Eating during the biological night is associated with nausea.

OBJECTIVES: This study assessed whether there was a time-of-day effect on nausea reports in participants during studies employing circadian protocols. METHODS: Visual-analog-scales of nausea ratings were recorded from 34 participants (18-70years; 18 women) during forced desynchrony studies, where meals were scheduled at different circadian phases. Subjective nausea reports from a further 81 participants (18-35years; 36 women) were recorded during constant routine studies, where they ate identical isocaloric hourly snacks for 36-40 hours. RESULTS: Feelings of nausea varied by circadian phase in the forced desynchrony studies, peaking during the biological night. Nausea during the constant routine was reported by 27% of participants, commencing 2.9 ± 5.2 hours after the midpoint of usual sleep timing, but was never reported to start in the evening (4-9 PM). CONCLUSIONS: Nausea occurred more often during the biological night and early morning hours. This timing is relevant to overnight and early morning shift workers and suggests that a strategy to counteract that is to pay careful attention to meal timing.

Circadian- and wake-dependent influences on face-name memory in healthy men and women over 3weeks of chronic sleep restriction.

OBJECTIVES: Facial recognition is one of the key functions of the human brain, and linking a face to a name is critical in many social and occupational settings. This study assessed circadian- and wake-dependent effects on face-name recognition in healthy adults. METHODS: Thirteen healthy adults (20-70years; 7 F) were studied in a 39-day inpatient protocol that included 3weeks of 28 hours forced desynchrony with sleep restriction (6.5:21.5 hours sleep:wake). Starting 3 hours after scheduled wake, 6 novel face-name pairs were presented every 4 waking hours; recognition was tested 2 hours later. Performance data were averaged across ∼4 hours circadian phase or time-awake bins. RESULTS: Face-name recognition deteriorated with increased time awake (p < .0001) and exhibited significant circadian variation (p < .0001), with worst performance shortly after the core temperature nadir. There was a significant interaction between sex and circadian phase (p = .0177), with women performing significantly better than men at all circadian phases except 60° and 120°. Women exhibited a significantly higher amplitude than men during the third week of forced desynchrony (p < .01). CONCLUSIONS: Like many other aspects of neurobehavioral performance, recalling face-name associations is impacted by both duration of time awake and circadian phase. These results have implications for face recognition testing in medical contexts, such as in testing for dementia, because performance may be impacted by sleep deficiency and the time of testing.

Desynchronizing the sleep---wake cycle from circadian timing to assess their separate contributions to physiology and behaviour and to estimate intrinsic circadian period.

Circadian clocks drive cyclic variations in many aspects of physiology, but some daily variations are evoked by periodic changes in the environment or sleep-wake state and associated behaviors, such as changes in posture, light levels, fasting or eating, rest or activity and social interactions; thus, it is often important to quantify the relative contributions of these factors. Yet, circadian rhythms and these evoked effects cannot be separated under typical 24-h day conditions, because circadian phase and the length of time awake or asleep co-vary. Nathaniel Kleitman's forced desynchrony (FD) protocol was designed to assess endogenous circadian rhythmicity and to separate circadian from evoked components of daily rhythms in multiple parameters. Under FD protocol conditions, light intensity is kept low to minimize its impact on the circadian pacemaker, and participants have sleep-wake state and associated behaviors scheduled to an imposed non-24-h cycle. The period of this imposed cycle, Τ, is chosen so that the circadian pacemaker cannot entrain to it and therefore continues to oscillate at its intrinsic period (τ, ~24.15 h), ensuring circadian components are separated from evoked components of daily rhythms. Here we provide detailed instructions and troubleshooting techniques on how to design, implement and analyze the data from an FD protocol. We provide two procedures: one with general guidance for designing an FD study and another with more precise instructions for replicating one of our previous FD studies. We discuss estimating circadian parameters and quantifying the separate contributions of circadian rhythmicity and the sleep-wake cycle, including statistical analysis procedures and an R package for conducting the non-orthogonal spectral analysis method that enables an accurate estimation of period, amplitude and phase.

Increased sleep duration and delayed sleep timing during the COVID-19 pandemic.

Many studies have examined how the 2019 Coronavirus Disease (COVID-19) has impacted sleep health. Early evidence suggests that lockdown policies worldwide have led to changes in sleep timing, duration, and quality; however, few studies have attempted to look at the longer-term effects across multiple countries in a large data set. This study uses self-reported data from 64,858 users of the Sleep As Android smartphone application from around the world over a 24-month period in 2019 to 2020. We found a significant but modest increase in time in bed (TIB), as well as a significant delay in sleep timing that was especially prominent on weekdays. While this effect persisted throughout the year, differences in sleep timing were more widespread and pronounced in the earlier months of the pandemic. We observed a small overall increase in TIB when comparing 2020 to 2019, but these changes depended on location and time of year, suggesting that sleep duration may have more closely tracked the progression of the pandemic in each country. Our findings suggest that pandemic-induced changes in lifestyle, such as remote work and lockdown policies, may have facilitated later sleep timing but that these changes may diminish as restrictions are lifted.

Impact of chronic sleep restriction on sleep continuity, sleep structure, and neurobehavioral performance.

Chronic sleep restriction (CSR) has been associated with adverse effects including cognitive impairment and increased risk of diabetes and cardiovascular disease. Yet, sleep restriction therapy is an essential component of most behavioral treatments for insomnia. Moreover, little is known about the impact of CSR on sleep continuity and structure in healthy people whose need for sleep is satiated. We investigated the impact of CSR on sleep continuity and structure in nine healthy participants. They had 4 nights of sleep extension, 2 nights of post-extension sleep, 21 nights of CSR (5/5.6-hour time-in-bed), and 9 nights of recovery sleep. Compared to postextension sleep, during CSR sleep duration was reduced by 95.4 ±â€…21.2 min per night, Slow-Wave Activity was significantly increased, and sleep was more consolidated. During recovery, sleep duration was increased by 103.3 ±â€…23.8 min compared to CSR, and the CSR-induced increase in Slow-Wave Activity persisted, particularly after the 5-hour exposure. Yet, we found that sustained vigilant attention was not fully recovered even after nine nights of recovery sleep. Our results suggest that CSR improves traditional metrics of sleep quality and may have a persistent impact on sleep depth, which is consistent with the reported benefits on sleep continuity and structure of sleep restriction therapy. However, these improvements in traditional metrics of sleep quality were associated with deterioration rather than improvement in neurobehavioral performance, demonstrating that sleep duration should be included in assessments of sleep quality. These results have implications for the long-term use of sleep restriction in the behavioral treatment of insomnia. Clinical Trial Registration: Impact of Chronic Circadian Disruption vs. Chronic Sleep Restriction on Metabolism (https://clinicaltrials.gov/ct2/show/; #NCT02171273).

Chronic circadian disruption on a high-fat diet impairs glucose tolerance.

BACKGROUND: Nearly 14% of Americans experience chronic circadian disruption due to shift work, increasing their risk of obesity, diabetes, and other cardiometabolic disorders. These disorders are also exacerbated by modern eating habits such as frequent snacking and consumption of high-fat foods. METHODS: We investigated the effects of recurrent circadian disruption (RCD) on glucose metabolism in C57BL/6 mice and in human participants exposed to non-24-h light-dark (LD) schedules vs. those on standard 24-h LD schedules. These LD schedules were designed to induce circadian misalignment between behaviors including rest/activity and fasting/eating with the output of the near-24-h central circadian pacemaker, while minimizing sleep loss, and were maintained for 12 weeks in mice and 3 weeks in humans. We examined interactions of these circadian-disrupted schedules compared to control 24-h schedules with a lower-fat diet (LFD, 13% in mouse and 25-27% in humans) and high-fat diet (HFD, 45% in mouse and 45-50% in humans). We also used young vs. older mice to determine whether they would respond differently to RCD. RESULTS: When combined with a HFD, we found that RCD caused significant weight gain in mice and increased body fat in humans, and significantly impaired glucose tolerance and insulin sensitivity in both mice and humans, but this did not occur when RCD was combined with a LFD. This effect was similar in both young and older mice. CONCLUSION: These results in both humans and a model organism indicate that circadian disruption has an adverse effect on metabolism among individuals eating a high-fat Western-style diet, even in the absence of significant sleep loss, and suggest that reducing dietary fat may protect against the metabolic consequences of a lifestyle (such as shift work) that involves chronic circadian disruption.

Chronic Sleep Restriction While Minimizing Circadian Disruption Does Not Adversely Affect Glucose Tolerance.

Insufficient sleep, which has been shown to adversely affect metabolism, is generally associated with prolonged exposure to artificial light at night, a known circadian disruptor. There is growing evidence suggesting that circadian disruption adversely affects metabolism, yet few studies have attempted to evaluate the adverse metabolic effects of insufficient sleep while controlling for circadian disruption. We assessed postprandial glucose and insulin responses to a standard breakfast meal in healthy adults (n = 9) who underwent 3 weeks of chronic sleep restriction (CSR) in a 37-day inpatient study while minimizing circadian disruption by maintaining the same duration of light exposure each study day. We compared these results to findings from an earlier inpatient study which used a forced desynchrony (FD) protocol to assess the influence of 3 weeks of CSR combined with recurrent circadian disruption (RCD) on glycemic control in healthy adults (n = 21). CSR combined with RCD resulted in significantly elevated postprandial plasma glucose levels (p < 0.0001), while CSR with minimized circadian disruption had no adverse glycemic effects after 3 weeks of exposure (EXP). These results suggest that one mechanism by which sleep restriction impacts metabolism may be via concurrent circadian disruption.

Differential effect of sleep deprivation on place cell representations, sleep architecture, and memory in young and old mice.

Poor sleep quality is associated with age-related cognitive decline, and whether reversal of these alterations is possible is unknown. In this study, we report how sleep deprivation (SD) affects hippocampal representations, sleep patterns, and memory in young and old mice. After training in a hippocampus-dependent object-place recognition (OPR) task, control animals sleep ad libitum, although experimental animals undergo 5 h of SD, followed by recovery sleep. Young controls and old SD mice exhibit successful OPR memory, whereas young SD and old control mice are impaired. Successful performance is associated with two cellular phenotypes: (1) "context" cells, which remain stable throughout training and testing, and (2) "object configuration" cells, which remap when objects are introduced to the context and during testing. Additionally, effective memory correlates with spindle counts during non-rapid eye movement (NREM)/rapid eye movement (REM) sigma transitions. These results suggest SD may serve to ameliorate age-related memory deficits and allow hippocampal representations to adapt to changing environments.

Google Trends reveals increases in internet searches for insomnia during the 2019 coronavirus disease (COVID-19) global pandemic.

STUDY OBJECTIVES: The 2019 coronavirus disease (COVID-19) has become a global health and economic crisis. Recent evidence from small samples suggest that it has increased mood and sleep disturbances, including insomnia, around the world. This study aimed to estimate the effect of COVID-19 on insomnia levels worldwide and in the United States during the acute phase of the pandemic. METHODS: We analyzed search query data recorded between January 2004 and May 2020 from Google Trends and Google Keyword Planner for the search term "insomnia". RESULTS: The number of search queries for insomnia has increased over the past decade and is greater than the number of search queries for other major sleep disorders. The COVID-19 pandemic increased search queries for insomnia both worldwide and in the United States, with the number in the United States increasing by 58% during the first 5 months of 2020 compared with the same months from the previous 3 years. There is a robust diurnal pattern in insomnia search queries in the United States, with the number of queries peaking around 3 am and the overall pattern remaining stable during the pandemic. CONCLUSIONS: These results highlight the impact the COVID-19 pandemic has had on sleep health and the urgent need for making effective interventions accessible. Future studies will be needed to determine whether the increase in insomnia symptoms will persist and lead to higher rates of chronic insomnia in the population.

Fasting blood triglycerides vary with circadian phase in both young and older people.

Daily rhythms in several physiological processes are important for cardiometabolic health. The lipid panel is used clinically to assess cardiovascular disease risk, but previous attempts to demonstrate circadian variation in lipids have failed to uncouple the endogenous circadian rhythm from the effects of meals and wake duration. Changes in basal lipid levels and dampening of circadian rhythms have been reported with aging, but it is unknown whether aging is also associated with changes in the rhythmic variation of lipids. We measured fasting lipid panels (triglycerides, total cholesterol, high-density lipoprotein, and low-density lipoprotein) in blood at wake time in 21 healthy adults using a specialized laboratory protocol that uncouples sleep-wake and activity-related effects from the endogenous circadian rhythm. Young and older adults exhibited endogenous circadian variations in fasting triglycerides, with both groups peaking in the early biological morning. Young adults also exhibited significant circadian rhythmicity in total cholesterol and low-density lipoprotein, while older adults did not exhibit circadian rhythmicity in any other lipids. These results reveal that triglyceride metabolism may be regulated by the central circadian pacemaker. Moreover, our findings may have clinical implications in assessing cardiovascular risk in shift workers and younger adults, since routine measurement of morning/fasting lipids may not fully and reliably assess triglyceride- and other lipid-related biomarkers of cardiovascular disease risk in these groups.

Human Resting Energy Expenditure Varies with Circadian Phase.

There is emerging evidence that circadian misalignment may alter energy expenditure, leading to obesity risk among those with irregular schedules [1-5]. It has been reported that energy expenditure is affected by the timing of sleep, exercise, and meals [6]. However, it is unclear whether the circadian system also modulates energy expenditure, independent of behavioral state and food intake. Here, we used a forced desynchrony protocol to examine whether fasted resting energy expenditure (REE) varies with circadian phase in seven participants. This protocol allowed us to uncouple sleep-wake and activity-related effects from the endogenous circadian rhythm, demonstrating that REE varies by circadian phase. REE is lowest at circadian phase ∼0°, corresponding to the endogenous core body temperature (CBT) nadir in the late biological night, and highest at circadian phase ∼180° in the biological afternoon and evening. Furthermore, we found that respiratory quotient (RQ), reflecting macronutrient utilization, also varies by circadian phase. RQ is lowest at circadian phase ∼240° and highest at circadian phase ∼60°, which corresponds to biological morning. This is the first characterization of a circadian profile in fasted resting energy expenditure and fasted respiratory quotient (with rhythmic profiles in both carbohydrate and lipid oxidation), decoupled from effects of activity, sleep-wake cycle, and diet in humans. The rhythm in energy expenditure and macronutrient metabolism may contribute to greater weight gain in shift workers and others with irregular schedules.

HDAC I inhibition in the dorsal and ventral hippocampus differentially modulates predator-odor fear learning and generalization.

Although predator odors are ethologically relevant stimuli for rodents, the molecular pathways and contribution of some brain regions involved in predator odor conditioning remain elusive. Inhibition of histone deacetylases (HDACs) in the dorsal hippocampus has been shown to enhance shock-induced contextual fear learning, but it is unknown if HDACs have differential effects along the dorso-ventral hippocampal axis during predator odor fear learning. We injected MS-275, a class I HDAC inhibitor, bilaterally in the dorsal or ventral hippocampus of mice and found that it had no effects on innate anxiety in either region. We then assessed the effects of MS-275 at different stages of fear learning along the longitudinal hippocampal axis. Animals were injected with MS-275 or vehicle after context pre-exposure (pre-conditioning injections), when a representation of the context is first formed, or after exposure to coyote urine (post-conditioning injections), when the context becomes associated with predator odor. When MS-275 was administered after context pre-exposure, dorsally injected animals showed enhanced fear in the training context but were able to discriminate it from a neutral environment. Conversely, ventrally injected animals did not display enhanced learning in the training context but generalized the fear response to a neutral context. However, when MS-275 was administered after conditioning, there were no differences between the MS-275 and vehicle control groups in either the dorsal or ventral hippocampus. Surprisingly, all groups displayed generalization to a neutral context, suggesting that predator odor exposure followed by a mild stressor such as restraint leads to fear generalization. These results may elucidate distinct functions of the dorsal and ventral hippocampus in predator odor-induced fear conditioning as well as some of the molecular mechanisms underlying fear generalization.

Extinction of Learned Fear Induces Hippocampal Place Cell Remapping.

The extinction of learned fear is a hippocampus-dependent process thought to embody new learning rather than erasure of the original fear memory, although it is unknown how these competing contextual memories are represented in the hippocampus. We previously demonstrated that contextual fear conditioning results in hippocampal place cell remapping and long-term stabilization of novel representations. Here we report that extinction learning also induces place cell remapping in C57BL/6 mice. Specifically, we observed cells that preferentially remapped during different stages of learning. While some cells remapped in both fear conditioning and extinction, others responded predominantly during extinction, which may serve to modify previous representations as well as encode new safe associations. Additionally, we found cells that remapped primarily during fear conditioning, which could facilitate reacquisition of the original fear association. Moreover, we also observed cells that were stable throughout learning, which may serve to encode the static aspects of the environment. The short-term remapping observed during extinction was not found in animals that did not undergo fear conditioning, or when extinction was conducted outside of the conditioning context. Finally, conditioning and extinction produced an increase in spike phase locking to the theta and gamma frequencies. However, the degree of remapping seen during conditioning and extinction only correlated with gamma synchronization. Our results suggest that the extinction learning is a complex process that involves both modification of pre-existing memories and formation of new ones, and these traces coexist within the same hippocampal representation.

Precise spatial coding is preserved along the longitudinal hippocampal axis.

Compared with the dorsal hippocampus, relatively few studies have characterized neuronal responses in the ventral hippocampus. In particular, it is unclear whether and how cells in the ventral region represent space and/or respond to contextual changes. We recorded from dorsal and ventral CA1 neurons in freely moving mice exposed to manipulations of visuospatial and olfactory contexts. We found that ventral cells respond to alterations of the visuospatial environment such as exposure to novel local cues, cue rotations, and contextual expansion in similar ways to dorsal cells, with the exception of cue rotations. Furthermore, we found that ventral cells responded to odors much more strongly than dorsal cells, particularly to odors of high valence. Similar to earlier studies recording from the ventral hippocampus in CA3, we also found increased scaling of place cell field size along the longitudinal hippocampal axis. Although the increase in place field size observed toward the ventral pole has previously been taken to suggest a decrease in spatial information coded by ventral place cells, we hypothesized that a change in spatial scaling could instead signal a shift in representational coding that preserves the resolution of spatial information. To explore this possibility, we examined population activity using principal component analysis (PCA) and neural location reconstruction techniques. Our results suggest that ventral populations encode a distributed representation of space, and that the resolution of spatial information at the population level is comparable to that of dorsal populations of similar size. Finally, through the use of neural network modeling, we suggest that the redundancy in spatial representation along the longitudinal hippocampal axis may allow the hippocampus to overcome the conflict between memory interference and generalization inherent in neural network memory. Our results indicate that ventral population activity is well suited for generalization across locations and contexts.

Differential roles of the dorsal and ventral hippocampus in predator odor contextual fear conditioning.

The study of fear memory is important for understanding various anxiety disorders in which patients experience persistent recollections of traumatic events. These memories often involve associations of contextual cues with aversive events; consequently, Pavlovian classical conditioning is commonly used to study contextual fear learning. The use of predator odor as a fearful stimulus in contextual fear conditioning has become increasingly important as an animal model of anxiety disorders. Innate fear responses to predator odors are well characterized and reliable; however, attempts to use these odors as unconditioned stimuli in fear conditioning paradigms have proven inconsistent. Here we characterize a contextual fear conditioning paradigm using coyote urine as the unconditioned stimulus. We found that contextual conditioning induced by exposure to coyote urine produces long-term freezing, a stereotypic response to fear observed in mice. This paradigm is context-specific and parallels shock-induced contextual conditioning in that it is responsive to extinction training and manipulations of predator odor intensity. Region-specific lesions of the dorsal and ventral hippocampus indicate that both areas are independently required for the long-term expression of learned fear. These results in conjunction with c-fos immunostaining data suggest that while both the dorsal and ventral hippocampus are required for forming a contextual representation, the ventral region also modulates defensive behaviors associated with predators. This study provides information about the individual contributions of the dorsal and ventral hippocampus to ethologically relevant fear learning.

Long-term stabilization of place cell remapping produced by a fearful experience.

Fear is an emotional response to danger that is highly conserved throughout evolution because it is critical for survival. Accordingly, episodic memory for fearful locations is widely studied using contextual fear conditioning, a hippocampus-dependent task (Kim and Fanselow, 1992; Phillips and LeDoux, 1992). The hippocampus has been implicated in episodic emotional memory and is thought to integrate emotional stimuli within a spatial framework. Physiological evidence supporting the role of the hippocampus in contextual fear indicates that pyramidal cells in this region, which fire in specific locations as an animal moves through an environment, shift their preferred firing locations shortly after the presentation of an aversive stimulus (Moita et al., 2004). However, the long-term physiological mechanisms through which emotional memories are encoded by the hippocampus are unknown. Here we show that during and directly after a fearful experience, new hippocampal representations are established and persist in the long term. We recorded from the same place cells in mouse hippocampal area CA1 over several days during predator odor contextual fear conditioning and found that a subset of cells changed their preferred firing locations in response to the fearful stimulus. Furthermore, the newly formed representations of the fearful context stabilized in the long term. Our results demonstrate that place cells respond to the presence of an aversive stimulus, modify their firing patterns during emotional learning, and stabilize a long-term spatial representation in response to a fearful encounter. The persistent nature of these representations may contribute to the enduring quality of emotional memories.