Assessing whether the adult neocortex can incorporate new projection neurons

描述（由申请人提供）：评估成人新皮层是否可以合并新的投射神经元。 新皮层是我们最高认知功能的所在地。新皮质投射神经元可能由于神经退行性疾病而丢失，并且一旦丢失，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，以减轻症状并延缓神经退行性疾病的发作，例如阿尔茨海默氏症，其中新皮质投射神经元丢失。然而，额外的治疗，如皮质投射神经元的替代，最终将有必要使患者恢复到疾病前的状态。由于新皮层的复杂性和大小，开发替代丢失的投射神经元的策略是一项艰巨的任务。先前尝试使用几种类型的移植神经干细胞或前体细胞来替换新皮层中的投射神经元，但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，移植的细胞主要在移植部位保持成团。为了实现在新皮层的广泛区域中功能性整合新投射神经元的目标，需要考虑细胞分散的新策略。这项建议的主要目的是制定一项 在成人新皮层中引入新的，广泛分布的投射神经元的方法，为测试它们是否可以功能整合提供了一个范例。我们的初步数据表明，我们可以在成年人的新皮层中实现广泛的前体分布，新的神经元可以沿着沿着它们的正常轨道延伸长的投射到它们的正常目标。在第一个目标中，我们正在工程前体，其具有在成人新皮层中分散的天然能力，具有强力霉素诱导的转录因子，一旦前体分散，将允许它们重新编程为皮层投射神经元的命运。在第二个目标中，我们将测试桶皮层中的新神经元对丘脑神经元的刺激和对触须刺激的电生理反应;我们还将测试前运动皮层中的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元细胞在健康环境中分散和整合的能力，并与投射神经元退化的环境进行比较。

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.