Interlinked Dual-Time Feedback Loops can Enhance Robustness to Stochasticity and Persistence of Memory

TL;DR

This study shows that interlinked dual-time feedback loops in biochemical systems improve response speed, robustness to noise, and memory persistence, with implications for long-term synaptic potentiation.

Contribution

It demonstrates that dual-time feedback loops confer noise resistance and response robustness, extending previous models to include long-term synaptic potentiation mechanisms.

Findings

Dual-time feedback loops enhance noise resistance.

Fast response and memory stability are maintained with altered coupling.

Model suggests increased kinases contribute to LTP resistance.

Abstract

Multiple interlinked positive feedback loops shape the stimulus responses of various biochemical systems, such as the cell cycle or intracellular calcium release. Recent studies with simplified models have identified two advantages of coupling fast and slow feedback loops. Namely, this dual-time structure enables a fast response while enhancing resistances of responses and bistability to stimulus noise. We now find that in addition: 1) the dual-time structure confers resistance to internal noise due to molecule number fluctuations, and 2) model variants with altered coupling, which better represent some specific systems, share all the above advantages. We develop a similar bistable model with a fast autoactivation loop coupled to a slow loop, which minimally represents positive feedback that may be essential for long-term synaptic potentiation (LTP). The advantages of fast response and noise resistance carry over to this model. Empirically, LTP develops resistance to reversal over ~1 h. The model suggests this resistance may result from increased amounts of synaptic kinases involved in positive feedback.