General anesthesia is often compared to sleep but may more closely resemble a medically induced coma. While all three states involve a loss of awareness, the extent of their neural similarity remains unclear. Electrophysiological markers, such as delta activity (< 4 Hz), are present in slow wave sleep, disorders of consciousness (DoC, including coma), and propofol anesthesia but are absent during rapid eye movement (REM) sleep. Frontal alpha oscillations are a key feature of propofol anesthesia and detectable via intraoperative EEG. However, it remains unclear whether alpha and delta activity fully define the brain state. Using whole-head EEG, we analyzed brain activity in individuals under propofol anesthesia, during sleep, or in DoC in the intensive care unit. Our spectral parameterization and similarity analyses revealed that propofol anesthesia exhibits spatiotemporal patterns resembling both coma and sleep. We introduced a spectral orthogonalization approach, identifying unique signatures of propofol anesthesia, including posterior slow waves, frontocentral delta, and reduced aperiodic activity. Critically, the reduction in aperiodic activity partially overlaps with REM sleep and may reflect decreased cortical excitability, contributing to reduced arousal, muscle atonia, and immobility common to both states. These results imply that propofol anesthesia creates a brain state where some features resemble sleep while others are more similar to coma. Embracing its full spatiotemporal complexity could improve titration of sedation, thus minimizing excessive suppression and the risk of postoperative cognitive deficits.

Alzheimer's disease (AD) is characterized by progressive cognitive deterioration and significant depression. However, the mechanisms linking depression to AD pathology remain unclear. Here, we investigated whether Notch2 signaling mediates depression-like behaviors in presenilin-2 (PS2) N141I mutant mice, an early-onset AD model. PS2 wild-type (WT) and mutant (MT) mice aged 12-15 months were subjected to unpredictable chronic mild stress (UCMS) for 4 weeks, followed by sucrose preference, tail-hanging, and forced swimming tests. Behavioral assessments showed that UCMS exacerbated anhedonia and immobility only in PS2 MT mice. Molecular analysis revealed concomitant increases in plasma corticosterone, hippocampal γ-secretase activity, and Notch2 expression, and elevated total and phosphorylated glucocorticoid receptor levels in PS2 MT-UCMS mice. Gene expression profiling of human hippocampal datasets confirmed upregulation of NOTCH2 in Alzheimer's disease and depression. Pharmacological inhibition of γ-secretase and Notch signaling with DAPT normalizes depressive behavior, reduces corticosterone release, attenuates GR phosphorylation, and inhibits Notch2 signaling in PS2 MT mice. These findings identify Notch2 as a pivotal mediator linking chronic stress to molecular changes associated with depression and AD, and suggest that targeting Notch2 signaling may provide therapeutic benefits for comorbid mood and neurodegenerative disorders.