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纳入新的投射神经元。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，导致永久性的功能缺陷。有许多治疗方法正在开发中，以减轻症状和延缓神经退行性疾病的发作，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换，最终将需要使患者恢复到疾病前的状态。由于新皮质的复杂性和体积，开发替代失去的投射神经元的策略是一项艰巨的任务。以前尝试使用几种类型的移植神经干或前体细胞替代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簇。为了在新皮层的广大区域实现功能整合新投射神经元的目标，需要一种考虑细胞分散的新策略。这项建议的中心目标是发展一个

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.