Sleep reinforces homeostatic set-points in neural activity and mitigates neurodegenerative disease - 1 PROJECT SUMMARY 2 Our broad, long-term objective is to leverage the intimate relationship between sleep and neurodegenerative disease 3 to diminish, delay, and prevent pathology. Our approach is based on first-principles reasoning. First, neurodegenera- 4 tive disease is functionally defined by the failure of homeostatic set-points to maintain complex computation. Second, 5 sleep is widely understood to subserve the homeostatic reinstatement of set-points necessary for complex computation. 6 Thus, we propose that the well-established association between sleep disturbances and neurodegenerative disease is 7 the result of sleep’s progressive inability to achieve its central homeostatic set-point. This set-point has recently been 8 identified as criticality, an optimal computational regime that maximizes information processing. Based on extensive 9 preliminary data, we propose that: 1) criticality is the locus of tauopathy’s impact on neuronal activity, 2) reinforcement 10 of criticality via homeostatic sleep enhancement prevents neurodegenerative disease, and 3) mechanistically, sleep- 11 related patterns of neuronal activity reduce DNA damage, while disease-related patterns increase DNA damage. To 12 move forward, it is imperative that we identify how sleep reinforces function, and ask whether this process can be aug- 13 mented to counteract disease. To make progress in this arena, we will apply novel computational tools to continuous, 14 months-long, multi-site recordings of neural activity in P301S mice, a robust model of tauopathy. In this context, we will 15 deploy two distinct, non-invasive, and rapidly translatable methods of sleep-enhancement to bolster homeostatic control 16 of criticality. We will then quantify neurodegenerative disease progression and cognitive function using a sophisticated 17 prey capture task. To evaluate our hypothesis that criticality mechanistically links sleep and neurodegenerative disease, 18 we will disentangle criticality from the myriad of changes that occur during sleep. We will impose sleep-related patterns 19 of neuronal spiking in the brains of tauopathy mice and measure subsequent 1) neuronal health (DNA damage), and 20 2) fidelity of the critical set-point. Likewise, we will impose supercritical dynamics, which are characteristic of both 21 neurodegenerative disease and sleep deprivation, in the WT brain and measure the same end points. We present 22 three aims: test the hypothesis that 1) inducing homeostatic supercompensation promotes criticality and mitigates sub- 23 sequent tauopathy, 2) pharmacological enhancement of sleep promotes criticality and reduces subsequent tauopathy, 24 and 3) critical network dynamics directly influence neuronal health. These experiments test a novel mechanism by 25 which sleep and neurodegenerative disease may interact, and have the potential to reveal a fundamental principle of 26 neurobiology—that activity regimes directly determine neuronal integrity. In terms of the mission of the agency, our test- 27 ing of this theory takes the form of clinically-relevant and immediately applicable interventions that are complementary 28 to extant molecular biological approaches to treating neurodegeneration.
