Elizabeth M. Harrison

REM, not incubation, improves creativity by priming associative networks

The hypothesized role of rapid eye movement (REM) sleep, which is rich in dreams, in the formation of new associations, has remained anecdotal. We examined the role of REM on creative problem solving, with the Remote Associates Test (RAT). Using a nap paradigm, we manipulated various conditions of prior exposure to elements of a creative problem. Compared with quiet rest and non-REM sleep, REM enhanced the formation of associative networks and the integration of unassociated information. Furthermore, these REM sleep benefits were not the result of an improved memory for the primed items. This study shows that compared with quiet rest and non-REM sleep, REM enhances the integration of unassociated information for creative problem solving, a process, we hypothesize, that is facilitated by cholinergic and noradrenergic neuromodulation during REM sleep.

Sleep deprivation and Pavlovian fear conditioning.

Sleep has been suggested to play a role in memory consolidation. Prior rodent studies have used sleep deprivation to examine this relationship. First, we reexamined the effects of sleep deprivation on Pavlovian fear conditioning. We found that the deprivation method itself (i.e., gentle handling) induced deficits independent of sleep. Second, we examined an alternative method of sleep deprivation using amphetamine and found that this method failed to induce amnesia. These data indicate that sleep deprivation is a problematic way to examine the role of sleep in memory consolidation, and an alternative paradigm is proposed.

Implementation of Sleep and Circadian Science: Recommendations from the Sleep Research Society and National Institutes of Health Workshop.

Sairam Parthasarathy, MD1; Mary A. Carskadon, PhD2,3; Girardin Jean-Louis, PhD4; Judith Owens, MD, MPH5; Adam Bramoweth, PhD6; Daniel Combs, MD1; Lauren Hale, PhD7; Elizabeth Harrison, PhD8; Chantelle N. Hart, PhD9; Brant P. Hasler, PhD10; Sarah M. Honaker, PhD, CBSM11; Elisabeth Hertenstein, PhD12; Samuel Kuna, MD13; Clete Kushida, MD, PhD14; Jessica C. Levenson, PhD10; Caitlin Murray, MA15; Allan I. Pack, MD, PhD13; Vivek Pillai, PhD16; Kristi Pruiksma, PhD17; Azizi Seixas, PhD4; Patrick Strollo, MD18; Saurabh S. Thosar, PhD19; Natasha Williams, MD4; Daniel Buysse, MD6

Changing the Waveform of Circadian Rhythms: Considerations for Shift-Work

Circadian disruption in shift-work is common and has deleterious effects on health and performance. Current efforts to mitigate these harms reasonably focus on the phase of the circadian pacemaker, which unfortunately in humans, shifts slowly and often incompletely. Temporal reorganization of rhythmic waveform (i.e., the shape of its 24 h oscillation), rather than phase, however, may better match performance demands of shift-workers and can be quickly and feasibly implemented in animals. In fact, a bifurcated pacemaker waveform may permit stable entrainment of a bimodal sleep/wake rhythm promoting alertness in both night and daylight hours. Although bifurcation has yet to be formally assessed in humans, evidence of conserved properties of circadian organization and plasticity predict its occurrence: humans respond to conventional manipulations of waveform (e.g., photoperiodism); behaviorally, the sleep/wake rhythm is adaptable; and finally, the human circadian system likely derives from the same multiple cellular oscillators that permit waveform flexibility in the rodent pacemaker. In short, investigation into untried manipulations of waveform in humans to facilitate adjustment to challenging schedules is justified.

The effect of narrowband 500 nm light on daytime sleep in humans

Naps frequently take place during the daytime under some ambient light. People are commonly advised to wear eyeshades, or use black-out curtains while sleeping, as light is thought to inhibit sleep. Little is known, however, about how light during daytime sleep may affect the quality or architecture of that sleep. The present within-subjects design administered green narrowband light via light masks to 17 young adults (23.2 ± 4.7 years) during four 90-minute afternoon naps. Subjects were exposed to each of four light conditions that approximate the intensity of 1) physiological darkness (~0 lx), 2) moonlight (~1 lx), 3) typical indoor lighting (~80 lx) and 4) indirect outdoor light (~6400 lx). All subjects were able to sleep in all lighting conditions, with no differences in sleep quality or architecture. Power analysis revealed sufficient power to detect meaningful differences. Sleep inertia measured upon waking showed a general effect of the nap, independent of condition. Although light has various alerting effects at night, 500 nm LED light presented via light mask does not appear to inhibit daytime sleep. The finding that this light had no effect on the ability of individuals to fall asleep or stay asleep during an afternoon nap may inform decisions regarding the use of the nap as a facilitator of schedule adjustment, and challenges the assumption of light as a barrier to napping.

Rapid Adjustment of Circadian Clocks to Simulated Travel to Time Zones across the Globe.

Daily rhythms in mammalian physiology and behavior are generated by a central pacemaker located in the hypothalamic suprachiasmatic nuclei (SCN), the timing of which is set by light from the environment. When the ambient light-dark cycle is shifted, as occurs with travel across time zones, the SCN and its output rhythms must reset or re-entrain their phases to match the new schedule—a sluggish process requiring about 1 day per hour shift. Using a global assay of circadian resetting to 6 equidistant time-zone meridians, we document this characteristically slow and distance-dependent resetting of Syrian hamsters under typical laboratory lighting conditions, which mimic summer day lengths. The circadian pacemaker, however, is additionally entrainable with respect to its waveform (i.e., the shape of the 24-h oscillation) allowing for tracking of seasonally varying day lengths. We here demonstrate an unprecedented, light exposure–based acceleration in phase resetting following 2 manipulations of circadian waveform. Adaptation of circadian waveforms to long winter nights (8 h light, 16 h dark) doubled the shift response in the first 3 days after the shift. Moreover, a bifurcated waveform induced by exposure to a novel 24-h light-dark-light-dark cycle permitted nearly instant resetting to phase shifts from 4 to 12 h in magnitude, representing a 71% reduction in the mismatch between the activity rhythm and the new photocycle. Thus, a marked enhancement of phase shifting can be induced via nonpharmacological, noninvasive manipulation of the circadian pacemaker waveform in a model species for mammalian circadian rhythmicity. Given the evidence of conserved flexibility in the human pacemaker waveform, these findings raise the promise of flexible resetting applicable to circadian disruption in shift workers, frequent time-zone travelers, and any individual forced to adjust to challenging schedules.

Increased photic sensitivity for phase resetting but not melatonin suppression in Siberian hamsters under short photoperiods.

Light regulates a variety of behavioral and physiological processes, including activity rhythms and hormone secretory patterns. Seasonal changes in the proportion of light in a day (photoperiod) further modulate those functions. Recently, short (SP) versus long days (LP) were found to markedly increase light sensitivity for phase shifting in Syrian hamsters. To our knowledge, photoperiod effects on light sensitivity have not been studied in other rodents, nor is it known if they generalize to other circadian responses. We tested whether photic phase shifting and melatonin suppression vary in Siberian hamsters maintained under LP or SP. Select irradiances of light were administered, and shifts in activity were determined. Photic sensitivity for melatonin suppression was examined in a separate group of animals via pulses of light across a 4 log-unit photon density range, with post-pulse plasma melatonin levels determined via RIA. Phase shifting and melatonin suppression were greater at higher irradiances for both LP and SP. The lower irradiance condition was below threshold for phase shifts in LP but not SP. Melatonin suppression did not vary by photoperiod, and the half saturation constant for fitted sigmoid curves was similar under LP and SP. Thus, the photoperiodic modulation of light sensitivity for phase shifting is conserved across two hamster genera. The dissociation of photoperiod effects on photic phase shifting and melatonin suppression suggests that the modulation of sensitivity occurs downstream of the common retinal input pathway. Understanding the mechanistic basis for this plasticity may yield therapeutic targets for optimizing light therapy practices.

Extraordinary behavioral entrainment following circadian rhythm bifurcation in mice

The mammalian circadian timing system uses light to synchronize endogenously generated rhythms with the environmental day. Entrainment to schedules that deviate significantly from 24 h (T24) has been viewed as unlikely because the circadian pacemaker appears capable only of small, incremental responses to brief light exposures. Challenging this view, we demonstrate that simple manipulations of light alone induce extreme plasticity in the circadian system of mice. Firstly, exposure to dim nocturnal illumination (<0.1 lux), rather than completely dark nights, permits expression of an altered circadian waveform wherein mice in light/dark/light/dark (LDLD) cycles “bifurcate” their rhythms into two rest and activity intervals per 24 h. Secondly, this bifurcated state enables mice to adopt stable activity rhythms under 15 or 30 h days (LDLD T15/T30), well beyond conventional limits of entrainment. Continuation of dim light is unnecessary for T15/30 behavioral entrainment following bifurcation. Finally, neither dim light alone nor a shortened night is sufficient for the extraordinary entrainment observed under bifurcation. Thus, we demonstrate in a non-pharmacological, non-genetic manipulation that the circadian system is far more flexible than previously thought. These findings challenge the current conception of entrainment and its underlying principles, and reveal new potential targets for circadian interventions.

Circadian rhythm bifurcation induces flexible phase resetting by reducing circadian amplitude

Shift‐work and jet‐lag–related disorders are caused by the limited flexibility of the suprachiasmatic nucleus (SCN), a master circadian clock in the hypothalamus, to adjust to new light–dark (LD) cycles. Recent findings confirmed here establish that behavioral jet lag after simulated time‐zone travel is virtually eliminated following bifurcated circadian entrainment under a novel and atypical 24‐h light:dark:light:dark (LDLD) cycle. To investigate the mechanisms of this fast resetting, we examined the oscillatory stability of the SCN and peripheral tissues in LDLD‐bifurcated mice employing the dissection procedure as a perturbing resetting stimulus. SCN, lung, liver, and adrenal tissue were extracted at times throughout the day from female and male PER2::Luciferase knock‐in mice entrained to either LDLD or a normal LD cycle. Except for adrenals, the phase of the cultured explants was more strongly set by dissection under LDLD than under normal LD. Acute bioluminescence levels of SCN explants indicate that the rhythm amplitude of PER2 is reduced and phase is altered in LDLD. Real‐time quantitative PCR suggests that amplitude and rhythmicity of canonical clock genes in the lung, liver, and kidney are also significantly reduced in LDLD in vivo. Furthermore, spatiotemporal patterns of PER2 peak time in cultured SCN were altered in LDLD. These results suggest that altered gene expression patterns in the SCN caused by bifurcation likely result in fast resetting of behavior and cultured explants, consistent with previously reported mathematical models. Thus, non‐invasive, simple light manipulations can make circadian rhythms more adaptable to abrupt shifts in the environmental LD cycle.

Circadian waveform bifurcation, but not phase-shifting, leaves cued fear memory intact

In mammals, memory acquisition and retrieval can be affected by time of day, as well as by manipulations of the light/dark cycle. Under bifurcation, a manipulation of circadian waveform, two subjective days and nights are experimentally induced in rodents. We examined the effect of bifurcation on Pavlovian fear conditioning, a prominent model of learning and memory. Here we demonstrate that bifurcation of the circadian waveform produces a small deficit in acquisition, but not on retrieval of fear memory. In contrast, repeated phase-shifting in a simulated jet-lag protocol impairs retrieval of memory for cued fear. The results have implications for those attempting to adjust to shift-work or other challenging schedules.