Neuronal turnover and plasticity in the hippocampal dentate gyrus

记忆取决于塑料的改变，这些改变可能持续几秒钟，也可能持续一生。我的研究计划的长期愿景是揭示终身海马神经发生的可塑性如何在整个生命周期中对记忆和行为做出贡献。在成年期，未成熟的神经元具有增强的突触可塑性，这通常被认为赋予它们在记忆中的主导作用。然而，围绕未成熟的成人出生的神经元的兴奋是以理解其长期功能特性以及在生命其他阶段出生的神经元的功能为代价的。对海马齿状回的研究表明，细胞和突触的总数不会随着年龄的增长而明显变化，这与我们估计的成年期增加了40-50%的齿状回神经元不一致。然而，通常认为成熟的神经元不会在健康的大脑中死亡。在我们最近的工作中，我们发现许多出生在出生后早期发育的神经元在年轻时经历延迟的细胞死亡。因此，成年期新神经元的增加可能会被现有神经元的去除所抵消。同样，我们发现成年人出生的神经元发育至少需要6个月，这远远超过了人们普遍认为的可塑性增强的关键时期。它们最终比发育中出生的神经元具有更多，更大的突触结构。发育中出生的神经元是否在成年后丢失，以及它们是否表现出与年龄相关的可塑性变化，目前尚不清楚。目前的提议将调查出生后早期发育和成年期神经元的长期存活和可塑性。我们的总体假设是，发育和成年神经发生之间存在一种稳态平衡，发育中出生的细胞突触退化，并被移除，为新的神经元腾出空间。在目标1中，我们将描述整个生命周期中细胞损失和增加的动态。我们将使用胸苷类似物来标记大鼠中发育中的神经元，我们将跟踪它们在整个生命周期中的存活情况。在相同的动物中，我们将量化成年出生的颗粒细胞和总颗粒细胞，以确定成年神经发生是否在数字上补偿发育中出生的细胞的损失。在目标2中，我们将确定发育中出生的细胞的结构和生理特性。由于进入的成年出生的神经元与预先存在的神经元竞争突触空间，发育出生的细胞可能在完全从海马回路中移除之前在功能上被击败。为了验证这一点，我们将使用转基因小鼠与荧光蛋白的神经元出生，随后的形态和电生理分析。我们假设，随着大鼠年龄的增长，发育中出生的细胞发生结构性萎缩，失去突触，并降低了长期突触可塑性的能力。

Memory depends on plastic modifications that may persist for seconds or last for the lifetime. The long-term vision of my research program is to reveal how plasticity, resulting from lifelong hippocampal neurogenesis, contributes to memory and behavior throughout the lifespan. In adulthood, immature neurons have enhanced synaptic plasticity, which is generally thought to endow them with a dominant role in memory. However, excitement surrounding immature adult-born neurons has come at the expense of understanding their long-term functional properties, and the functions of neurons born at other stages of life. Seminal studies of the hippocampal dentate gyrus have shown that the total number of cells and synapses does not change appreciably with age, which is at odds with our estimates that up to 40-50% of dentate gyrus neurons are added in adulthood. However, it is typically assumed that mature neurons do not die in the healthy brain. In our recent work, we have found that many neurons born in early postnatal development undergo delayed cell death in young adulthood. Thus, the addition of new neurons in adulthood may be offset by the removal of existing neurons. Likewise, we have found that adult-born neurons develop over at least 6 months, which is far longer than the generally appreciated critical period for enhanced plasticity. They ultimately have more, and larger, synaptic structures than developmentally-born neurons. Whether developmentally-born neurons are lost beyond young adulthood, and whether they show age-related changes in plasticity, remains unclear. The current proposal will investigate the long-term survival and plasticity properties of neurons born in early postnatal development and adulthood. Our overarching hypothesis is that there is a homeostatic balance between developmental and adult neurogenesis, and that developmentally-born cells synaptically degenerate and are removed to make room for incoming new neurons. In Aim 1 we will characterize the dynamics of cell loss and addition throughout the lifespan. We will use thymidine analogs to label developmentally-born neurons in rats and we will track their survival across the lifespan. In the same animals we will quantify adult-born and total granule cells, to determine whether adult neurogenesis numerically compensates for the loss of developmentally-born cells. In Aim 2 we will identify structural and physiological properties of developmentally-born cells. Since incoming adult-born neurons compete with pre-existing neurons for synaptic space, developmentally-born cells may be functionally outcompeted prior to being entirely removed from hippocampal circuits. To test this we will use transgenic mice to birthdate neurons with fluorescent proteins, for subsequent morphometric and electrophysiological analyses. We hypothesize that, as rats age, developmentally-born cells undergo structural atrophy, lose synapses, and have reduced capacity for long-term synaptic plasticity.