Probing sleep and memory as targets for rejuvenation - Project Summary Growing evidence points to sleep loss playing a causal role in age-related memory decline. Sleep improves memory consolidation, but little is known about how sleep and memory formation change with aging. Further, how memory decline can be rescued is a critical unanswered question. We will elucidate changes in sleep, memory and synaptic plasticity that occur with age. We will reveal mechanisms by which we can prevent or reverse age-related memory decline. Our recent work shows nematode sleep promotes specific olfactory memory and whole-brain activity mapping reveals how sleep affects full-brain network function. C. elegans age extremely quickly; aging-related behavior declines within 24 hours as we and others have shown. Importantly, we discovered that sleep is also degraded in aged C. elegans. Manipulations that induce the unfolded protein response in the ER (UPRER) in the nervous system protect animals from age-dependent memory declines. The declines and their restoration by upregulated UPRER is conserved in nematodes and mammals. Here we will probe the system-level, cellular and molecular processes that decline with aging and are impacted by sleep to identify aging processes that can be restored. In Aim 1, we will probe how aging affects the period of sleep that is required for memory consolidation and sleep- dependent synaptic changes during long-term memory formation. Specifically, in Aim 1A, we will characterize post-training sleep in older animals. We will examine: feeding rates, posture, movement and arousal delay in older and young animals after training. In Aim 1B, we will determine olfactory synaptic plasticity during memory consolidation is impaired in aged animals by assessing whether synapses, visualized with the split-GFP based NLG-1 GFP Across Synaptic Partners (GRASP), are remodelled during sleep in older animals as we have shown occurs in younger worms. Dysregulation of neural plasticity underlies age-dependent declines in mammals. In Aim 1C, we will determine whether brain activity patterns differ between older and younger animals following behavioral training. In Aim 2, we will elucidate how sleep-dependent long-term memory formation is restored by increasing the UPRER . We have discovered that, as in mammals, the long-term memory defect in aged C. elegans is restored by increasing the level of the UPRER via XBP1s overexpression. In Aim 2A, we will determine if upregulation of the UPRER restores post-training sleep characteristics in older animals. Aim 2B we will test the hypothesis that overexpression of XBP1s restores memory by increasing Fibroblast Growth Factor activity. In Aim 2C we will ask if rejuvenation employs the phagocytosis protein CED-5/Dock, as phagocytoses is a mechanism for removing synapses. Plasticity provided by both these proteins is required for perception, learning and memory in many systems. Dysregulated plasticity underlies disorders, such as dementia. These studies will provide insights that will inform the development of future therapeutic strategies for age-dependent memory loss.
