Central and Peripheral Clock Control of Circadian Feeding Rhythms.

Many behaviors exhibit ~24-h oscillations under control of an endogenous circadian timing system that tracks time of day via a molecular circadian clock. In the fruit fly, Drosophila melanogaster, most circadian research has focused on the generation of locomotor activity rhythms, but a fundamental question is how the circadian clock orchestrates multiple distinct behavioral outputs. Here, we have investigated the cells and circuits mediating circadian control of feeding behavior. Using an array of genetic tools, we show that, as is the case for locomotor activity rhythms, the presence of feeding rhythms requires molecular clock function in the ventrolateral clock neurons of the central brain. We further demonstrate that the speed of molecular clock oscillations in these neurons dictates the free-running period length of feeding rhythms. In contrast to the effects observed with central clock cell manipulations, we show that genetic abrogation of the molecular clock in the fat body, a peripheral metabolic tissue, is without effect on feeding behavior. Interestingly, we find that molecular clocks in the brain and fat body of control flies gradually grow out of phase with one another under free-running conditions, likely due to a long endogenous period of the fat body clock. Under these conditions, the period of feeding rhythms tracks with molecular oscillations in central brain clock cells, consistent with a primary role of the brain clock in dictating the timing of feeding behavior. Finally, despite a lack of effect of fat body selective manipulations, we find that flies with simultaneous disruption of molecular clocks in multiple peripheral tissues (but with intact central clocks) exhibit decreased feeding rhythm strength and reduced overall food intake. We conclude that both central and peripheral clocks contribute to the regulation of feeding rhythms, with a particularly dominant, pacemaker role for specific populations of central brain clock cells.

A circadian output center controlling feeding:fasting rhythms in Drosophila.

Circadian rhythms allow animals to coordinate behavioral and physiological processes with respect to one another and to synchronize these processes to external environmental cycles. In most animals, circadian rhythms are produced by core clock neurons in the brain that generate and transmit time-of-day signals to downstream tissues, driving overt rhythms. The neuronal pathways controlling clock outputs, however, are not well understood. Furthermore, it is unclear how the central clock modulates multiple distinct circadian outputs. Identifying the cellular components and neuronal circuitry underlying circadian regulation is increasingly recognized as a critical step in the effort to address health pathologies linked to circadian disruption, including heart disease and metabolic disorders. Here, building on the conserved components of circadian and metabolic systems in mammals and Drosophila melanogaster, we used a recently developed feeding monitor to characterize the contribution to circadian feeding rhythms of two key neuronal populations in the Drosophila pars intercerebralis (PI), which is functionally homologous to the mammalian hypothalamus. We demonstrate that thermogenetic manipulations of PI neurons expressing the neuropeptide SIFamide (SIFa) as well as mutations of the SIFa gene degrade feeding:fasting rhythms. In contrast, manipulations of a nearby population of PI neurons that express the Drosophila insulin-like peptides (DILPs) affect total food consumption but leave feeding rhythms intact. The distinct contribution of these two PI cell populations to feeding is accompanied by vastly different neuronal connectivity as determined by trans-Tango synaptic mapping. These results for the first time identify a non-clock cell neuronal population in Drosophila that regulates feeding rhythms and furthermore demonstrate dissociable control of circadian and homeostatic aspects of feeding regulation by molecularly-defined neurons in a putative circadian output hub.

The longitudinal impact of diet, physical activity, sleep, and screen time on Canadian adolescents' academic achievement: An analysis from the COMPASS study.

Adequate amounts of physical activity, sleep, and screen time along with a healthy diet have been demonstrated to have positive associations with academic achievement. No longitudinal study has investigated the simultaneous relationship between all of these behaviours and academic achievement. Data from 11,016 adolescent participants of the COMPASS study in Alberta and Ontario were analysed. Students self-reported their adherence to Canadian recommendations for health behaviours and academic achievement in Math and English on school-based surveys administered in the 2015/16 and 2016/17 waves of COMPASS. Multinomial generalized estimating equations were used to evaluate the association between longitudinal changes in adherence to recommendations and academic achievement at follow-up. Models were adjusted for self-reported sociodemographic information, body weight status, and baseline academic achievement. Students who adhered to a greater number of recommendations performed better than students who adhered to fewer recommendations. Meeting recommendations for Meat and Alternatives (protein-rich foods) and screen time were consistently associated with higher academic achievement compared to students who did not meet these recommendations. A change from not meeting recommendations for Vegetables and Fruit to meeting the recommendation in the following year was associated with higher achievement in both subjects. There was no association between sleep behaviours or physical activity and academic achievement. Results indicate that adherence to recommendations for protein-rich foods, screen time, and vegetables and fruit show promise as behavioural targets for higher academic achievement among youth. Further study using objectives measurements of behaviours and further consideration of socioeconomic variables is merited.

Physical activity, sedentary behaviour, and psychosocial well-being among young South Korean children.

OBJECTIVE: To examine associations between television (TV) viewing, reading, physical activity (PA), and psychosocial well-being among a representative sample of young South Korean children aged 0-5 years. METHODS: Findings are based on 1,774 children who participated in the Korea Children and Youth Survey. All measures were questionnaire-derived. Psychosocial well-being included social, interactive, and emotional skills (α = .7-.9), and the top quartile denoted high psychosocial well-being. Multiple logistic regressions were performed to examine relationships after controlling for several confounders. RESULTS: Compared to children who participated in PA for <1 hr/week, those who participated in PA for 1- <3 hr/week were more likely to show high emotional skills (odds ratio [OR]: 1.40, 95% confidence interval [CI] [1.02, 1.93]), and those who participated ≥3 hr/week were more likely to show high social (OR: 2.01, 95% CI [1.45, 2.78]) and interactive skills (OR: 1.39, 95% CI [1.01, 1.92]). During weekdays, children who read 1- <3 hr/day and ≥3 hr/day, compared to <1 hr/day, were more likely to show high social (OR: 1.61, 95% CI [1.20, 2.16] and OR: 2.47, 95% CI [1.31, 4.67]) and emotional skills (OR: 1.57, 95% CI [1.16, 2.13] and OR: 2.58, 95% CI [1.34, 4.98]). In addition, children who read 1- <3 hr/day, compared to <1 hr/day, were more likely to show high interactive skills (OR: 1.44, 95% CI [1.08, 1.92]). Similar findings for reading on weekends were observed. TV viewing was not associated with social skills or interactive skills. TV viewing for 1- <3 hr/day, compared to <1 hr/day, was associated with increased odds of high emotional skills (OR: 1.71, 95% CI [1.28, 2.27] on weekdays; OR: 1.90, 95% CI [1.39, 2.61] on weekends). CONCLUSION: PA and reading primarily showed favourable associations with psychosocial well-being, whereas TV viewing did not; thus, PA or reading may be a better option over TV viewing for optimal psychosocial well-being among young South Korean children. These findings should be confirmed with stronger study designs.

Interactions between sleep, movement and other non-movement behaviours in the pathogenesis of childhood obesity.

Research examining the health effects of physical activity, sedentary behaviour and sleep on different health outcomes has largely been conducted independently or in isolation of the other behaviours. However, the fact that time is finite (i.e. 24 h) suggests that the debate on whether or not the influence of a single behaviour is independent of another one is conceptually incorrect. Time spent in one behaviour should naturally depend on the composition of the rest of the day. Recent evidence using more appropriate analytical approaches to deal with this methodological issue shows that the combination of sleep, movement and non-movement behaviours matters and all components of the 24-h movement continuum should be targeted to enhance health and prevent childhood obesity. The objective of this review is to discuss research investigating how combinations of physical activity, sedentary behaviour and sleep are related to childhood obesity. Emerging statistical approaches (e.g. compositional data analysis) that can provide a good understanding of the best 'cocktail' of behaviours associated with lower adiposity and improved health are also discussed. Finally, future research directions are provided. Collectively, it becomes clearer that guidelines and public health interventions should target all movement behaviours synergistically to optimize health of children and youth around the world.

Mediating effects of dietary intake on associations of TV viewing, body mass index and metabolic syndrome in adolescents.

OBJECTIVE: Evidence suggests that TV viewing is associated with body mass index (BMI) and metabolic syndrome (MetS) in adolescents. However, it is unclear whether dietary intake mediates these relationships. METHODS: A cross-sectional analysis was conducted in adolescents (12-19 years) participating in the 2003-2006 United States National Health and Nutrition Examination Survey. BMI z scores (zBMI) (n = 3,161) and MetS (n = 1,379) were calculated using age- and sex-specific criteria for adolescents. TV viewing (h/day) was measured via a self-reported questionnaire, and dietary intake was assessed using two 24-h recalls. Using the MacKinnon method, a series of mediation analyses were conducted examining five dietary mediators (total energy intake, fruit and vegetable intake, discretionary snacks, sugar-sweetened beverages and diet quality) of the relationships between TV viewing and zBMI and MetS. RESULTS: Small positive relationships were observed between TV viewing and zBMI (ß = 0.99, p < 0.001) and TV viewing and MetS (OR = 1.18, p = 0.046). No dietary element appeared to mediate the relationship between TV viewing and zBMI. However, sugar-sweetened beverage consumption and fruit and vegetable intake partially mediated the relationship between TV viewing and MetS, explaining 8.7% and 4.1% of the relationship, respectively. CONCLUSIONS: These findings highlight the complexity of the relationships between TV viewing, dietary intake and cardiometabolic health outcomes, and that TV viewing should remain a target for interventions.

ROS-induced nanotherapeutic approach for ovarian cancer treatment based on the combinatorial effect of photodynamic therapy and DJ-1 gene suppression.

This study represents a novel approach for intraoperative ovarian cancer treatment based on the combinatorial effect of a targeted photodynamic therapy (PDT) associated with suppression of the DJ-1 protein, one of the key players in the ROS defense of cancer cells. To assess the potential of the developed therapy, dendrimer-based nanoplatforms for cancer-targeted delivery of near-infrared photosensitizer, phthalocyanine, and DJ-1 siRNA have been constructed. In vitro studies revealed that therapeutic efficacy of the combinatorial approach was enhanced when compared to PDT alone and this enhancement was more pronounced in ovarian carcinoma cells, which are characterized by higher basal levels of DJ-1 protein. Moreover, the ovarian cancer tumors exposed to a single dose of combinatorial therapy were completely eradicated from the mice and the treated animals showed no evidence of cancer recurrence. Thus, the developed therapeutic approach can be potentially employed intraoperatively to eradicate unresactable cancer cells. FROM THE CLINICAL EDITOR: The complete clearance of microscopic residual tumor cells during excision surgery is important to improve survival of the patient. In this interesting paper, the authors developed a novel approach using targeted photodynamic therapy (PDT), combining a photosensitizer, phthalocyanine, and DJ-1 siRNA for the treatment of ovarian cancer. The data showed that this approach increased cancer cell killing and may pave way for future clinical studies.

Physical environments, policies and practices for physical activity and screen-based sedentary behaviour among preschoolers within child care centres in Melbourne, Australia and Kingston, Canada.

BACKGROUND: Characteristics of preschool and child care centres have previously been shown to be associated with children's health behaviours such as physical activity and screen-based sedentary behaviour. This paper investigates differences in physical environments, policies and practices between child care centres in Melbourne, Australia and Kingston, Canada which may be associated with such behaviours. METHODS: Audits of child care centres were undertaken by trained research assistants for the Healthy Active Preschool and Primary Years (Melbourne, Australia; n = 136) study and the Healthy Living Habits in Pre-School Children (Kingston, Canada; n = 46) study. Twenty-one of the audit items (nine physical environment; 12 policies and practices) were assessed in both samples. Example items included outdoor play and shaded areas, availability of equipment, physical activity instruction for children and staff, opportunities to use electronic media and staff/child interaction during physical activity time. Analyses were completed using SAS version 9.2. RESULTS: Compared with Australian centres, a higher per cent of Canadian centres had a formal physical activity policy, reported children sat more frequently for 30 min or more and allowed children to watch television. A higher per cent of Australian centres provided an indoor area for physical activity, shade outdoors and physical activity education to staff. Children in Australian centres had access to more fixed play equipment and spent more time outdoors than in Canadian centres. CONCLUSIONS: These findings may help inform the development of best practice and policy guidelines to enhance opportunities for healthy levels of physical activity and screen-based sedentary behaviour within child care centres in both countries.

Vigorous physical activity and longitudinal associations with cardiometabolic risk factors in youth.

OBJECTIVE: To examine the longitudinal associations between different physical activity (PA) intensities and cardiometabolic risk factors among a sample of Canadian youth. METHODS: The findings are based on a 2-year prospective cohort study in a convenience sample of 315 youth aged 9-15 years at baseline from rural and urban schools in Alberta, Canada. Different intensities (light, moderate and vigorous) of PA were objectively assessed with Actical accelerometers. The main outcome measures were body mass index (BMI) z-score, waist circumference, cardiorespiratory fitness and systolic blood pressure at 2-year-follow-up and conditional BMI z-score velocity. A series of linear regression models were conducted to investigate the associations after adjusting for potential confounders. RESULTS: At follow-up, cardiorespiratory fitness increased (quartile 1 vs quartile 4=43.3 vs 50.2; P(trend)<0.01) and waist circumference decreased (quartile 1 vs quartile 4=79.0 vs 72.6; P(trend)=0.04; boys only) in a dose-response manner across quartiles of baseline vigorous-intensity PA. A similar trend was observed for systolic blood pressure (quartile 1 vs quartile 4=121.8 vs 115.3; P(trend)=0.07; boys only). Compared with quartile 1 of vigorous-intensity PA, BMI z-score at follow-up and conditional BMI z-score velocity were significantly lower in the quartile 2 and 3 (P<0.05). Waist circumference at follow-up also decreased (quartile 1 vs quartile 4=75.3 vs 73.8; P(trend)=0.04) across quartiles of baseline moderate-intensity PA. CONCLUSIONS: Time spent in vigorous-intensity PA was associated with several positive health outcomes 2 years later. These findings suggest that high-intensity activities in youth help to reduce the risk for several chronic diseases.

Examination of behavioral strategies regulating cocaine intake in rats.

RATIONALE: It has long been observed that rats self-administer psychostimulants in a highly regular pattern. The inverse relationship between dose and rate of drug intake has been interpreted as a titration phenomenon wherein brain-cocaine levels are maintained within a range. Most studies examining this phenomenon have used fixed, unit doses in which case the only titration strategy available to the animal is to adjust inter-infusion intervals. OBJECTIVES: In this study, we examined whether selection of dose size could also be a factor in regulation of intake. We used a schedule of reinforcement, under which the dose can vary through a wide range and is determined by the behavior of the animal. METHODS: Rats self-administered cocaine using a behaviorally dependent dosing schedule of reinforcement, under which the size of each dose was determined by the length of time the lever was held down. The concentration of cocaine was changed across sessions. RESULTS: Total pump-time self-administered decreased by 56 % following each doubling of the concentration, which led to an average 11 % increase in total intake. Similarly, estimated brain levels of cocaine increased by 12 % for each doubling of concentration. These adjustments were the result of manipulation of both the size and spacing of infusions. CONCLUSIONS: In agreement with previous studies, the regular pattern of intake appears to be the result of a titration mechanism in which animals maintain brain levels of cocaine above some threshold. Compensatory regulation appeared to involve both the selection of dose size and inter-infusion intervals.

Cocaine self-administration in rats: discrete trials procedures.

A discrete trials procedure involves splitting up a self-administration session so that there are multiple distinct trials and inter-trial-intervals. This schedule is well suited to be used over 24 h periods which allows insight into diurnal variability in self-administration behavior. DT is also well suited for investigations using pretreatments for increasing or decreasing both high and low probability behavior.

Brain-cocaine concentrations determine the dose self-administered by rats on a novel behaviorally dependent dosing schedule.

A novel behaviorally dependent dosing (BDD) schedule was used to examine the relationship between doses of cocaine self-administered by rats and brain drug levels within a session. The BDD schedule used a hold-down response to activate a syringe pump. The length of time the lever was held down determined the duration that the syringe pump was activated. In the first experiment, rats self-administered cocaine for daily 3 h sessions and brain levels of cocaine were modeled using well-established parameters. Although analysis revealed that rats self-administered doses within a predicted range, one extremely large dose was consistently observed at the beginning of each session when brain levels of cocaine were low. In the second experiment, we introduced a range of timeout periods (10-25 min) in order to produce variability in brain-cocaine concentrations. Animals self-administered larger doses immediately following each timeout period and the dose size was inversely correlated with the length of the timeout. These results show that the dose of cocaine that rats self-administer within a session is inversely related to the amount of drug on board.

Inbred Lewis and Fischer 344 rat strains differ not only in novelty- and amphetamine-induced behaviors, but also in dopamine transporter activity in vivo.

Inbred Lewis (LEW) and Fischer 344 (F344) rats are differentially sensitive to drugs of abuse, making them useful for studying addiction-related neural mechanisms. Here, we investigated whether strain differences in dopamine transporters (DATs) in dorsal striatum (dSTR) and/or nucleus accumbens (NAc) may help to explain their behavioral differences. The behavior of male LEW and F344 rats was assessed in an open-field arena during habituation to novelty and after an i.v. infusion of saline and/or 0.5 mg/kg d-amphetamine (AMPH). In vitro measures of DAT binding, protein and cell-surface expression, as well as in vitro and in vivo measures of function, were used to compare DATs in dSTR and NAc of these two strains. We found that LEW rats exhibited higher novelty- and AMPH-induced locomotion, but F344 rats exhibited greater AMPH-induced rearing and stereotypy. An initial habituation session with i.v. saline minimized the strain differences in AMPH-induced behaviors except that the more frequent AMPH-induced rearing in F344 rats persisted. Strain differences in DAT total protein and basal activity were also observed, with LEW rats having less protein and slower in vivo clearance of locally applied DA in dSTR and NAc. AMPH inhibited in vivo DA clearance in dSTR and NAc of both strains, but to a greater extent in F344 rats. Taken together, the lower basal DAT function in LEW rats is consistent with their greater novelty-induced locomotor activation, whereas the greater inhibition of DA clearance by AMPH in F344 rats is consistent with their marked AMPH-induced rearing behavior.

Low and high locomotor responsiveness to cocaine predicts intravenous cocaine conditioned place preference in male Sprague-Dawley rats.

Outbred, male Sprague-Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on cocaine-induced locomotor activity in an open-field arena. This difference reflects cocaine's ability to inhibit the striatal dopamine transporter and predicts development of sensitization. To investigate the relationship between initial cocaine locomotor responsiveness and cocaine reward, here we first classified rats as either LCRs or HCRs in a conditioned place preference (CPP) apparatus. Subsequently, we conducted cocaine conditioning trials, twice-daily over 4 days with vehicle and cocaine (10 mg/kg, i.p. or 1 mg/kg, i.v.). When cocaine was administered by the i.p. route, similar to previous findings in the open-field, LCRs and HCRs were readily classified and locomotor sensitization developed in LCRs, but not HCRs. However, cocaine CPP was not observed. In contrast, when cocaine was administered by the i.v. route, the LCR/HCR classification not only predicted sensitization, but also CPP, with only LCR rats exhibiting sensitization and cocaine conditioning. Our findings show that the initial locomotor response to cocaine can predict CPP in male Sprague-Dawley rats under conditions when place conditioning develops, and that LCRs may be more prone to develop conditioning in the context of cocaine reward.

Effects of the competitive N-methyl-D-aspartate receptor antagonist, LY235959 [(-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid], on responding for cocaine under both fixed and progressive ratio schedules of reinforcement.

It is difficult to determine the precise role of the N-methyl-D-aspartate (NMDA) receptor system in the reinforcing effects of cocaine since uncompetitive NMDA receptor antagonists alter cocaine self-administration in different ways, depending on the antagonist examined and the behavior being measured. To increase understanding of the role of the NMDA system in cocaine's reinforcing effects, this study measured the effects of the competitive NMDA receptor antagonist, LY235959 [(-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid], in rats that self-administered cocaine under both fixed ratio (FR) 1 and progressive ratio (PR) schedules of reinforcement. Rats were trained to self-administer cocaine (0.33 mg/infusion) under an FR1 schedule of reinforcement. Thereafter, the effects of pretreatment with LY235959, or the uncompetitive antagonists dextromethorphan and dizocilpine, were examined. The number of infusions earned during the first 10 min of responding under the FR1 schedule was analyzed separately. When rats responded for 0.33 mg/infusion cocaine under an FR1 schedule of reinforcement, 3 mg/kg LY235959 decreased cocaine self-administration only during the first 10 min of the responding. This effect was dose and time dependent and blocked by the competitive NMDA receptor agonist, NMDA. LY235959 (3 mg/kg) decreased total responding for cocaine only when the self-administered dose of cocaine was small (0.02-0.04 mg/infusion) or when responding was reinforced under the PR schedule. In contrast, dizocilpine decreased responding under the FR1 schedule but increased responding under the PR schedule. These data suggest that LY235959 decreased the reinforcing effectiveness of cocaine, a finding reported with systemically administered NMDA receptor antagonists other than dizocilpine.

Depression as a complicating factor for home care patients.

Medical nurses usually are uncomfortable addressing psychiatric diagnoses. Yet, under PPS it is essential that medical nurses and physical therapists recognize depression and intervene appropriately. This article provides the necessary information regarding the importance of addressing depression, cues to look for, and some strategies to respond to depression.

Psychiatric home care: clinically valid and cost effective.

A lot can happen when a psychiatric home care program hooks up with patients' families, practitioners, and the community to ensure quality care. According to a recent study, one home care agency's experience demonstrates that psychiatric home care is not only cost effective, but also a clinical success.