Sleep entails sensory disconnection, a state where external stimuli fail to elicit a meaningful behavioral response and do not affect perceptual awareness. While during NREM sleep and anesthesia thalamocortical neurons are bistable and the thalamus may not relay sensory signals effectively to the cortex, disconnection persists throughout REM sleep with its wake-like activity, as well as during other physiological and pathological states. This proposal seeks to reveal the markers and mechanisms of sensory disconnection and determine to what extent sleep and cognitive factors bring about similar disconnection. I hypothesize that sensory disconnection is a result of neuromodulatory changes, leading to a functional decoupling between early sensory cortex and higher order cortices. Specifically, reduced locus coeruleus-norepinephrine (LC-NE) activity may be a key mechanism, possibly affecting high-order thalamic nuclei and preventing ascending signals from effectively driving high-order cortical neurons. The proposed research will employ a combined approach in animal models (to experimentally dissect the underlying mechanisms and obtain detailed recordings of neuronal activity) and human studies (for carefully teasing apart cognitive factors, obtaining perceptual reports, and performing whole-brain imaging). I will address the following specific aims: (Aim1) identify markers of sensory incorporation vs. disconnection during physiological sleep/wake using auditory stimulation, (Aim2) reveal the underlying mechanisms by optogenetics (rodents) and pharmacological imaging (humans), and (Aim3) compare the effects of cognitive variables on sensory processing to those of vigilance states and the experimental manipulations. Understanding sensory disconnection will help reveal how states of behavior and activity affect cortical processing in health and disease, thereby addressing a fundamental open question in sleep research and system neuroscience.