Mammalian Rest/Activity Patterns Explained by Physiologically Based Modeling

A J K Phillips,B D Fulcher,E B Klerman,P A Robinson

doi:10.1371/journal.pcbi.1003213

A J K Phillips, B D Fulcher + Show 2 more

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https://doi.org/10.1371/journal.pcbi.1003213

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Abstract

Circadian rhythms are fundamental to life. In mammals, these rhythms are generated by pacemaker neurons in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN is remarkably consistent in structure and function between species, yet mammalian rest/activity patterns are extremely diverse, including diurnal, nocturnal, and crepuscular behaviors. Two mechanisms have been proposed to account for this diversity: (i) modulation of SCN output by downstream nuclei, and (ii) direct effects of light on activity. These two mechanisms are difficult to disentangle experimentally and their respective roles remain unknown. To address this, we developed a computational model to simulate the two mechanisms and their influence on temporal niche. In our model, SCN output is relayed via the subparaventricular zone (SPZ) to the dorsomedial hypothalamus (DMH), and thence to ventrolateral preoptic nuclei (VLPO) and lateral hypothalamus (LHA). Using this model, we generated rich phenotypes that closely resemble experimental data. Modulation of SCN output at the SPZ was found to generate a full spectrum of diurnal-to-nocturnal phenotypes. Intriguingly, we also uncovered a novel mechanism for crepuscular behavior: if DMH/VLPO and DMH/LHA projections act cooperatively, daily activity is unimodal, but if they act competitively, activity can become bimodal. In addition, we successfully reproduced diurnal/nocturnal switching in the rodent Octodon degu using coordinated inversions in both masking and circadian modulation. Finally, the model correctly predicted the SCN lesion phenotype in squirrel monkeys: loss of circadian rhythmicity and emergence of ∼4-h sleep/wake cycles. In capturing these diverse phenotypes, the model provides a powerful new framework for understanding rest/activity patterns and relating them to underlying physiology. Given the ubiquitous effects of temporal organization on all aspects of animal behavior and physiology, this study sheds light on the physiological changes required to orchestrate adaptation to various temporal niches.

Highlights

Sleep recordings in 127 mammalian species [1] have revealed a rich array of phenotypes with respect to the temporal organization of rest/activity and sleep/wake patterns [2]
The Nocturnal-Diurnal Spectrum The lack of correspondence between suprachiasmatic nucleus (SCN) firing patterns and diurnal/nocturnal preference indicates that other mechanisms must be involved in determining temporal niche
We hypothesized that modulation of SCN output by the subparaventricular zone (SPZ) could account for the degree to which an animal is either diurnal or nocturnal

Summary

Introduction

Sleep recordings in 127 mammalian species [1] have revealed a rich array of phenotypes with respect to the temporal organization of rest/activity and sleep/wake patterns [2]. These phenotypic differences between species are thought to reflect evolutionary adaptations to specific temporal niches (the times at which an animal is usually active) [3]. Temporal niches span a continuum from diurnal (day-active) to cathemeral (no time-of-day preference) to nocturnal (night-active) [4]. Some rodents switch from diurnal to nocturnal in the laboratory when provided access to a running wheel [8,9,10]. Our goal is to develop a theoretical framework to compare these diverse phenotypes and quantitatively relate them to a small number of underlying physiological mechanisms

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