Newborn Neurons in the Adult Hippocampal Network

描述（由申请人提供）：海马成体神经发生已经引起了神经科学界的注意，因为它突出了以前未被认识到的成年大脑内的可塑性和再生能力。新生神经元整合到成熟神经回路中参与海马依赖性行为已被广泛接受。成熟神经元的增殖和存活受到外部刺激（如运动、环境富集和压力）的严格调控，这一点也已得到充分证实。因此，神经发生提供了一种机制，将经验与成人神经回路的可塑性和再生联系起来。尽管大量文献支持神经发生的经验依赖性调节，但对这种调节是如何实现的知之甚少。这个项目的目标是阐明，在单细胞和电路水平上，经验如何通过控制新生神经元的存活来调节神经发生。虽然产生了许多新生神经元，但只有一小部分存活下来。我们将检验这样的假设，即成年产生的神经元的长期命运在其成熟的关键时期由GABA能突触输入控制，并且突触输入以经验依赖的方式调节。我们将使用转基因的方法来确定成人产生的神经元在一个特定的发展阶段和电生理技术，以评估他们的突触连接。在具体目标1和2中，我们将建立新生神经元在决定命运的关键时期如何响应网络活动。在具体目标3中，我们将确定新生神经元的突触输入如何被经验和遗传条件改变，从而提高存活率。然后，我们将测试突触活动和神经元存活之间的因果关系。这些结果将揭示海马回路特定组件的活动如何有助于成人生成的神经元的存活，从而允许成人神经网络的经验依赖性长期修改。成体产生的神经元的存活受损涉及许多神经病理学状况，包括神经退行性疾病和精神疾病，因此这些结果也将提供对潜在治疗靶点的深入了解，以促进疾病状态下新生神经元的存活。 公共卫生相关性：这个项目的目标是阐明，在单细胞和电路水平上，经验如何通过控制新生神经元的存活来调节神经发生。成体产生的神经元的存活受损涉及许多神经病理学状况，包括神经退行性疾病和精神疾病，因此这些结果也将提供对潜在治疗靶点的深入了解，以促进疾病状态下新生神经元的存活。

DESCRIPTION (provided by applicant): Hippocampal adult neurogenesis has captured the attention of the neuroscience community because it highlights a previously unrecognized capacity for plasticity and regeneration within the adult brain. It is widely accepted that newly generated neurons integrate into the mature circuit and participate in hippocampal dependent behaviors. It is also well established that the proliferation and survival of adult generated neurons are tightly regulated by external stimuli such as exercise, environmental enrichment and stress. Thus neurogenesis provides a mechanism that links experiences with plasticity and regeneration of the adult neural circuit. Despite the extensive literature supporting experience-dependent regulation of neurogenesis, very little is known about how such regulation is achieved. The goal of this project is to elucidate, at the single cell and circuit level, how experience regulates neurogenesis by controlling the survival of newborn neurons. Although many newborn neurons are produced, only a fraction survives. We will test the hypothesis that the long-term fate of adult generated neurons is controlled by GABAergic synaptic input during a critical period of their maturation and that synaptic input is regulated in an experience dependent- manner. We will use transgenic methods to identify adult generated neurons at a specific developmental stage and electrophysiological techniques to assess their synaptic connectivity. In Specific Aim 1 & 2 we will establish how newborn neurons respond to network activity during their critical period for fate determination. In Specific Aim 3 we will determine how the synaptic input of newborn neurons is altered by experiential and genetic conditions that enhance survival. Then we will test the causal link between synaptic activity and neuron survival. These results will reveal how activity in specific components of the hippocampal circuit contributes to the survival of adult generated neurons, thereby allowing experience-dependent long-term modifications of the adult neural network. Impaired survival of adult generated neurons has been implicated in many neuropathological conditions including neurodegenerative diseases and psychiatric illnesses, thus these results will also provide insight into potential therapeutic targets to promote the survival of newborn neurons in disease states. PUBLIC HEALTH RELEVANCE: The goal of this project is to elucidate, at the single cell and circuit level, how experience regulates neurogenesis by controlling the survival of newborn neurons. Impaired survival of adult generated neurons has been implicated in many neuropathological conditions including neurodegenerative diseases and psychiatric illnesses, thus these results will also provide insight into potential therapeutic targets to promote the survival of newborn neurons in disease states.