Hypothesis

Von Economo neurons (VENs) function as a specialized sleep‑active hub that simultaneously drives intracellular autophagosome‑lysosomal clearance and extracellular glymphatic CSF influx. During deep sleep, VENs fire in synchrony with slow‑wave oscillations, releasing orexin‑A and vasoactive intestinal peptide (VIP) that (1) activate TFEB‑dependent lysosomal biogenesis in projection neurons and (2) trigger astrocytic AQP4 polarization via VIP‑VPAC2 signaling, thereby boosting glymphatic convective transport. Chronic sleep fragmentation reduces VEN firing, uncoupling these two clearance arms and leading to a selective buildup of toxic aggregates in VEN‑rich circuits (anterior cingulate, frontoinsular cortex). This uncoupling, rather than global clearance failure, predicts the early emergence of neuropsychiatric symptoms seen in sleep‑disordered neurodegeneration.

Mechanistic Rationale

• VEN anatomy matches clearance demands: VENs possess large somata and exceptionally long, thin dendrites that traverse high‑density cortical layers, creating a bottleneck for autophagosome transport along microtubules (5). Their high mitochondrial density makes them reliant on efficient lysosomal degradation to prevent autophagosome backlog.
• Dual‑output signaling: Orexin‑A, known to stabilize wakefulness, also potentiates lysosomal acidification via mTORC1 inhibition in downstream neurons (1). VIP, co‑released with orexin from VENs, directly increases astrocytic intracellular calcium, promoting AQP4‑mediated water efflux and CSF influx (3).
• Sleep‑locked oscillation coupling: VEN subthreshold membrane potentials oscillate in phase with cortical slow waves (<1 Hz), a coupling shown to be necessary for glymphatic CSF velocity peaks (4). Disruption of this phase‑locking reduces both TFEB nuclear translocation and AQP4 polarization.

Testable Predictions

1. Chemogenetic silencing of VENs during NREM sleep in mice will:
   • Decrease LC3‑II/LAMP1 ratio (indicative of blocked autophagosome‑lysosome fusion) in projection neurons of the hippocampus and striatum.
   • Reduce CSF influx tracer influx by >30 % as measured by two‑photon imaging of intrathecal fluorescein.
   • Increase extracellular tau and amyloid‑β levels in the CSF after 4 weeks of chronic sleep fragmentation.
2. Optogenetic activation of VENs during fragmented sleep will rescue:
   • TFEB nuclear localization and lysosomal acidification markers in downstream neurons.
   • Glymphatic flow velocity to baseline levels, despite ongoing sleep disruption.
   • Cognitive performance in the novel object recognition test, preventing the decline seen in fragmentation‑only controls.
3. Human translational marker: In patients with insomnia or obstructive sleep apnea, PET‑derived TSPO binding (neuroinflammation) will correlate positively with reduced VEN density (derived from post‑mortem MRI‑histology atlases) and negatively with CSF Aβ42 clearance rates measured via lumbar puncture.

Falsifiability

If VEN manipulation does not alter either autophagosome‑lysosome flux or glymphatic CSF dynamics, or if rescuing VEN activity fails to mitigate toxin accumulation and cognitive decline under sleep fragmentation, the hypothesis would be falsified. Conversely, observing the predicted bidirectional effects would support the model that VENs serve as a sleep‑dependent triage hub linking intracellular autophagy to extracellular waste clearance.