Neuronal turnover and plasticity in the hippocampal dentate gyrus

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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.