A functional analysis of circadian pacemakers in nocturnal rodents

Entrainment of the human circadian pacemaker to longer-than-24-h days

“…Note that both MEL on and MEL off phases were slightly delayed on CR3 compared with D2, D3, and CR1 (ANOVA, Student-Newman-Keuls, P Ͻ 0.0001). This change, which likely occurred in response to the phasedelaying effect of 5 days in 450 lux, is consistent with previous finding in animals (9,13) and humans (23), showing that the phase angle narrows with increased light intensities.…”

“…As shown both in nonhuman species (13,25) and humans (22,23), the phase angle of entrainment between the imposed T-cycle and the phase marker of an entrained rhythm is a function of the difference in their period [ ϭ f(T Ϫ )] and of the strength of the zeitgeber. Phase angle widens as T differs from , and narrows as zeitgeber strength increases (13). In our study, the difference in the period of T and was equal for each subject (1 h by protocol design).…”

“…Well described in animals (9)(10)(11) and only recently confirmed in humans (12), entrainment of the circadian system depends on (i) its intrinsic period ( ), (ii) the light:dark cycle to which it is exposed (T; T-cycle), and (iii) the strength of the entraining stimulus (zeitgeber, from German for "time giver"). The generally accepted nonparametric model of circadian entrainment predicts immediate phase shifting in response to light, according to a phase response curve (PRC) (3,9,13). In humans, for whom the intrinsic period is on average Ϸ24.2 h (14), entrainment to the solar day of earth (T ϭ 24 h) requires that the biological clock be ''reset'' by on average of Ϸ0.2 h per day in the advance direction.…”

“…At the individual level, persons with Ͻ 24 h require a daily phase delay (Ϫ⌬ ), whereas individuals with Ͼ 24 h require a daily advance (ϩ⌬ ) to synchronize to T ϭ 24 h. Entrainment is achieved when T ϭ Ϫ ⌬ with a stable phase relationship (or phase angle, ) between a phase marker for the synchronizing cycle (e.g., light offset) and a phase marker of the driven rhythm [e.g., melatonin onset (MEL on )]. In animals, there is a well known quantitative relationship between and T, such that generally widens as T differs from , and narrows when the strength of the zeitgeber increases (13). Additionally, the response to a resetting stimulus is correlated with , such that animals with short (fast pacemakers) tend to be more phase delayed and less phase advanced by light than animals with longer (slow pacemakers) (9).…”

Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules

“…I n mammals, the mechanism for the generation and entrainment of circadian rhythms resides in the hypothalamic suprachiasmatic nuclei (SCN), and the principal signal that adjusts this biological clock with environmental timing is the light-dark (LD) cycle (1,2). Light reaches the SCN through the retinohypothalamic tract and causes the release of neurotransmitters (glutamate and PACAP), which initiates a signal transduction cascade in SCN neurons that ultimately results in a phase shift of the circadian system (3)(4)(5)(6)(7)(8)(9).…”