Hypothesis

Age-related interoceptive decline results not from loss of Von Economo neurons (VENs) but from excessive perineuronal net (PNN) deposition around these cells in the anterior insula, which locks their synaptic output into a high‑confidence, low‑surprise mode. Consequently, the interoceptive system over‑predicts bodily states and fails to update predictions when novel visceral signals arrive, manifesting as diminished interoceptive accuracy and reduced behavioral flexibility in older adults.

Mechanistic Basis

VENs express high levels of extracellular matrix‑binding proteoglycans such as aggrecan and link protein, making them preferential substrates for PNN scaffolding. With age, chondroitin sulfate proteoglycans accumulate 67‑117% around parvalbumin‑positive interneurons in hippocampal and subcortical circuits, and a similar trend occurs in agranular insular layers where VENs reside 3. The dense PNN mesh restricts lateral diffusion of AMPA receptors and reduces activity‑dependent insertion of GABA_A receptors, shifting the excitation/inhibition balance toward sustained depolarization. This depolarized state drives homeostatic downregulation of KCC2, elevating intracellular chloride and converting GABAergic signaling from inhibitory to excitatory, thereby reinforcing a rigid, high‑gain mapping of interoceptive input 4. Because VEN numbers remain stable across the lifespan 5, the functional deficit arises from altered synaptic dynamics rather than cell loss.

Testable Predictions

1. In aged rodents, enzymatic degradation of PNNs in the anterior insula using chondroitinase ABC will increase VEN‑associated spontaneous excitatory postsynaptic current variance without changing VEN density.
2. Animals receiving anterior insula chondroitinase ABC will show improved performance on interoceptive discrimination tasks (e.g., heartbeat detection analog) and greater behavioral flexibility in reversal learning, whereas control‑treated aged animals will not.
3. Younger animals treated with chondroitinase ABC will not display further interoceptive enhancement, indicating a ceiling effect tied to baseline PNN levels.
4. Pharmacological blockade of KCC2 in young animals will mimic the aged interoceptive phenotype, and this effect will be occluded by prior PNN degradation.

Potential Falsification

If chondroitinase ABC application to the anterior insula fails to alter VEN electrophysiological variability, does not improve interoceptive task accuracy, or does not rescue reversal learning deficits in aged subjects, the hypothesis that PNN‑mediated VEN rigidity underlies age‑related interoceptive decline would be falsified. Conversely, a rescue of function without changes in VEN count would support the mechanism.