Sleep provides a nightly window in which the glymphatic system performs an active triage of extracellular proteins, deciding which species are cleared and which are retained to support synaptic plasticity {1}. Sleep also acts as a circuit 'auditor' that triages memories and emotions {3}. We hypothesize that psilocybin amplifies this triage by increasing wake‑dependent ATP release, which drives astrocytic calcium signaling and redirects aquaporin‑4 (AQP4) polarization toward perivascular endfeet, thereby boosting convective flow that preferentially clears oligomeric amyloid‑β and tau while sparing plasticity‑related proteins such as PSD‑95 and synapsin‑I. It's likely that this mechanism operates preferentially during slow‑wave sleep, when extracellular space expands and CSF influx peaks {2}. This selective clearance lowers the burden of toxic aggregates without eroding the synaptic tags that underlie memory consolidation, providing a mechanistic link between psilocybin‑induced changes in sleep architecture and its antidepressant efficacy {5}.

To test this, we propose three complementary experiments. First, in awake mice administered a sub‑psychedelic dose of psilocybin, we will measure extracellular ATP levels in the cortex using luciferase‑based biosensors and correlate these with subsequent AQP4 polarity shifts imaged by two‑photon microscopy of GFP‑tagged AQP4 {4}. Second, during the ensuing NREM sleep, we will inject a fluorescent tracer conjugated to an oligomer‑specific antibody (e.g., 'anti‑tau‑oligo') and quantify its clearance from the interstitial fluid via in vivo microscopy, comparing psilocybin‑treated versus vehicle controls {6}. Third, we will assess behavioral outcomes in a chronic stress model of depression, measuring sucrose preference and forced‑ swim immobility, while pharmacologically blocking AQP4 with TGN‑020 to determine whether abolishing the enhanced glymphatic flow eliminates both the reduction in oligomeric tau and the antidepressant‑like phenotype. Predictions: psilocybin will raise cortical ATP by ~30 %, increase perivascular AQP4 enrichment by ~25 %, accelerate oligomer tracer clearance by ~40 %, and lower hippocampal oligomeric tau by ~35 %; AQP4 blockade will nullify these effects and prevent behavioral improvement. Confirmation would reframe sleep‑dependent glymphatic activity as a substrate‑selective editing process that psychedelics can tune, whereas failure to observe the predicted selectivity or ATP‑AQP4 coupling would falsify the hypothesis.