Neuronal turnover and plasticity in the hippocampal dentate gyrus

记忆依赖于可塑的改变，这种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目标是揭示终生海马神经发生所产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，对未成熟的成年神经元的兴奋，是以理解它们的长期功能特性为代价的，以及在生命其他阶段出生的神经元的功能。对海马齿状回的开创性研究表明，细胞和突触的总数不会随着年龄的增长而发生明显的变化，这与我们估计的在成年期增加多达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发育早期的神经元在成年早期经历了延迟的细胞死亡。因此，成年期新神经元的增加可能会被现有神经元的移除所抵消。同样，我们发现，成年神经元的发育至少需要6个月，这远远超过了人们普遍认为的增强可塑性的关键时期。它们最终拥有比发育中出生的神经元更多、更大的突触结构。发育出生的神经元是否会在成年后消失，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。目前的建议将研究出生后发育早期和成年期出生的神经元的长期存活和可塑性特性。我们的首要假设是，在发育和成人神经发生之间存在一种稳态平衡，发育出生的细胞突触退化并被移除，为进入的新神经元腾出空间。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。我们将使用胸腺嘧啶类似物来标记大鼠发育出生的神经元，并在整个生命周期中跟踪它们的存活情况。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了发育出生细胞的损失。在目标2中，我们将确定发育出生细胞的结构和生理特性。由于成年出生的神经元与先前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体回路中移除之前在功能上处于劣势。为了测试这一点，我们将使用转基因小鼠产生具有荧光蛋白的神经元，用于随后的形态测量和电生理分析。我们假设，随着大鼠年龄的增长，发育出生的细胞经历结构萎缩，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.