Non-associative learning in intra-cellular signaling networks

TL;DR

This paper studies how the MAPK signaling cascade in cells exhibits adaptive behaviors like habituation and sensitization when repeatedly stimulated, revealing complex dynamics similar to excitable systems.

Contribution

It demonstrates that intra-cellular signaling networks can show non-associative learning behaviors and complex adaptive responses to periodic stimuli.

Findings

The MAPK cascade exhibits habituation and sensitization depending on stimulus frequency.

The cascade shows a response threshold and refractory behavior.

Under certain conditions, the response resembles excitable media phenomena.

Abstract

Nonlinear systems driven by recurrent signals are known to exhibit complex dynamical responses which, in the physiological context, can have important functional consequences. One of the simplest biological systems that is exposed to such repeated stimuli is the intra-cellular signaling network. In this paper we investigate the periodic activation of an evolutionarily conserved motif of this network, viz., the mitogen-activated protein kinase (MAPK) signaling cascade, with a train of pulses. The resulting response of the cascade, which shows integrative capability over several successive pulses, is characterized by complex adaptive behavior. These include aspects of non-associative learning, in particular, habituation and sensitization, which are observed in response to high- and low-frequency stimulation, respectively. In addition, the existence of a response threshold of the cascade, an apparent refractory behavior following stimulation with short inter-pulse interval, and an alternans-like response under certain conditions suggest an analogy with excitable media.