Newborn Neurons in the Adult Hippocampal Network

齿状回通过转换致密的皮质参与了海马区的记忆编码 将感觉和空间信息的模式转化为特定上下文的稀疏神经表示。的确有 现在，压倒性的证据表明，在齿状回中持续的成人神经发生对能力很重要 辨别空间背景，但尚不清楚新产生的神经元如何参与齿状回 功能。大多数理论都聚焦于这样一个事实，即新生成的未成熟神经元具有明显的 潜在地赋予它们独特的处理能力的生理特性 成熟神经元的群体。或者，一种新的想法是，成年出生的神经元促进广泛传播 通过以某种方式改变现有神经元的功能来实现预先存在的皮质-齿状回回路的可塑性 这促进了稀少活动。这也可以通过反馈抑制等间接电路作用来实现 通过与现有兴奋性突触连接的直接相互作用。我们最近有选择地展示了 增加小鼠齿状回中成年神经元的数量可减少兴奋性突触 成熟神经元的连通性，导致内嗅齿状核的功能和解剖变化 电路。这些结果和现有文献支持这样一个模型，即大脑皮质前突触的静态池 终末在新整合的成年出生的神经元和发育中的神经元之间动态分布 产生了成熟的神经元。这个项目的目标是测试突触的总体假设 成年出生神经元的整合通过重新分布神经元而对电路功能产生不成比例的影响 皮质突触连接。首先，我们将绘制并量化伴随而来的突触前变化 神经发生导致与成熟神经元的皮质突触丢失。第二，我们将检验这一预测 皮质突触前终末的可用性是新生儿GC整合的限制因素，可能 导致成年后新神经元成熟速度减慢。最后，我们将测试潜力 突触重新分布对神经活动和突触可塑性的稀疏性的影响，以及 神经发生敏感行为对突触重分布的要求。我们将使用病毒的组合 手法、电生理学、成像和行为分析，以检验突触重新启动的预测 分布限制了成年后出生的神经元的整合，也减少了神经活动。 AS导致对神经发生敏感的行为。我们的成果将共同产生根本性的 关于神经发生在皮质-齿状回回路中的作用的新知识，并潜在地提供了对 随着神经发生功能的衰退，这一回路在成年期发生了怎样的变化。了解神经发生是如何 对海马区功能的贡献对于制定策略来抵消 在衰老和许多神经疾病期间发生的神经发生中断。

The dentate gyrus contributes to hippocampal memory encoding by transforming dense cortical patterns of sensory and spatial information into sparse neural representations of specific contexts. There is now overwhelming evidence that continual adult neurogenesis in the dentate gyrus in important for the ability to discriminate spatial contexts, but it is not clear how newly generated neurons contribute to dentate circuit function. Most theories have focused on the fact that newly-generated immature neurons have distinct physiological properties that potentially endow them with unique processing capabilities compared to larger population of mature neurons. Alternatively, an emerging idea is that adult-born neurons promote wide-spread plasticity of the pre-existing cortical-dentate circuit by modifying the function of existing neurons in a manner that promotes sparse activity. This could occur either by indirect circuit actions like feedback inhibition, as well as via direct interactions with existing excitatory synaptic connectivity. We recently showed that selectively increasing the number of adult-born neurons in mouse dentate gyrus reduces the excitatory synaptic connectivity of mature neurons, resulting in both functional and anatomical changes in entorhinal-dentate circuitry. These results and existing literature support a model wherein a static pool of cortical pre-synaptic terminals is dynamically distributed between newly integrating adult-born neurons and developmentally- generated mature neurons. The goal of this project is to test the overarching hypothesis that synaptic integration of adult-born neurons has disproportionate effects on circuit function via redistribution of cortical synaptic connectivity. First, we will map and quantify the presynaptic changes that accompany neurogenesis-induced loss of cortical synapses with mature neurons. Second, we will test the prediction that availability of cortical presynaptic terminals is a limiting factor in the integration of newborn GCs that potentially contributes to the reduced rate new neuron maturation across adulthood. Finally, we will test potential consequences of synaptic redistribution on the sparsity of neural activity and synaptic plasticity, and the requirement for synaptic redistribution for neurogenesis-sensitive behaviors. We will use a combination of viral manipulations, electrophysiology, imaging and behavioral analysis to test the prediction that synaptic re- distribution limits the integration of adult-born neurons during adulthood and sparsifies neural activity, as well as contributes to behaviors that are sensitive to neurogenesis. Together our results will generate fundamental new knowledge about the role of neurogenesis in cortical-dentate circuitry, and potentially provide insight into how this circuit changes across adulthood as neurogenesis declines. Understanding how neurogenesis contributes to hippocampal function is important for devising strategies to counteract the consequences of disrupted neurogenesis that occurs during aging and many neurological conditions.