Hypothesis

We propose that persistent mTORC1 activity in layer V anterior cingulate and insular von Economo neurons (VENs) converts these high‑metabolic‑demand projection cells from a ‘civilization’ mode that supports synchronized interoceptive‑social networks into a ‘survival’ mode dominated by autonomous growth and suppressed autophagy. This shift produces synaptic over‑connection, impaired protein turnover, and selective VEN vulnerability, manifesting as early deficits in social cognition and interoceptive awareness in aging and frontotemporal dementia.

Mechanistic Basis

• mTORC1 hyperactivation in ACC/insular pyramidal neurons drives p70S6K‑ and 4E‑BP1‑dependent synthesis of PSD‑95, GluA1, and NR2B, increasing AMPAR/NMDAR‑PSD‑95 colocalization and spine density (1).
• In VENs, which already exhibit elevated basal metabolic rates, this anabolic push outpaces autophagy‑mediated clearance, leading to accumulation of damaged mitochondria and aggregation‑prone proteins (e.g., tau) (2).
• Concurrently, mTORC2‑Akt signaling sustains cell‑surface growth factor receptors, further insulating VENs from nutrient‑sensing feedback that would normally trigger a survival‑mode downregulation of mTORC1 (3).
• The resulting electrophysiological phenotype features hyperexcitability and disrupted gamma‑band synchrony, undermining the VENs’ role as hubs for rapid interoceptive‑social integration (4).

Predictions & Experimental Design

1. Cell‑autonomous phenotype – In human PSC‑derived organoids enriched for ACC/insular VEN‑like neurons, CRISPR‑mediated Raptor knockout will reduce spine density (measured by DiI labeling) and restore LC3‑II autophagic flux without altering overall neuron survival.
2. Network consequence – Multi‑electrode array recordings will show decreased cross‑regional gamma coherence between VEN‑rich zones and neighboring pyramidal layers after Raptor loss, indicating weakened collective signaling.
3. In vivo validation – A VEN‑specific Cre line (e.g., Fezf2‑CreERT2) driving inducible Raptor knockdown in aged mice will preserve social interaction scores (three‑chamber test) and interoceptive accuracy (cutaneous‑stimulus detection) relative to controls, while rapamycin treatment yields comparable but less specific effects.
4. Molecular readout – Phospho‑S6 and p‑4EBP1 levels will drop in sorted VENs post‑knockout, accompanied by increased lysosomal cathepsin activity and reduced p‑tau immunoreactivity.

Potential Implications

If validated, this hypothesis reframes mTOR inhibition not merely as a longevity extension tool but as a strategy to preserve the ‘civilization’ function of uniquely human neurons. It suggests that cell‑type‑specific mTORC1 modulation could delay the socio‑emotional decline seen in neurodegenerative diseases, offering a mechanistic bridge between metabolic signaling, interoceptive neuroscience, and social cognition.