考虑细胞分散的新策略。这项提议的中心目标是开发一种 在成人大脑皮层引入新的、广泛分布的投射神经元的方法，为测试它们是否能够在功能上整合提供了一个范例。我们的初步数据表明，我们可以在成年新皮质实现前体的广泛分散，并且新的神经元可以沿着它们的正常轨迹向它们的正常靶点延伸长的投射。在第一个目标中，我们正在利用多西环素诱导的转录因子来设计前体，这些前体具有在ADUL新皮质中分散的自然能力，一旦前体分散，将允许它们重新编程为皮质投射神经元的命运。在第二个目标中，我们将测试桶形皮质新神经元对丘脑神经元刺激和胡须刺激的电生理反应；我们还将测试运动前皮质新神经元刺激纹状体神经元的能力。对于这两个目标，我们将评估移植的神经细胞在健康环境中分散和整合的能力，与投射神经元退化的环境相比。

DESCRIPTION (provided by applicant): Assessing whether the adult neocortex can incorporate new projection neurons. The neocortex is the seat of our highest cognitive functions. Neocortical projection neurons can be lost due to neurodegenerative diseases and once lost they are not normally replaced, leading to permanent functional deficits. There are a number of therapies in development to alleviate the symptoms and retard the onset of neurodegenerative diseases, such as Alzheimer's, in which neocortical projection neurons are lost. However, additional treatment, such as the replacement of cortical projection neurons, will eventually be necessary to return patients to pre-disease states. Developing strategies to replace lost projection neurons is a daunting task because of the complexity and size of the neocortex. Previous attempts at replacing projection neurons in the neocortex using several types of transplanted neural stem or precursor cells have not provided viable strategies. One reason for the limited integration of new neurons is that thus far transplanted cells have remained primarily in a clump at the transplant site. To achieve the goal of functionally integrating new projection neurons throughout broad areas of the neocortex, a novel strategy is required that takes into account cell dispersion. The central aim of this proposal is to develop an approach for introducing new, widely dispersed, projection neurons in the adult neocortex, providing a paradigm for testing whether they can functionally integrate. Our preliminary data suggest that we can achieve the wide dispersion of precursors in the adult neocortex and that new neurons can extend long projections along their normal tracks and to their normal targets. In a first aim, we are engineering precursors, which have a natural ability to disperse in the adul neocortex, with doxycycline-inducible transcription factors that will, once the precursors have dispersed, allow their reprogramming to a cortical projection neuron fate. In a second aim, we will test the electrophysiological response of new neurons in the barrel cortex to stimulation of thalamic neurons and to whisker stimulation; we will also test the ability of new neurons in the premotor cortex to stimulate striatal neurons. For both aims, we will assess the ability of transplanted neuronal cells to disperse and integrate in a healthy environment compared with one in which projection neurons are degenerating.