Hypothesis

Aging‑related network rigidity stems from circadian‑driven calcium dyshomeostasis that biases synaptic plasticity toward long‑term depression (LTD) and impairs late‑phase long‑term potentiation (LTP), leading to dedifferentiated functional networks. Restoring robust circadian rhythms via timed bright‑light exposure will normalize L‑type calcium channel activity, rebalance the LTP/LTD threshold, and rescue modular connectivity.

Mechanistic Rationale

• Calcium influx through L‑type channels rises with age, shifting the plasticity threshold toward LTD (Calcium dyshomeostasis shifts plasticity thresholds via elevated influx).
• Circadian clocks regulate expression of L‑type channel subunits and calcium‑buffering proteins; disruption amplifies this influx (Circadian regulation of calcium channels).
• Elevated LTD weakens synaptic strength in hippocampal‑cortical pathways, reducing intra‑network connectivity while compensatory cross‑talk increases, producing the observed dedifferentiation (Network dedifferentiation in aging).
• Strong circadian signaling boosts cAMP/CREB pathways that support late‑phase LTP and synaptic protein synthesis, counteracting maintenance failures (cAMP/CREB in memory maintenance).

Predictions

1. Older adults exposed to 30 min of 10 000 lux blue-enriched light at subjective morning will show reduced L‑type calcium channel‑mediated calcium transients in peripheral blood mononuclear cells compared with dim‑light controls.
2. The same group will exhibit increased late‑phase LTP‑like indices (measured via paired‑associative stimulation paired with EEG) and decreased LTD‑like indices after two weeks.
3. Resting‑state fMRI will reveal increased modularity (higher Q‑score) and decreased between‑network integration, correlating with improved performance on surprise‑sensitive tasks (e.g., oddball detection).
4. If calcium channel blockade (e.g., oral verapamil low dose) mimics the light effect, then the circadian mechanism is calcium‑dependent.

Experimental Design

• Recruit 120 participants aged 60‑80, randomize to (a) morning bright‑light, (b) evening dim‑light control, (c) bright‑light + verapamil, (d) verapamil alone for 14 days.
• Pre‑ and post‑intervention assessments: serum calcium flux assay (Fluo‑4), TMS‑EEG plasticity protocols, resting‑state fMRI, cognitive battery (processing speed, surprise‑based learning).
• Statistical plan: mixed‑effects models testing interaction between time and group; falsifiability criterion – no significant change in LTP/LTD indices or network modularity in the bright‑light group versus control rejects the hypothesis.

Significance

If confirmed, this would re‑frame cognitive aging as a reversible state of circadian‑gated calcium maladynamics rather than irreversible over‑consolidation, offering a non‑pharmacological route to restore adaptive surprise tolerance.