Newborn Neurons in the Adult Hippocampal Network

齿状回通过转化致密皮层参与海马记忆编码 将感觉和空间信息的模式转化为特定背景的稀疏神经表征。有 现在有压倒性的证据表明，齿状回中持续的成年神经发生对这种能力很重要， 但尚不清楚新产生的神经元如何参与齿状回回路 功能大多数理论都集中在这样一个事实上，即新产生的未成熟神经元具有独特的神经元结构。 这些生理特性可能赋予它们与较大的 成熟的神经元。另外，一个新兴的观点是，成年人出生的神经元促进了广泛的 通过以某种方式修改现有神经元的功能， 促进稀疏的活动。这也可以通过间接的电路动作，如反馈抑制， 如通过与现有兴奋性突触连接的直接相互作用。我们最近发现， 增加小鼠齿状回中成年出生的神经元数量， 成熟神经元的连接，导致内鼻齿状回的功能和解剖变化， 电路这些结果和现有的文献支持这样一种模型，其中皮质突触前神经元的静态池 终末动态地分布在新整合的成年出生的神经元和发育中， 产生成熟的神经元。这个项目的目标是测试突触的总体假设， 成人出生的神经元的整合通过神经元的重新分布对回路功能有不成比例的影响。 皮层突触连接首先，我们将绘制并量化伴随的突触前变化， 神经发生诱导的与成熟神经元的皮质突触的丧失。第二，我们将测试预测， 皮质突触前末梢的可用性是新生GC整合的限制因素， 导致成年期新神经元成熟率降低。最后，我们将测试潜力 突触再分布对神经活动稀疏性和突触可塑性的影响，以及 神经发生敏感行为的突触再分布的要求。我们将使用病毒和 操作，电生理学，成像和行为分析，以测试突触重建的预测， 分布限制了成年期神经元的整合，也使神经活动稀疏化。 as contributes贡献to behaviors行为that are sensitive敏感to neurogenesis神经新生.我们的成果将共同产生 关于神经发生在皮质齿状回中的作用的新知识，并可能提供对以下方面的见解： 随着神经发生的减少，这个回路在成年期是如何变化的。了解神经发生 对海马功能的贡献对于设计策略来抵消 在衰老和许多神经系统疾病中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.