Hypothesis

ECM over‑consolidation in the aged brain and obese adipose tissue creates a biomechanical feedback loop that suppresses surprise signaling through nuclear translocation of YAP/TAZ, locking neural circuits and adipocytes into a low‑plasticity state. Restoring matrix compliance re‑activates YAP/TAZ‑dependent transcription of surprise‑related genes (e.g., Nr4a1, Adipoq) and thereby reverses functional decline.

Mechanistic Basis

• In the aged hippocampus, increased perineuronal nets (PNNs) rich in aggrecan elevate tissue stiffness, engaging integrin‑β1 signaling that activates the Hippo effectors YAP/TAZ PNN stiffness integrin YAP. Nuclear YAP/TAZ drives expression of CSPG‑producing enzymes, reinforcing the matrix—a self‑reinforcing over‑consolidation loop.
• Parallelly, hypoxic, inflamed adipocytes deposit collagen VI, raising ECM rigidity and stimulating the same integrin‑YAP/TAZ axis Collagen VI HIF‑1 TGFβ. Activated YAP/TAZ suppresses adiponectin transcription and promotes profibrotic gene expression, further stiffening the niche.
• Both contexts share upstream HIF‑1 and TGF‑β activation HIF‑1 TGFβ ECM, which not only drives ECM synthesis but also primes YAP/TAZ nuclear retention by inhibiting LATS1/2 kinases.
• Nuclear YAP/TAZ suppresses surprise‑related transcriptional programs: in PV interneurons it represses Nr4a1, an immediate‑early gene linked to novelty detection; in adipocytes it represses Adipoq, reducing adiponectin‑mediated AMPK activation that normally signals metabolic surprise.

Thus, ECM over‑consolidation does not merely passively restrict plasticity; it actively reprograms cellular mechanotransduction to dampen surprise signaling, making the system overly confident in its internal model.

Testable Predictions

1. Pharmacological or genetic reduction of YAP/TAZ nuclear activity in aged hippocampal CA2 PV interneurons will decrease PNN‑associated CSPG expression and restore novelty‑induced Nr4a1 spikes, improving performance on surprise‑dependent memory tasks YAP knockdown memory.
2. Selective softening of adipose ECM via collagen VI‑targeting antibodies or LOX inhibition will decrease nuclear YAP/TAZ in adipocytes, increase adiponectin secretion, and improve insulin sensitivity in obese mice Collagen VI LOX adiponectin.
3. Dual‑tissue intervention (e.g., systemic low‑dose verteporfin to inhibit YAP/TAZ) will concurrently reduce hippocampal PNN density and adipose collagen VI deposition, yielding synergistic improvements in spatial memory and glucose tolerance beyond either tissue‑specific treatment alone.
4. Surprise signaling readouts—such as locus coeruleus norepinephrine release during unexpected stimuli or circulating adiponectin spikes after a glucose challenge—will be blunted in aged/obese animals with high nuclear YAP/TAZ and rescued when YAP/TAZ activity is curtailed.

Potential Interventions

• Repurpose FDA‑approved YAP/TAZ inhibitors (e.g., verteporfin) at low doses to modulate matrix stiffness without cytotoxic effects.
• Use adipose‑directed nanocarriers delivering siRNA against YAP to break the fibrosis‑surprise loop.
• Combine intermittent hypoxia‑reduction (e.g., CPAP for sleep apnea) with YAP/TAZ modulation to lower the HIF‑1/TGF‑β drive.

Falsifiability

If YAP/TAZ nuclear activity is not elevated in aged hippocampal PV interneurons or obese adipocytes, or if reducing YAP/TAZ fails to decrease ECM stiffness and restore surprise‑linked molecular markers, the hypothesis would be refuted.