Forced Desynchronization of Activity Rhythms in a Model of Chronic Jet Lag in Mice

Abstract

We studied locomotor activity rhythms of C57/Bl6 mice under a chronic jet lag (CJL) protocol (ChrA(6/2) ), which consisted of 6-hour phase advances of the light-dark schedule (LD) every 2 days. Through periodogram analysis, we found 2 components of the activity rhythm: a short-period component (21.01 ± 0.04 h) that was entrained by the LD schedule and a long-period component (24.68 ± 0.26 h). We developed a mathematical model comprising 2 coupled circadian oscillators that was tested experimentally with different CJL schedules. Our simulations suggested that under CJL, the system behaves as if it were under a zeitgeber with a period determined by (24 - [phase shift size/days between shifts]). Desynchronization within the system arises according to whether this effective zeitgeber is inside or outside the range of entrainment of the oscillators. In this sense, ChrA(6/2) is interpreted as a (24 - 6/2 = 21 h) zeitgeber, and simulations predicted the behavior of mice under other CJL schedules with an effective 21-hour zeitgeber. Animals studied under an asymmetric T = 21 h zeitgeber (carried out by a 3-hour shortening of every dark phase) showed 2 activity components as observed under ChrA(6/2): an entrained short-period (21.01 ± 0.03 h) and a long-period component (23.93 ± 0.31 h). Internal desynchronization was lost when mice were subjected to 9-hour advances every 3 days, a possibility also contemplated by the simulations. Simulations also predicted that desynchronization should be less prevalent under delaying than under advancing CJL. Indeed, most mice subjected to 6-hour delay shifts every 2 days (an effective 27-hour zeitgeber) displayed a single entrained activity component (26.92 ± 0.11 h). Our results demonstrate that the disruption provoked by CJL schedules is not dependent on the phase-shift magnitude or the frequency of the shifts separately but on the combination of both, through its ratio and additionally on their absolute values. In this study, we present a novel model of forced desynchronization in mice under a specific CJL schedule; in addition, our model provides theoretical tools for the evaluation of circadian disruption under CJL conditions that are currently used in circadian research.

Effects of Circadian Disruption on Physiology and Pathology: From Bench to Clinic (and Back)

“…Indeed, either a delay (c) or an advance (d) of the LD cycle will impose a delaying or advancing light-input to the clock, respectively, which will gradually entrain to the new conditions. Finally, chronic jet lag schedules (e, f) or T-cycles outside the entrainment range (g, h) (see Casiraghi et al 2012), are used in the laboratory to study the circadian system under extreme entraining conditions. While the clock can entrain to gradual changes in the LD cycle, when animals are subjected to frequent phase advances of the LD cycle, relative coordination and/or forced desynchronization of behavioral rhythms can be observed described as follows: (a) permanent: people work regularly on one shift only, i.e.…”

“…In addition, we have developed a chronic jet lag schedule consisting of a 6 h LD-advance each two days, which generated a stable desynchronization of two activity components in mice (Casiraghi et al 2012) and exerted severe metabolic alterations (unpublished results). Moreover, animals under similar chronic jet lag protocols showed biphasic corticosterone rhythms (Filipski et al 2004), attenuated AVP and Pk2 expression in the SCN (Yan 2011), and alterations in PER2 expression rhythms in the SCN, thymus, and liver (Castañon-Cervantes et al 2010).…”

Sincronização fótica e não fótica dos ritmos circadianos em roedores subterrâneos (Ctenomys aff. knighti) e roedores modelo de laboratório (Mus musculus)

“…It has been shown that entrainment of a free-running circadian oscillator occurs only for a specific range of period and light intensity combinations of the light/dark cycle which set the "range of entrainment" (Abraham et al, 2010;Casiraghi et al, 2012;Granada et al, 2011). In our "random pulse" paradigm, we have fixed the period of the For a fixed light intensity L of 1,000 lux, entrainment was lost after I was gradually increased to 20 hours, as predicted by our computer simulations (Flôres et al, 2013).…”

“…Each day the light stimulus impinges a phase-shift on the oscillator, but the shift occurs only after transient slow changes in amplitude (Abraham et al, 2010;Casiraghi et al, 2012;Granada et al, 2011;Peterson, 1980). If the amplitude were instantly recovered our random pulse regimens would presumably cause equally random back and forth changes in the phase of the circadian oscillator, possibly failing to keep the phase stable within a 24-hour day.…”

Ritmos circadianos em Gracilaria birdiae (Rhodophyta): oscilação do desempenho fotossintético e caracterização enzimática da nitrato redutase

“…Não somente em organismos fotossintetizantes, mas para qualquer modelo tal conceito é essencial, um exemplo são as análises do comportamento de camundongos em rodas de exercício que registram ao longo de meses a frequência da atividade dos animais submetidos a diversas condições. (CASIRAGHI et al, 2012;VALENTINUZZI et al, 2009), utilizando o menor esforço possível do observador.…”