The "neural autopsy"—the active, sleep-dependent triage of synaptic architectures—is likely not an autonomous CNS process but one systemically licensed by the skeletal system. Specifically, the pulsatile release of undercarboxylated osteocalcin (Glu-OCN) during bone remodeling acts as a gating signal for the glymphatic-autophagic transition.

In this model, chronic sleep disruption or aging-related bone decay doesn't merely accumulate damage; rather, the lack of bone-derived Glu-OCN prevents the brain from "authorizing" the metabolic cost of neural pruning. As bone matrix crystallinity increases and HA crystals become more disordered with age increased carbonate substitution, the kinetic release of Glu-OCN is dampened. This leads to a failure in the nightly verdict of which neural structures deserve to persist and which should be cleared.

Mechanistic Reasoning: The GPR158-AQP4 Bridge

While research often focuses on Glu-OCN's role in rescuing cognitive decline via hippocampal GPR158 receptors, I suspect it has a more fundamental function: Metabolic Licensing.

1. Skeletal Pulsatility: Bone remodeling is highly circadian. The surge of Glu-OCN during the transition to NREM sleep serves as a systemic indicator of metabolic readiness.
2. Astroglial Polarization: Glu-OCN binding to GPR158 or related receptors on the perivascular endfeet of astrocytes triggers a signaling cascade that enhances Aquaporin-4 (AQP4) polarization. Without this skeletal signal, glymphatic flow remains sluggish, regardless of how long a person actually sleeps.
3. The Triage Verdict: Sleep-dependent autophagy—the "autopsy" of proteins and synapses—requires high-intensity waste removal. By linking this to bone turnover (the body's primary mineral reservoir), the organism ensures that large-scale neural editing only happens when systemic resources are stable.

The "Crystal Sequestration" Failure

In aging, the shift toward smaller, disordered HA crystals and the decrease in circulating Glu-OCN create a state of "skeletal-derived cognitive inertia." The brain is physically capable of sleep, but because the skeletal license (Glu-OCN) is missing, the glymphatic system never reaches the threshold for active triage. We aren't just losing memories; we're losing the ability to decide which ones to delete. This leads to a cluttered, dysfunctional neural architecture that I call "Skeletal Neuro-Congestion."

Testability and Falsification

We can test this hypothesis through several avenues:

• Pharmacological Manipulation: Increasing Glu-OCN levels via Vitamin K antagonism in aged mouse models should restore AQP4 polarization and glymphatic clearance rates to youthful levels, even if sleep duration and timing remain unchanged.
• Real-time Imaging: Using two-photon microscopy to observe glymphatic flux in Ocn−/− mice. If the hypothesis holds, these mice should show significant clearance deficits despite normal EEG-verified sleep.
• Correlation: Human studies could measure the ratio of carboxylated to undercarboxylated osteocalcin in CSF against markers of proteinopathy (p-Tau/Aβ42) across different bone density phenotypes.

If glymphatic flux is entirely independent of OCN-signaling, or if GPR158 is absent on glia-vasculature interfaces, the "Licensing" model is falsified. However, if bone is indeed the clock that times the brain's autopsy, we can't view osteoporosis and dementia as merely comorbid neighbors. They'd be the same systemic failure of the bone-brain clearance axis.