Phase shifts to light are altered by antagonists to neuropeptide receptors.

The mammalian circadian clock in the suprachiasmatic nucleus (SCN) is a heterogeneous structure. Two key populations of cells that receive retinal input and are believed to participate in circadian responses to light are cells that contain vasoactive intestinal polypeptide (VIP) and gastrin-releasing peptide (GRP). VIP acts primarily through the VPAC2 receptor, while GRP works primarily through the BB2 receptor. Both VIP and GRP phase shift the circadian clock in a manner similar to light when applied to the SCN, both in vivo and in vitro, indicating that they are sufficient to elicit photic-like phase shifts. However, it is not known if they are necessary signals for light to elicit phase shifts. Here we test the hypothesis that GRP and VIP are necessary signaling components for the photic phase shifting of the hamster circadian clock by examining two antagonists for each of these neuropeptides. The BB2 antagonist PD176252 had no effect on light-induced delays on its own, while the BB2 antagonist RC-3095 had the unexpected effect of significantly potentiating both phase delays and advances. Neither of the VIP antagonists ([d-p-Cl-Phe6, Leu17]-VIP, or PG99-465) altered phase shifting responses to light on their own. When the BB2 antagonist PD176252 and the VPAC2 antagonist PG99-465 were delivered together to the SCN, phase delays were significantly attenuated. These results indicate that photic phase shifting requires participation of either VIP or GRP; phase shifts to light are only impaired when signalling in both pathways are inhibited. Additionally, the unexpected potentiation of light-induced phase shifts by RC-3095 should be investigated further for potential chronobiotic applications.

Cognitive Test Performance in Relation to Health and Function in 12 European Countries: The SHARE Study.

BACKGROUND: Even subtle impairments on cognitive test scores can be associated with future cognitive decline and dementia. We assayed the relationships between test score impairment and adverse outcomes. METHODS: Secondary analyses were performed on data from non-institutionalized participants, 50+ years of age (N = 30,038), from 12 countries taking part in the Survey of Health, Ageing and Retirement in Europe (SHARE) longitudinal study on aging. At baseline, participants' cognition was tested using verbal fluency, immediate recall, and delayed recall tasks. RESULTS: Greater levels of cognitive impairment at baseline were strongly associated with future poor health outcomes and functional impairment. Controlling for age, sex and education, those with 1 (OR = 1.58, 95% CI = 1.34-1.87) or ≥ 2 (OR = 2.59, 95% CI = 2.17-3.09) impaired tests at baseline were more likely to die after an average of 40 months compared to individuals with no impairments. After selecting for participants who reported the absence of dementia initially, those with ≥ 2 cognitive impairments at baseline (OR = 3.34, 95% CI = 2.27-4.92) were more likely to report dementia at follow-up compared to those with no impairment. CONCLUSIONS: People with impaired cognitive test scores at baseline are at greater risk to die or develop dementia within four years than their less impaired or unimpaired counterparts.

Sleep disturbance in older ICU patients.

Maintaining a stable and adequate sleeping pattern is associated with good health and disease prevention. As a restorative process, sleep is important for supporting immune function and aiding the body in healing and recovery. Aging is associated with characteristic changes to sleep quantity and quality, which make it more difficult to adjust sleep-wake rhythms to changing environmental conditions. Sleep disturbance and abnormal sleep-wake cycles are commonly reported in seriously ill older patients in the intensive care unit (ICU). A combination of intrinsic and extrinsic factors appears to contribute to these disruptions. Little is known regarding the effect that sleep disturbance has on health status in the oldest of old (80+), a group, who with diminishing physiological reserve and increasing prevalence of frailty, is at a greater risk of adverse health outcomes, such as cognitive decline and mortality. Here we review how sleep is altered in the ICU, with particular attention to older patients, especially those aged ≥80 years. Further work is required to understand what impact sleep disturbance has on frailty levels and poor outcomes in older critically ill patients.

Phase delays to light and gastrin-releasing peptide require the protein kinase A pathway.

Daily photic resetting of the circadian system relies on the transmission of light information from the retina to retinorecipient cells within the ventrolateral suprachiasmatic nucleus (SCN) core, and subsequent activation of rhythmic clock cells in the dorsolateral region. Some neurochemicals such as gastrin-releasing peptide (GRP) mimic the phase shifting effects of light and induce Ca(2+)-dependent gene expression in the SCN. Activation of the cAMP-response element binding protein (CREB) is necessary for Ca(2+)-dependent transcription to occur and accompanies behavioral phase shifting; however, several biochemical cascades are involved in this phenomenon. One pathway that has been implicated in photic responses involves protein kinase A (PKA). It is not known if this pathway participates in mediating phase shifts to GRP. Here we show that preventing PKA activation attenuates both light- and GRP-induced phase shifts in locomotor behavior, but only during the early-subjective night. This finding demonstrates that activation of PKA is an important component in the photic signaling pathway and may mediate GRP output signaling from the SCN core to the shell; however, this effect appears to be temporally dependent.

Sleep disturbance is associated with incident dementia and mortality.

People with Alzheimer' s disease (AD) commonly complain of sleep disturbances, which are seen in a wide variety of conditions that become more common in late life. It is not known whether sleep-related symptoms are associated with AD independently of their association with other illnesses. Secondary analyses of sleep-related measures collected through the Survey of Health, Ageing and Retirement in Europe (SHARE; i.e., sleeping problems, fatigue, taking sleeping medication, and trouble sleeping or a change in pattern) were conducted on those who reported the absence of AD or dementia at baseline. A 'sleep disturbance index' (SDI) using sleep-related measures was created and compared to a frailty index reflecting overall health status. Each sleep measure independently predicted self-reported AD or dementia and mortality within ~4 years. Combined, the SDI was associated with an increased risk of developing AD or dementia (OR= 1.23, 95%CI = 1.11-1.36) and mortality (OR = 1.18, 95% CI = 1.12-1.24), and remained a strong factor for dementia when overall health status was added to the risk model (p = 0.054). These findings indicate that sleep disturbance may exist prior to the manifestation of other typical symptoms observed in AD (e.g., memory loss). Sleep-related questions may be useful for screening individuals at risk for dementia and may allow for the earlier detection of AD at the preclinical stage.

Characterization of the 3xTg-AD mouse model of Alzheimer's disease: part 2. Behavioral and cognitive changes.

Alzheimer's disease (AD) is characterized by distinct behavioral and cognitive deficits that differ from those observed in normal aging. Transgenic models of AD are a promising tool in understanding the underlying mechanisms and cause of disease. The triple-transgenic mouse model of AD (3xTg-AD) is the only model to exhibit both Abeta and tau pathology that is characteristic of the human form. The present study characterized the performance of 3xTg-AD mice on several tasks measuring behavioral and cognitive ability. Aged 3xTg-AD females exhibited a higher level of fear and anxiety demonstrated by increased restlessness, startle responses, and freezing behaviors. No differences were observed in muscle strength and visuo-motor coordination. Understanding the behavioral manifestations that occur in this model of AD may aid in the early diagnosis and appropriate treatment of AD symptomology.

Characterization of the 3xTg-AD mouse model of Alzheimer's disease: part 1. Circadian changes.

Circadian disturbances, including a fragmented sleep-wake pattern and sundowning, are commonly reported early in the progression of Alzheimer's disease (AD). These changes are distinctly different from those observed in non-pathological aging. Transgenic models of AD are a promising tool in understanding the underlying mechanisms and cause of disease. A novel triple-transgenic model of AD, 3xTg-AD, is the only model to exhibit both Abeta and tau pathology, and mimic human AD. The present study characterized changes pertaining to circadian rhythmicity that occur prior to and post-AD pathology. Both male and female 3xTg-AD mice demonstrated alterations to their circadian pacemaker with decreased nocturnal behavior when compared to controls. Specifically, males showed greater locomotor activity during the day and shorter freerunning periods prior to the onset of AD-pathology, and females had a decrease in activity levels during their typical active phase. Both sexes did not differ in terms of their freerunning periods or photic phase shifting ability. A decrease in vasoactive intestinal polypeptide-containing and vasopressin-containing cells was observed in the suprachiasmatic nucleus of 3xTg-AD mice relative to controls. This study demonstrates that abnormalities in circadian rhythmicity in 3xTg-AD mice precede expected AD pathology. This suggests that human studies may wish to determine if similar circadian dysfunction is predictive of early-onset AD.

Investigating the role of substance P in photic responses of the circadian system: individual and combined actions with gastrin-releasing peptide.

The suprachiasmatic nucleus (SCN) contains the master mammalian circadian pacemaker. It is comprised of several phenotypically distinct cell groups, some of which are situated in the weakly rhythmic retinoresponsive ventrolateral region while others are found in the rhythmic, non-retinoresponsive dorsomedial region. The mechanism by which retinorecipient cells convey photic information to the dorsomedial clock cells is unclear. The ventrolateral SCN core contains a variety of cell phenotypes. Two neuropeptides, namely substance P (SP) and gastrin-releasing peptide (GRP) extensively colocalize with calbindin D28K, a marker for SCN cells that are strongly light-responsive. Previous studies have implicated these neuropeptides in photic phase shifting of the circadian system. The present study examines how these peptides interact to regulate photic responses of the circadian system. It was observed that 55.5 +/- 9.1% of SP cells colocalized GRP. SP did not enhance GRP-induced phase shifts in the early-subjective night, while it significantly attenuated GRP-induced phase shifts during the late-subjective night. SP induced significant phase shifts that did not resemble light in the early-subjective night, but was not necessary for light-induced phase shifts and Fos expression at this time. SP induced significant Fos expression only in the late subjective night. SP may not be a necessary component in the pathway(s) involved in photic phase shifting during the early-subjective night, but may modulate phase shifts during the late-subjective night. Distinct biochemical mechanisms that underlie behavioral phase shifts may account for the differences observed in the early- vs. late-subjective night.

Physiological responses of the circadian clock to acute light exposure at night.

Circadian rhythms in physiological, endocrine and metabolic functioning are controlled by a neural clock located in the suprachiasmatic nucleus (SCN). This structure is endogenously rhythmic and the phase of this rhythm can be reset by light information from the eye. A key feature of the SCN is that while it is a small structure containing on the order of about 20,000 cells, it is amazingly heterogeneous. It is likely that anatomical heterogeneity reflects an underlying functional heterogeneity. In this review, we examine the physiological responses of cells in the SCN to light stimuli that reset the phase of the circadian clock, highlighting where possible the spatial pattern of such responses. Increases in intracellular calcium are an important signal in response to light, and this increase triggers many biochemical cascades that mediate responses to light. Furthermore, only some cells in the SCN are actually endogenously rhythmic, and these cells likely do not receive strong direct input from the retina. Therefore, this review also considers how light information is conveyed from the retinorecipient cells to the endogenously rhythmic cells that track circadian phase. A number of neuropeptides, including vasoactive intestinal polypeptide, gastrin-releasing peptide and substance P, may be particularly important in relaying such signals, but other neurochemicals such as GABA and nitric oxide may participate as well. A thorough understanding of the intracellular and intercellular responses to light, as well as the spatial arrangements of such responses may help identify important pharmacological targets for therapeutic interventions to treat sleep and circadian disorders.

Non-photic phase shifting of the circadian clock: role of the extracellular signal-responsive kinases I/II/mitogen-activated protein kinase pathway.

The master circadian clock, located in the suprachiasmatic nucleus (SCN), is synchronized to the external world primarily through exposure to light. A second class of stimuli based on arousal or activity can also reset the hamster circadian clock in a manner distinct from light. The mechanism underlying these non-photic phase shifts is unknown, although suppression of canonical clock genes and immediate early genes has been implicated. Recently, suppression of one of the mitogen-activated protein kinases (MAPK), namely extracellular signal-responsive kinases I/II (ERK), has been implicated in phase shifts to dark pulses, a stimulus with both photic and non-photic components. We investigated the involvement of the ERK/MAPK pathway in phase shifts in response to 3 h of sleep deprivation initiated at mid-day. About three-quarters of animals subjected to this procedure demonstrated large phase advances of about 3 h. Those that shifted exhibited a significant decrease in phosphorylated ERK (p-ERK) in the SCN. Those animals that were perfused during the sleep deprivation also exhibited immunoreactivity for p-ERK in a distinct portion of the ventrolateral SCN. Finally, injections of U0126 to the SCN to prevent phosphorylation of ERK significantly decreased levels of p-ERK but did not produce phase shifts. These data demonstrate that a purely non-photic manipulation is able to alter the activity of the MAPK pathway in the SCN, with downregulation in the SCN shell and activation in a portion of the SCN core.

Non-photic modulation of phase shifts to long light pulses.

Circadian rhythms can be reset by both photic and non-photic stimuli. Recent studies have used long light exposure to produce photic phase shifts or to enhance non-photic phase shifts. The presence or absence of light can also influence the expression of locomotor rhythms through masking; light during the night attenuates locomotor activity, while darkness during the day induces locomotor activity in nocturnal animals. Given this dual role of light, the current study was designed to examine the relative contributions of photic and non-photic components present in a long light pulse paradigm. Mice entrained to a light/dark cycle were exposed to light pulses of various durations (0, 3, 6, 9, or 12 h) starting at the time of lights-off. After the light exposure, animals were placed in DD and were either left undisturbed in their home cages or had their wheels locked for the remainder of the subjective night and subsequent subjective day. Light treatments of 6, 9, and 12 h produced large phase delays. These treatments were associated with decreased activity during the nocturnal light and increased activity during the initial hours of darkness following light exposure. When the wheels were locked to prevent high-amplitude activity, the resulting phase delays to the light were significantly attenuated, suggesting that the activity following the light exposure may have contributed to the overall phase shift. In a second experiment, telemetry probes were used to assess what effect permanently locking the wheels had on the phase shift to the long light pulses. These animals had phase shifts fully as large as animals without any form of wheel lock, suggesting that while non-photic events can modulate photic phase shifts, they do not play a role in the full phase-shift response observed in animals exposed to long light pulses. This paradigm will facilitate investigations into non-photic responses of the mouse circadian system.

An inverse relationship between typical alcohol consumption and facial symmetry detection ability in young women.

The relationship between monthly alcohol consumption over the past 6 months and facial symmetry perception ability was examined in young sober women with typical college-age drinking patterns. Facial symmetry detection performance was inversely related to typical monthly alcohol consumption, r (41) = -0.57, p < 0.001. Other variables that were predictive of facial symmetry detection included alcohol-related hangover and blackout frequency over the past 6 months, number of alcoholic drinks over the past week, early adolescent alcohol consumption and frequency of drug use. The relationship between alcohol use and symmetry detection could not be explained by individual differences in personality, family alcoholism history or other drug use. These findings suggest the possibility of a neurotoxic effect of alcohol on facial symmetry perception ability in female undergraduate students. As similar results did not emerge for a test of dot symmetry detection, the findings appear specific to facial symmetry. No previous studies have examined the effect of alcohol history on symmetry detection. The findings add to a growing literature indicating negative visuospatial effects of early alcohol use, and suggest the importance of further research examining alcohol and drug effects on sober facial perception in non-alcoholic populations.