Diversity in the integration of granule neurons into the postnatal olfactory bulb

描述(申请人提供)：人脑的修复能力有限，因此，神经系统的疾病或损伤通常是不可逆转的。成年哺乳动物大脑的嗅球和海马体中增加了新的神经元，这表明细胞替代可能是一种很有前途的大脑修复策略。然而，开发成功的基于细胞替换的大脑修复策略需要了解新生成的神经元如何整合到成人大脑中预先存在的、功能正常的神经回路中。之前的观察表明，新生动物的嗅球中加入新神经元的效率比成年动物更高。这项提议的目的是了解可能调节新生大脑中产生的新神经元与成年出生的神经元相比，整合到嗅球中的能力增加的机制，长期目标是将这种理解应用于改进大脑修复的策略。一条重要的线索来自我们最近的发现，即新生啮齿动物嗅球中增加的新神经元整合到球状回路中，其连接模式与成年动物不同。这种差异提供了一个理想的实验机会，可以用来揭示调节新神经元如何整合到功能大脑回路中的机制。在这项建议中，我们将集中努力实现三个目标。首先，我们将通过用逆转录病毒标记神经前体细胞来分析它们的形态，并将使用遗传标记来揭示它们的突触输入，从而研究成人和新生儿嗅球中产生的中间神经元连接的差异。其次，我们将通过分析神经前体细胞来源的颗粒神经元移植到等时或异时宿主体内后的形态，来分析细胞自主或靶向依赖机制在建立出生后嗅球新生神经元不同连接模式中的作用。第三，我们将通过向神经前体细胞传递三种不同的结构来改变新生成的球状神经元的内在兴奋性和突触属性，从而表征活动的遗传操作如何影响在新生儿或成人的球状细胞中出生的新神经元的整合。这项提议将研究不同类别的神经元如何存活并与成年和新生动物大脑中的其他神经元连接。从我们描述的实验中获得的见解将指导未来利用神经元替换作为人类大脑修复策略的努力。

DESCRIPTION (provided by applicant): The human brain has a limited ability for repair, and thus, diseases or injuries to the nervous system are usually irreversible. The addition of new neurons into the olfactory bulb and hippocampus of the adult mammalian brain suggests that cell replacement may be a promising strategy for brain repair. However, developing successful strategies for cell-replacement based brain repair requires an understanding of how newly generated neurons integrate into pre-existing, functioning neural circuits in the adult brain. Previous observations suggest that the incorporation of new neurons into the olfactory bulb of newborn animals is more efficient than in adult animals. The goal of this proposal is to understand the mechanisms that may regulate the increased ability of new neurons generated in the newborn brain to integrate into the olfactory bulb, compared to adult-born neurons, with the long-term objective of applying this understanding towards improving strategies for brain repair. An important clue comes from our recent discovery that new neurons added to the olfactory bulb in newborn rodents integrate into the bulb circuit with a pattern of connectivity distinct from that of the adult animal. This difference offers an ideal experimental opportunity with which to uncover the mechanisms that regulate how new neurons integrate into functioning brain circuits. In this proposal we will concentrate our efforts on three aims. First, we will investigate the differences in the connectivity of interneurons generated in the adult versus the newborn olfactory bulb by labeling neuronal progenitors with retroviruses to analyze their morphology, and will use a genetic marker to reveal their synaptic input. Second, we will assay the contribution of cell-autonomous or target-dependent mechanisms in the establishment of the different patterns of connectivity of new neurons born in postnatal olfactory bulb by analyzing the morphology of granule neurons derived from neuronal progenitors after transplantation into isochronic or heterochronic hosts. Third, we will characterize how genetic manipulations of activity affect the integration of new neurons born in the bulb of newborns or adults by delivering into neural progenitors three different constructs to alter the intrinsic excitability and the synaptic properties of newly generated bulb neurons. This proposal will investigate how different classes of neurons survive and connect to other neurons in the brain of adult and newborn animals. The insights gained from the experiments that we describe will guide future efforts towards harnessing replacement of neurons as a strategy for brain repair in humans.