PROJECT SUMMARY Sleep disturbances predict risk of Alzheimer’s disease (AD). Sleep-wake cycles critically regulate brain interstitial fluid (ISF) levels of Aβ and tau, two critical proteins that accumulate in AD. Both Aβ and tau are released by neuronal activity, which is higher during wakefulness than in sleep. Moreover, sleep is a critical phase during which factors in the ISF are cleared from the brain. Therefore, sleep disturbances affect daily function and also contribute to disease progression. However, little is known about which brain regions are affected in AD to give rise to sleep disturbances, making it difficult to identify the circuit level mechanisms that drive dysfunction, or to design targeted therapeutic strategies. This project tests the hypothesis that the thalamic reticular nucleus (TRN) is a critical brain region in AD, and that impairments in its activity drive sleep disturbances and exacerbate disease progression. The TRN is a major component of the thalamocortical- corticothalamic network that regulates sleep, attention, and memory, which are all affected in AD. However, little is known about the state of TRN in AD patients or in animal models. We found that in transgenic mice expressing mutant human amyloid precursor protein (APP mice), TRN activity is strikingly reduced, in the absence of cell loss. Such reductions in TRN activity led to sleep fragmentation and reductions in slow wave sleep (SWS), and predicted the magnitude of Aβ deposition in both hippocampus and cortex, which may relate to the fact that SWS is the phase of sleep during which activity-dependent production of Aβ is reduced, and Aβ is cleared from the brain. Moreover, deficits in SWS and sleep maintenance manifest early in disease in APP mice, prior to hippocampal deficits, suggesting that TRN impairment may both predict and contribute to disease progression. The goals of this proposal are to identify cellular mechanisms that impair TRN activity, and test if selectively manipulating neuronal activity in the TRN can normalize sleep, reduce Aβ accumulation, and improve memory. To achieve these goals, in Aim 1 we will use electrophysiology and pharmacology in thalamic slices to identify the intrinsic, synaptic, and network properties of TRN that result in its hypoactivity in APP mice. In Aim 2, we will use DREADDs to acutely activate TRN cells in APP mice to test if TRN activation affects dynamics of interstitial Aβ, and/or memory consolidation. In Aim 3, we will use DREADD-mediated activation of TRN in APP mice to test if chronic activation of TRN can normalize sleep parameters, reduce Aβ accumulation, a...