Circadian Effects on Performance and Effort in Collegiate Swimmers.

Although individual athletic performance generally tends to peak in the evening, individuals who exhibit a strong diurnal preference perform better closer to their circadian peak. Time-of-day performance effects are influenced by circadian phenotype (diurnal preference and chronotype-sleep-wake patterns), homeostatic energy reserves and, potentially, genotype, yet little is known about how these factors influence physiological effort. Here, we investigate the effects of time of day, diurnal preference, chronotype, and PER3 (a circadian clock gene) genotype on both effort and performance in a population of Division I collegiate swimmers (n = 27). Participants competed in 200m time trials at 7:00 and 19:00 and were sampled pre- and post-trial for salivary α-amylase levels (as a measure of physiological effort), allowing for per-individual measures of performance and physiological effort. Hair samples were collected for genotype analysis (a variable-number tandem-repeat (VNTR) and a single nucleotide polymorphism (SNP) in PER3). Our results indicate significant and parallel time-of-day by circadian phenotype effects on swim performance and effort; evening-type swimmers swam on average 6% slower with 50% greater α-amylase levels in the morning than they did in the evening, and morning types required 5-7 times more effort in the evening trial to achieve the same performance result as the morning trial. In addition, our results suggest that these performance effects may be influenced by gene (circadian clock gene PER3 variants) by environment (time of day) interactions. Participants homozygous for the PER34,4 length variant (rs57875989) or who possess a single G-allele at PER3 SNP rs228697 swam 3-6% slower in the morning. Overall, these results suggest that intra-individual variation in athletic performance and effort with time of day is associated with circadian phenotype and PER3 genotype.

Context-dependent expression of the foraging gene in field colonies of ants: the interacting roles of age, environment and task.

Task allocation among social insect workers is an ideal framework for studying the molecular mechanisms underlying behavioural plasticity because workers of similar genotype adopt different behavioural phenotypes. Elegant laboratory studies have pioneered this effort, but field studies involving the genetic regulation of task allocation are rare. Here, we investigate the expression of the foraging gene in harvester ant workers from five age- and task-related groups in a natural population, and we experimentally test how exposure to light affects foraging expression in brood workers and foragers. Results from our field study show that the regulation of the foraging gene in harvester ants occurs at two time scales: levels of foraging mRNA are associated with ontogenetic changes over weeks in worker age, location and task, and there are significant daily oscillations in foraging expression in foragers. The temporal dissection of foraging expression reveals that gene expression changes in foragers occur across a scale of hours and the level of expression is predicted by activity rhythms: foragers have high levels of foraging mRNA during daylight hours when they are most active outside the nests. In the experimental study, we find complex interactions in foraging expression between task behaviour and light exposure. Oscillations occur in foragers following experimental exposure to 13 L : 11 D (LD) conditions, but not in brood workers under similar conditions. No significant differences were seen in foraging expression over time in either task in 24 h dark (DD) conditions. Interestingly, the expression of foraging in both undisturbed field and experimentally treated foragers is also significantly correlated with the expression of the circadian clock gene, cycle Our results provide evidence that the regulation of this gene is context-dependent and associated with both ontogenetic and daily behavioural plasticity in field colonies of harvester ants. Our results underscore the importance of assaying temporal patterns in behavioural gene expression and suggest that gene regulation is an integral mechanism associated with behavioural plasticity in harvester ants.

The genome of the fire ant Solenopsis invicta.

Ants have evolved very complex societies and are key ecosystem members. Some ants, such as the fire ant Solenopsis invicta, are also major pests. Here, we present a draft genome of S. invicta, assembled from Roche 454 and Illumina sequencing reads obtained from a focal haploid male and his brothers. We used comparative genomic methods to obtain insight into the unique features of the S. invicta genome. For example, we found that this genome harbors four adjacent copies of vitellogenin. A phylogenetic analysis revealed that an ancestral vitellogenin gene first underwent a duplication that was followed by possibly independent duplications of each of the daughter vitellogenins. The vitellogenin genes have undergone subfunctionalization with queen- and worker-specific expression, possibly reflecting differential selection acting on the queen and worker castes. Additionally, we identified more than 400 putative olfactory receptors of which at least 297 are intact. This represents the largest repertoire reported so far in insects. S. invicta also harbors an expansion of a specific family of lipid-processing genes, two putative orthologs to the transformer/feminizer sex differentiation gene, a functional DNA methylation system, and a single putative telomerase ortholog. EST data indicate that this S. invicta telomerase ortholog has at least four spliceforms that differ in their use of two sets of mutually exclusive exons. Some of these and other unique aspects of the fire ant genome are likely linked to the complex social behavior of this species.

Sex-specific associations between circadian-related genes and depression in UK Biobank participants highlight links to glucose metabolism, inflammation and neuroplasticity pathways.

Depressive disorders have increased in global prevalence, making improved management of these disorders a public health priority. Prior research has linked circadian clock genes to depression, either through direct interactions with mood-related pathways in the brain or by modulating the phase of circadian rhythms. Using machine learning and statistical techniques, we explored associations between 157,347 SNP variants from 51 circadian-related genes and depression scores from the patient health questionnaire 9 (PHQ-9) in 99,939 UK Biobank participants. Our results highlight multiple pathways linking the circadian system to mood, including metabolic, monoamine, immune, and stress-related pathways. Notably, genes regulating glucose metabolism and inflammation (GSK3B, LEP, RORA, and NOCT) were prominent factors in females, in addition to DELEC1 and USP46, two genes of unknown function. In contrast, FBXL3 and DRD4 emerged as significant risk factors for male depression. We also found epistatic interactions involving RORA, NFIL3, and ZBTB20 as either risk or protective factors for depression, underscoring the importance of transcription factors (ZBTB20, NFIL3) and hormone receptors (RORA) in depression etiology. Understanding the complex, sex-specific links between circadian genes and mood disorders will facilitate the development of therapeutic interventions and enhance the efficacy of multi-target treatments for depression.

Colony life history and lifetime reproductive success of red harvester ant colonies.

1. We estimate colony reproductive success, in numbers of offspring colonies arising from a colony's daughter queens, of colonies of the red harvester ant, Pogonomyrmex barbatus. 2. A measure of lifetime reproductive success is essential to understand the relation of ecological factors, phenotype and fitness in a natural population. This was possible for the first time in a natural population of ant colonies using data from long-term study of a population of colonies in south-eastern Arizona, for which ages of all colonies are known from census data collected since 1985. 3. Parentage analyses of microsatellite data from 5 highly polymorphic loci were used to assign offspring colonies to maternal parent colonies in a population of about 265 colonies, ages 1-28 years, sampled in 2010. 4. The estimated population growth rate Ro was 1.69 and generation time was 7.8 years. There was considerable variation among colonies in reproductive success: of 199 possible parent colonies, only 49 (˜ 25%) had offspring colonies on the site. The mean number of offspring colonies per maternal parent colony was 2.94 and ranged from 1 to 8. A parent was identified for the queen of 146 of 247 offspring colonies. There was no evidence for reproductive senescence; fecundity was about the same throughout the 25-30 year lifespan of a colony. 5. There were no trends in the distance or direction of the dispersal of an offspring relative to its maternal parent colony. There was no relationship between the number of gynes produced by a colony in 1 year and the number of offspring colonies subsequently founded by its daughter reproductive females. The results provide the first estimate of a life table for a population of ant colonies and the first estimate of the female component of colony lifetime reproductive success. 6. The results suggest that commonly used measures of reproductive output may not be correlated with realized reproductive success. This is the starting point for future investigation asking whether variation in reproductive success is related to phenotypic variation among colonies in behavioural and ecological traits.

Does an ecological advantage produce the asymmetric lineage ratio in a harvester ant population?

In dependent-lineage harvester ant populations, two lineages interbreed but are genetically distinct. The offspring of a male and queen of the same lineage are female reproductives; the offspring of a male and queen of different lineages are workers. Geographic surveys have shown asymmetries in the ratio of the two lineages in many harvester ant populations, which may be maintained by an ecological advantage to one of the lineages. Using census data from a long-term study of a dependent-lineage population of the red harvester ant, Pogonomyrmex barbatus, we identified the lineage of 130 colonies sampled in 1997-1999, ranging in age from 1 to 19 years when collected, and 268 colonies sampled in 2010, ranging in age from 1 to 28 years when collected. The ratio of lineages in the study population is similar across an 11-year interval, 0.59 J2 in 1999 and 0.66 J2 in 2010. The rare lineage, J1, had a slightly but significantly higher number of mates of the opposite lineage than the common lineage, J2, and, using data from previous work on reproductive output, higher male production. Mature colonies of the two lineages did not differ in nest mound size, foraging activity, or the propensity to relocate their nests. There were no strong differences in the relative recruitment or survivorship of the two lineages. Our results show no ecological advantage for either lineage, indicating that differences between the lineages in sex ratio allocation may be sufficient to maintain the current asymmetry of the lineage ratio in this population.

Machine learning analyses reveal circadian clock features predictive of anxiety among UK biobank participants.

Mood disorders, including depression and anxiety, affect almost one-fifth of the world's adult population and are becoming increasingly prevalent. Mutations in circadian clock genes have previously been associated with mood disorders both directly and indirectly through alterations in circadian phase, suggesting that the circadian clock influences multiple molecular pathways involved in mood. By targeting previously identified single nucleotide polymorphisms (SNPs) that have been implicated in anxiety and depressive disorders, we use a combination of statistical and machine learning techniques to investigate associations with the generalized anxiety disorder assessment (GAD-7) scores in a UK Biobank sample of 90,882 individuals. As in previous studies, we observed that females exhibited higher GAD-7 scores than males regardless of genotype. Interestingly, we found no significant effects on anxiety from individual circadian gene variants; only circadian genotypes with multiple SNP variants showed significant associations with anxiety. For both sexes, severe anxiety is associated with a 120-fold increase in odds for individuals with CRY2_AG(rs1083852)/ZBTB20_TT(rs1394593) genotypes and is associated with a near 40-fold reduction in odds for individuals with PER3-A_CG(rs228697)/ZBTB20_TT(rs1394593) genotypes. We also report several sex-specific associations with anxiety. In females, the CRY2/ZBTB20 genotype combination showed a > 200-fold increase in odds of anxiety and PER3/ZBTB20 and CRY1 /PER3-A genotype combinations also appeared as female risk factors. In males, CRY1/PER3-A and PER3-B/ZBTB20 genotype combinations were associated with anxiety risk. Mediation analysis revealed direct associations of CRY2/ZBTB20 variant genotypes with moderate anxiety in females and CRY1/PER3-A variant genotypes with severe anxiety in males. The association of CRY1/PER3-A variant genotypes with severe anxiety in females was partially mediated by extreme evening chronotype. Our results reinforce existing findings that females exhibit stronger anxiety outcomes than males, and provide evidence for circadian gene associations with anxiety, particularly in females. Our analyses only identified significant associations using two-gene combinations, underscoring the importance of combined gene effects on anxiety risk. We describe novel, robust associations between gene combinations involving the ZBTB20 SNP (rs1394593) and risk of anxiety symptoms in a large population sample. Our findings also support previous findings that the ZBTB20 SNP is an important factor in mood disorders, including seasonal affective disorder. Our results suggest that reduced expression of this gene significantly modulates the risk of anxiety symptoms through direct influences on mood-related pathways. Together, these observations provide novel links between the circadian clockwork and anxiety symptoms and identify potential molecular pathways through which clock genes may influence anxiety risk.

Risk for Seasonal Affective Disorder (SAD) Linked to Circadian Clock Gene Variants.

Molecular pathways affecting mood are associated with circadian clock gene variants and are influenced, in part, by the circadian clock, but the molecular mechanisms underlying this link are poorly understood. We use machine learning and statistical analyses to determine the circadian gene variants and clinical features most highly associated with symptoms of seasonality and seasonal affective disorder (SAD) in a deeply phenotyped population sample. We report sex-specific clock gene effects on seasonality and SAD symptoms; genotypic combinations of CLOCK3111/ZBTB20 and PER2/PER3B were significant genetic risk factors for males, and CRY2/PER3C and CRY2/PER3-VNTR were significant risk factors for females. Anxiety, eveningness, and increasing age were significant clinical risk factors for seasonality and SAD for females. Protective factors for SAD symptoms (in females only) included single gene variants: CRY1-GG and PER3-VNTR-4,5. Clock gene effects were partially or fully mediated by diurnal preference or chronotype, suggesting multiple indirect effects of clock genes on seasonality symptoms. Interestingly, protective effects of CRY1-GG, PER3-VNTR-4,5, and ZBTB20 genotypes on seasonality and depression were not mediated by chronotype, suggesting some clock variants have direct effects on depressive symptoms related to SAD. Our results support previous links between CRY2, PER2, and ZBTB20 genes and identify novel links for CLOCK and PER3 with symptoms of seasonality and SAD. Our findings reinforce the sex-specific nature of circadian clock influences on seasonality and SAD and underscore the multiple pathways by which clock variants affect downstream mood pathways via direct and indirect mechanisms.

Machine Learning Analyses Reveal Circadian Features Predictive of Risk for Sleep Disturbance.

Introduction: Sleep disturbances often co-occur with mood disorders, with poor sleep quality affecting over a quarter of the global population. Recent advances in sleep and circadian biology suggest poor sleep quality is linked to disruptions in circadian rhythms, including significant associations between sleep features and circadian clock gene variants. Methods: Here, we employ machine learning techniques, combined with statistical approaches, in a deeply phenotyped population to explore associations between clock genotypes, circadian phenotypes (diurnal preference and circadian phase), and risk for sleep disturbance symptoms. Results: As found in previous studies, evening chronotypes report high levels of sleep disturbance symptoms. Using molecular chronotyping by measuring circadian phase, we extend these findings and show that individuals with a mismatch between circadian phase and diurnal preference report higher levels of sleep disturbance. We also report novel synergistic interactions in genotype combinations of Period 3, Clock and Cryptochrome variants (PER3B (rs17031614)/ CRY1 (rs228716) and CLOCK3111 (rs1801260)/ CRY2 (rs10838524)) that yield strong associations with sleep disturbance, particularly in males. Conclusion: Our results indicate that both direct and indirect mechanisms may impact sleep quality; sex-specific clock genotype combinations predictive of sleep disturbance may represent direct effects of clock gene function on downstream pathways involved in sleep physiology. In addition, the mediation of clock gene effects on sleep disturbance indicates circadian influences on the quality of sleep. Unraveling the complex molecular mechanisms at the intersection of circadian and sleep physiology is vital for understanding how genetic and behavioral factors influencing circadian phenotypes impact sleep quality. Such studies provide potential targets for further study and inform efforts to improve non-invasive therapeutics for sleep disorders.

Intra-individual impact of the COVID-19 pandemic on mental health and sleep in young adults.

The COVID-19 pandemic has posed unique academic, social, financial, and health-related challenges for young adults. While numerous studies have documented average increases in reported mental health issues in the general population, few have measured the magnitude of changes in mental health symptoms and sleep difficulties within individuals. Here, we measure the impact of the COVID-19 pandemic on mental health and sleep of university students pre- and mid-pandemic. Prior to the pandemic (Fall 2019), individuals (n = 23) were recruited to participate in an eight-day, comprehensive sleep study using Fitbit® actigraphy. Participants also completed detailed mental health and sleep surveys, including depression (BDI-II), anxiety (STAI), and sleep disturbance (PROMIS) surveys. One year later, these individuals repeated the study during the pandemic (Fall 2020); participants completed the original surveys and sleep study, in addition to a targeted survey on mental and sleep health due to the pandemic. Self-reported levels of anxiety, depression, and sleep disturbance, and sleep parameters, measured by actigraphy, were compared within the same individuals pre- and mid-pandemic. Self-report survey data revealed that three-quarters of participants experienced an increase in stress and anxiety due to the pandemic. In addition, intra-individual depression and anxiety symptoms increased to clinically significant levels within individuals from pre- to mid-pandemic. Over two-thirds of participants reported sleeping less, and more than half reported that their sleep health had worsened during the pandemic. Changes in sleep disturbance were positively associated with changes in depression and anxiety, reinforcing the robust relationship between poor sleep quality and mental health. Furthermore, individuals who reported greater sleep disturbance during the pandemic experienced lower relative proportions of both REM and deep sleep. The impact of the COVID-19 pandemic on university students is multi-faceted-mental health, sleep quality, and the amount of restorative sleep are negatively affected by the pandemic environment. These compounded effects exacerbate the health consequences of the pandemic and highlight a need for increased attention to the prevention and treatment of mental health disorders, particularly in vulnerable populations of young adults.

Differential regulation of the foraging gene associated with task behaviors in harvester ants.

BACKGROUND: The division of labor in social insect colonies involves transitions by workers from one task to another and is critical to the organization and ecological success of colonies. The differential regulation of genetic pathways is likely to be a key mechanism involved in plasticity of social insect task behavior. One of the few pathways implicated in social organization involves the cGMP-activated protein kinase gene, foraging, a gene associated with foraging behavior in social insect species. The association of the foraging gene with behavior is conserved across diverse species, but the observed expression patterns and proposed functions of this gene vary across taxa. We compared the protein sequence of foraging across social insects and explored whether the differential regulation of this gene is associated with task behaviors in the harvester ant, Pogonomyrmex occidentalis. RESULTS: Phylogenetic analysis of the coding region of the foraging gene reveals considerable conservation in protein sequence across insects, particularly among hymenopteran species. The absence of amino acid variation in key active and binding sites suggests that differences in behaviors associated with this gene among species may be the result of changes in gene expression rather than gene divergence. Using real time qPCR analyses with a harvester ant ortholog to foraging (Pofor), we found that the brains of harvester ant foragers have a daily fluctuation in expression of foraging with mRNA levels peaking at midday. In contrast, young workers inside the nest have low levels of Pofor mRNA with no evidence of daily fluctuations in expression. As a result, the association of foraging expression with task behavior within a species changes depending on the time of day the individuals are sampled. CONCLUSIONS: The amino acid protein sequence of foraging is highly conserved across social insects. Differences in foraging behaviors associated with this gene among social insect species are likely due to differences in gene regulation rather than evolutionary changes in the encoded protein. The task-specific expression patterns of foraging are consistent with the task-specific circadian rhythms observed in harvester ants. Whether the molecular clock plays a role in regulating foraging gene expression (or vice versa) remains to be determined. Our results represent the first time series analysis of foraging gene expression and underscore the importance of assaying time-related expression differences in behavioral studies. Understanding how this gene is regulated within species is critical to explaining the mechanism by which foraging influences behavior.

Sleep Quality, Sleep Structure, and PER3 Genotype Mediate Chronotype Effects on Depressive Symptoms in Young Adults.

Depression and its related mood disorders are a major global health issue that disproportionately affects young adults. A number of factors that influence depressive symptoms are particularly relevant to the young adult developmental stage, including sleep loss, poor sleep quality, and the tendency toward eveningness in circadian preferences. However, relatively few studies have examined the relationship between sleep and circadian phenotypes, and their respective influences on mood, or considered potential molecular mechanisms driving these associations. Here, we use a multi-year, cross-sectional study of 806 primarily undergraduates to examine the relationships between sleep-wake chronotype, sleep disturbance, depression and genotypes associated with the PER3 variable number of tandom repeats (VNTR) polymorphism-circadian gene variants associated with both chronotype and sleep homeostatic drive. In addition, we use objective, Fitbit-generated sleep structure data on a subset of these participants (n = 67) to examine the relationships between chronotype, depression scores, actual measures of sleep duration, social jetlag, and the percent of deep and rapid eye movement (REM) sleep per night. In this population, chronotype is weakly associated with depressive symptoms and moderately correlated with self-reported sleep disturbance. Sleep disturbance is significantly associated with depression scores, but objective sleep parameters are not directly correlated with Beck Depression Inventory (BDI-II) scores, with the exceptions of a moderate correlation between social jetlag and depression scores in females and a marginal correlation between sleep duration and depression scores. Multiple regression and path analyses reveal that chronotype effects on depressive symptoms in this population are mediated largely by sleep disturbance. The PER3 VNTR genotype significantly predicts depressive symptoms in a model with objective sleep parameters, but it does not significantly predict depressive symptoms in a model with chronotype or subjective sleep disturbance. Interestingly, PER35,5 genotypes, in males only, are independently related to chronotype and depression scores. Our results support hypotheses linking subjective sleep quality and chronotype and provide a first step in understanding how objective sleep structure may be linked to chronotype and depressive symptoms. Our results also suggest that circadian gene variants may show sex-specific effects linking sleep duration and sleep structure to depression.

Expression patterns of a circadian clock gene are associated with age-related polyethism in harvester ants, Pogonomyrmex occidentalis.

BACKGROUND: Recent advances in sociogenomics allow for comparative analyses of molecular mechanisms regulating the development of social behavior. In eusocial insects, one key aspect of their sociality, the division of labor, has received the most attention. Age-related polyethism, a derived form of division of labor in ants and bees where colony tasks are allocated among distinct behavioral phenotypes, has traditionally been assumed to be a product of convergent evolution. Previous work has shown that the circadian clock is associated with the development of behavior and division of labor in honeybee societies. We cloned the ortholog of the clock gene, period, from a harvester ant (Pogonomyrmex occidentalis) and examined circadian rhythms and daily activity patterns in a species that represents an evolutionary origin of eusociality independent of the honeybee. RESULTS: Using real time qPCR analyses, we determined that harvester ants have a daily cyclic expression of period and this rhythm is endogenous (free-running under dark-dark conditions). Cyclic expression of period is task-specific; foragers have strong daily fluctuations but nest workers inside the nest do not. These patterns correspond to differences in behavior as activity levels of foragers show a diurnal pattern while nest workers tend to exhibit continuous locomotor activity at lower levels. In addition, we found that foragers collected in the early fall (relative warm, long days) exhibit a delay in the nightly peak of period expression relative to foragers collected in the early spring (relative cold, short days). CONCLUSION: The association of period mRNA expression levels with harvester ant task behaviors suggests that the development of circadian rhythms is associated with the behavioral development of ants. Thus, the circadian clock pathway may represent a conserved 'genetic toolkit' that has facilitated the parallel evolution of age-related polyethism and task allocation in social insects.

Chronotype mediates gender differences in risk propensity and risk-taking.

Risk-taking is a complex form of decision-making that involves calculated assessments of potential costs and rewards that may be immediate or delayed. Thus, making predictions about inter-individual variation in risk-taking due to personality traits, decision styles or other attributes can be difficult. The association of risk-taking with gender is well-supported; males report higher propensity for risk-taking and show higher risk-taking on tasks measuring actual risk-taking behavior. Risk-taking also appears to be associated with circadian phenotypes (chronotypes), with evening-types reporting higher levels of risk-taking-but this association may be confounded by the fact that, in certain age groups, males are more likely to be evening-types. Here, we test for gender by chronotype effects on risk-taking in young adults (n = 610) using a self-reported risk propensity questionnaire, the health domain of the DOSPERT, and a behavioral task measuring risk-taking, the Balloon Analog Risk Task (BART). Our results show that males report and take significantly more risks than females in this population. In addition, evening-type individuals have significantly higher self-reported risk propensity and tend to take more risks on the BART. Interestingly, there is no significant difference in risk propensity or risk-taking behavior across male circadian phenotypes, but evening-type females significantly report and take more risk than female intermediate and morning types. In regression analyses, we found both gender and chronotype predict risk propensity and risk-taking. Path analysis confirms that chronotype has an indirect effect on gender differences in both risk propensity and risk-taking. Furthermore, we found that trait anxiety (STAI) and sleep disturbance (PROMIS), significantly correlate with chronotype and gender in the complete dataset, but do not independently predict differences in female risk-taking. These results suggest that chronotype mediates gender effects on risk-taking and that these effects are driven primarily by morning-type females, but are not related to gender-specific differences in trait anxiety or sleep quality.

In vivo molecular chronotyping, circadian misalignment, and high rates of depression in young adults.

BACKGROUND: Young adults are disproportionately affected by depression and related mental disorders. Circadian misalignment (a phase advance or delay in the body's internal clock timing) is thought to exert adverse effects on downstream physiological processes regulating mood. Circadian disruption may represent an additional, under-appreciated risk factor affecting young adults. Here, we test the hypothesis that depression in young adults is associated with circadian misalignment-the lack of concordance between an individual's endogenous rhythm and their external social and academic environment. METHODS: We screened 528 individuals for morningness-eveningness diurnal preference and sleep-wake chronotype. We selected individuals with extreme scores (n = 130) for estimation of circadian phase by measuring clock gene mRNA oscillations in hair follicles (a peripheral clock). Using an independent, data-driven cluster analysis, we define the circadian misalignment of both advanced- and delayed-phase individuals from clock gene mRNA expression levels. We compare depression (BDI-II), anxiety (STAI), social jetlag, sleep duration, and sleep disturbance (PROMIS) scores between misaligned individuals and control individuals of intermediate chronotype (n = 173). RESULTS: We demonstrate that depression scores in young adults are significantly higher in individuals with circadian phase delays and in individuals with a mismatch between circadian behavioral phenotypes and circadian molecular phase. Evening-type individuals with circadian phase delays are 20 times more likely and mismatched individuals are 5-8 times more likely to be depressed than control individuals. Sleep disturbance shows a similar relationship with circadian phenotypes, but the mood effects described in this study are independent of sleep duration, social jetlag and gender. LIMITATIONS: Our study examined peripheral clock genes that represents a circadian rhythm potentially influenced by both intrinsic and external, environmental factors. Our study population spanned a limited age-group and our results cannot distinguish between cause and effect of circadian, sleep and mood variables. CONCLUSIONS: Our study validates previous theoretical predictions of circadian effects on mood disorders and highlights a critical, hidden risk factor affecting mood in young adults-circadian disruption.

Modeling Strengthens Molecular Link between Circadian Polymorphisms and Major Mood Disorders.

Anxiety and other mood disorders, such as major depressive disorder (MDD) and seasonal affective disorder (SAD), affect nearly one-fifth of the global population and disproportionately affect young adults. Individuals affected by mood disorders are frequently plagued by sleep and circadian problems, and recent genetic studies provide ample support for the association of circadian and sleep syndromes with depression and anxiety. Mathematical modeling has been crucial in understanding some of the essential features of the mammalian circadian clock and is now a vital tool for dissecting how circadian genes regulate the molecular mechanisms that influence mood. Here, we model the effect of five clock gene polymorphisms, previously linked to mood disorders, on circadian gene expression and, ultimately, on the period length and amplitude of the clock, two parameters that dictate the phase, or alignment, of the clock relative to the environment. We then test whether these gene variants are associated with circadian phenotypes (Horne-Ostberg Morningness-Eveningness scores) and well-established measures of depression (Beck Depression Inventory) and anxiety (State-Trait Anxiety Inventory) in a population of undergraduates ( n = 546). In this population, we find significant allelic and/or genotypic associations between CRY2 and two PER3 variants and diurnal preference. The PER3 length polymorphism (rs57875989) was significantly associated with depression in this sample, and individuals homozygous for the PER3 single nucleotide polymorphism (SNP) (rs228697) reported significantly higher anxiety. Our simple model satisfies available experimental knockdown conditions as well as existing data on clock polymorphisms associated with mood. In addition, our model enables us to predict circadian phenotypes (e.g., altered period length, amplitude) associated with mood disorders in order to identify critical effects of clock gene mutations on CRY/BMAL binding and to predict that the intronic SNPs studied represent gain-of-function mutations, causing increased transcription rate. Given the user-friendly structure of our model, we anticipate that it will be useful for further study of the relationships among clock polymorphisms, circadian misalignment, and mood disorders.

Circadian Clock Model Supports Molecular Link Between PER3 and Human Anxiety.

Generalized anxiety and major depression have become increasingly common in the United States, affecting 18.6 percent of the adult population. Mood disorders can be debilitating, and are often correlated with poor general health, life dissatisfaction, and the need for disability benefits due to inability to work. Recent evidence suggests that some mood disorders have a circadian component, and disruptions in circadian rhythms may even trigger the development of these disorders. However, the molecular mechanisms of this interaction are not well understood. Polymorphisms in a circadian clock-related gene, PER3, are associated with behavioral phenotypes (extreme diurnal preference in arousal and activity) and sleep/mood disorders, including seasonal affective disorder (SAD). Here we show that two PER3 mutations, a variable number tandem repeat (VNTR) allele and a single-nucleotide polymorphism (SNP), are associated with diurnal preference and higher Trait-Anxiety scores, supporting a role for PER3 in mood modulation. In addition, we explore a potential mechanism for how PER3 influences mood by utilizing a comprehensive circadian clock model that accurately predicts the changes in circadian period evident in knock-out phenotypes and individuals with PER3-related clock disorders.

Molecular insights into chronotype and time-of-day effects on decision-making.

Recent reports highlight that human decision-making is influenced by the time of day and whether one is a morning or evening person (i.e., chronotype). Here, we test whether these behavioral effects are associated with endogenous biological rhythms. We asked participants to complete two well-established decision-making tasks in the morning or evening: the matrix task (an ethical decision task) and the balloon analog risk task (BART; a risk-taking task), and we measured their chronotype in two ways. First, participants completed a self-report measure, the Horne-Östberg Morningness-Eveningness Questionnaire (MEQ). Second, we measured the expression of two circadian clock-regulated genes-Per3 and Nr1d2-from peripheral clock cells in participants' hair follicle samples. Using a cosinor model, we estimated the phase of the peripheral clock and assigned RNA chronotypes to participants with advanced (larks) or delayed (owls) phases. The behavioral data were analyzed independently for self-reported (MEQ) and RNA-based chronotypes. We find that significant chronotype and/or time-of-day effects between larks and owls in decision-making tasks occur only in RNA-based chronotypes. Our results provide evidence that time-of-day effects on decision-making can be explained by phase differences in oscillating clock genes and suggest that variation in the molecular clockwork may influence inter-individual differences in decision-making behavior.

Plasticity in queen number and social structure in the invasive Argentine ant (Linepithema humile).

In many polygynous social insect societies, ecological factors such as habitat saturation promote high queen numbers by increasing the cost of solitary breeding. If polygyny is associated with constrained environments, queen number in colonies of invasive social insects should increase as saturation of their new habitat increases. Here I describe the variation in queen number, nestmate relatedness, and nest size along a gradient of time since colonization in an invading population of Argentine ants (Linepithema humile) in Haleakala, Hawaii. Nest densities in this population increase with distance from the leading edge of the invasion, reaching a stable density plateau approximately 80 m from the edge (> 2 years after colonization). Although the number of queens per nest in Haleakala is generally lower than previously reported for Argentine ants, there is significant variation in queen number across this population. Both the observed and effective queen numbers increase across the density gradient, and nests in the center of the population contain queen numbers three to nine times higher than those on the edge of the invasion. The number of workers per nest is correlated with queen number, and nests in the center are six times larger than nests at the edge. Microsatellite analysis of relatedness among nestmates reveals that all nests in the Haleakala population are characterized by low relatedness and have evidence of multiple reproducing queens. Relatedness values are significantly lower in nests in the center of the population, indicating that the number of reproducing queens is greater in areas of high nest density. The variation in queen number and nestmate relatedness in this study is consistent with expectations based on changes in ecological constraints during the invasion of a new habitat, suggesting that the social structure of Argentine ant populations is strongly influenced by ecological factors. Flexibility in social structure may facilitate persistence in variable environments and may also confer significant advantages to a species when introduced into new areas.