ABSTRACT During sleep, the thalamus generates a characteristic brief pattern of 8-15 Hz electroencephalographic (EEG) waves that predominantly occur during light stages of non-rapid eye-movement sleep (NREMS). Reduced spindle may cause impaired learning and Mild Cognitive Impairment (MCI) in AD and is a biomarker for early AD-related changes in brain dynamics. Conversely, promoting sleep oscillations by transcranial stimulation enhances memory consolidation in MCI. By developing a set of novel, noninvasive, bacteriophytochrome-based optogenetic tools to control cAMP synthesis (adenylate cyclase, AC) and breakdown (phosphodiesterase, PDE), we will make spindles accessible for noninvasive manipulations that spare other sleep rhythms. These enzymes are activated by light in the so-called near-infrared optical window (NIRW). The NIRW light-activated modules are suitable for the rapid yet long-lasting and noninvasive manipulation of cAMP in thalamic neurons in intact animals, because NIRW light penetrates through mammalian skulls and brain tissues better than the light of any other spectral region. We will examine a provocative novel hypothesis that cellular pathology and cognitive decline caused by Alzheimer’s disease (AD) related mutations can be restored via enhancing thalamocortical spindles waves during sleep in vivo. We will first develop novel noninvasive optogenetic tools to manipulate AC and spindle oscillations (Aim 1). Then, we will examine whether NIRW-AC and NIRW-PDE bi-directionally modulate the progression of AD–related neuropathology and cognitive decline via their actions re: spindle wave regulations (Aim 2). Upon completion of this project, we will have developed genetically encoded NIRW-light activated tools, allowing noninvasive manipulation in deep brain regions of live animals. Results are expected to provide a sound basis for investigation in disease models that involve spindle wave and cAMP aberrations, such as AD, and suggest novel non- invasive intervention strategies to counteract brain dementias caused by AD.