Salivary cortisol concentration and perceived stress measure in response to acute natural stress: The role of morningness-eveningness preference.

Chronotype reflects the morningness-eveningness preference over a 24-h period. Significant data indicates meaningful differences between evening types (ET) and morning types (MT) in behavior, personality traits, health and well-being. The aim of this study was to investigate cortisol response and subjective perceived stress of MT and ET individuals in response to an acute natural stressor. Twenty six definite MT (mean age 23.4 ± 1.7) and twenty six definite ET (mean age 23.8 ± 1.3) college students were recruited for this study. Participants were instructed to evaluate their perceived subjective stress and to provide saliva samples for cortisol levels at four different time points: Morning of regular school day, morning immediately before a final exam, afternoon of a regular school day and afternoon immediately before a final exam. For general mood assessment, the participants were also asked to fill out the Positive and Negative Affect Schedule (PANAS) questionnaire. The most outstanding finding of this study was the blunting of cortisol increase in response to acute stress in the morning in the ET group: Salivary cortisol was higher before a final exam only in MT but not in ET. However, no differences between the groups were found in the subjective stress measure. In the PANAS scale, ET showed lower positive affect, and a trend towards a higher negative affect. Overall, our results suggest dysregulation of cortisol response in ET individuals, possibly due to their daily struggle to function in a morning-oriented society. These results further highlight the challenges faced by ET individuals and raise the question of possible interventions to assist them.

Changes in menstrual cycle length and in sleep-wake behaviors during COVID-19 related lockdown in Israel.

COVID-19 related lockdowns changed our life. Studies report that young women are more susceptible to lockdown-induced adverse effects and stress. As stress and menstrual cycle are associated, we hypothesized that menstrual cycle length might change during lockdown. We examined menstrual cycle length, and sleep-wake behaviors during lockdown in Israel. Participants were 97 women in their fertile years who used Tempdrop fertility sensor™ to track cycles. Data were collected before, during and after lockdown in Israel. Our main finding is that lockdown was associated with changes in menstrual cycle length of most participants, with either increased of decreased length. Changes were reversed when lockdown was terminated. Sleep duration increased during lockdown but we found no relationship between sleep and menstrual cycle. We suggest these findings contribute to the understanding of the relationship between stress, sleep, and menstrual cycle. Further studies should explore the sources for differential effects in sub-groups of women.

Changes in sleep patterns of college students in Israel during COVID-19 lockdown, a sleep diaries study.

To prevent and reduce the spread of COVID-19, governments around the world apply social restrictions and lockdowns. Such lockdowns significantly alter daily routine and habits. A growing body of research indicates that lockdowns affect sleep and circadian rhythms. The current study further explores this effect using sleep logs for a relatively long duration including lockdown and post-lockdown periods in Israel. For two consecutive months, both during lockdown and during post-lockdown periods, from March 13th, 2020 to May 12th, 2020, Israeli students were asked to fill out daily sleep logs in which they report their sleep and wake times. The participants were also asked to fill out the Morningness-Eveningness Questionnaire (MEQ) in the beginning of the study. Data show increase in sleep duration and a delayed midsleep point during lockdown, compared to post-lockdown periods, both on workdays and on weekends. An interaction between chronotype and lockdown was also observed; morning types sleep more both during lockdown and during post-lockdown periods. Interestingly, the midsleep point of late chronotypes is later during both workdays and weekends even during lockdown when social constrains on sleep time are in part removed. Overall, the current results based on detailed and relatively long-term sleep logs analysis confirm previous work using limited measures, such as one-time questionnaires. A lockdown period affects sleep-wake behavior: during lockdown people sleep duration is increased and their sleep onset is delayed. Nevertheless, the circadian preference of individuals is conserved across conditions.

Differential effects of COVID-19 lockdowns on well-being: interaction between age, gender and chronotype.

The unprecedented restrictions imposed due to the COVID-19 pandemic altered our daily habits and severely affected our well-being and physiology. The effect of these changes is yet to be fully understood. Here, we analysed highly detailed data on 169 participants for two to six months, before and during the second COVID-19 lockdown in Israel. We extracted 12 well-being indicators from sensory data of smartwatches and from self-reported questionnaires, filled daily using a designated mobile application. We found that, in general, lockdowns resulted in significant changes in mood, sleep duration, sport duration, social encounters, resting heart rate and number of steps. Examining subpopulations, we found that younger participants (aged 20-40 years) suffered from a greater decline in mood and number of steps than older participants (aged 60-80 years). Likewise, women suffered from a higher increase in stress and reduction in social encounters than men. Younger early chronotypes did not increase their sleep duration and exhibited the highest drop in mood. Our findings underscore that while lockdowns severely impacted our well-being and physiology in general, greater damage has been identified in certain subpopulations. Accordingly, special attention should be given to younger people, who are usually not in the focus of social support, and to women.

Developmental and social deficits and enhanced sensitivity to prenatal chlorpyrifos in PON1-/- mouse pups and adults.

The levels and activity of the enzyme paraoxonase 1 affect the vulnerability to the teratogenic effects of organophosphate pesticides. Mutant mice lacking the gene for paraoxonase1 (PON1-/-) are more susceptible to the toxic effects of chlorpyrifos, and were hypothesized to be more vulnerable to social behavior deficits induced by exposure to chlorpyrifos during gestation. Three experiments were performed comparing PON1-/- mice to PON1+/+ mice born to dams treated with 0.5 mg/kg chlorpyrifos or cornoil vehicle on gestational days 12-15. Chlofpyrifos-exposed male PON1-/- mouse pups had delayed development of reflexes in in the first experiment. In the second experiment, adult male and female PON1-/- mice and the female PON1+/+ mice all displayed lower social preference than the male vehicle-treated PON1+/+ mice. The PON1-/- mice and the female PON1+/+ mice displayed lower social preference compared to the PON1+/+ male mice. Male adult mice that had been exposed in utero to chlorpyrifos showed less conditioned social preference regardless of genotype. In the third study, the delayed reflex development was replicated in male and female PON1-/- mice, but chlorpyrifos did not augment this effect. Nest Odor Preference, a test of early social attachment to dam and siblings, was lower in PON1-/- mouse pups compared to PON1+/+ pups. This study shows for the first time that PON1-/- mice have a behavioral phenotype that indicates impaired reflex development and social behavior. Chlorpyrifos exposure during gestation tended to augment some of these effects.

Revisiting the validity of the mouse tail suspension test: Systematic review and meta-analysis of the effects of prototypic antidepressants.

Animal models in neuropsychiatric research need validation. One way to address external validity is systematic reviews and meta-analyses. The present study presents a meta-analysis of the effects of antidepressants in the mouse tail suspension test (TST). A PubMed search identified studies that examined imipramine and fluoxetine effects in the TST. Inclusion criteria were testing in the light phase; trial duration was six minutes; immobility time scored 6 or (last) 4 min; adult mice; acute intraperitoneal (IP) administration. Effect sizes (ES) were estimated using Cohen's d, heterogeneity of ES with Cochran's Q test, correlations between dose and ES with Pearson's correlation and differences between strains with Analysis of variance. Results show that antidepressants decrease immobility time in the TST and a correlation between drug dose and ES but no effects of strain. We suggest that the TST is a valid tool to quantitatively, consistently and reproducibly capture the immobility-reducing aspects of fluoxetine and imipramine and that the lack of strain effects is due to small number of experiments in many of the strains.

Impaired innate and conditioned social behavior in adult C57Bl6/J mice prenatally exposed to chlorpyrifos.

BACKGROUND: Signs of pervasive developmental disorder and social deficits were reported in toddlers and children whose mothers were exposed to organophosphate pesticides during pregnancy. Deficits in social preference were reported in adult male mice exposed to chlorpyrifos on gestational days 12-15. This study aimed (a) to test the hypothesis that adult female and male mice that were exposed prenatally to subtoxic doses of chlorpyrifos would be impaired in social behavior and (b) to determine if prenatal chlorpyrifos altered the expression of transcripts for oxytocin in the hypothalamus. Pregnant mice were treated by gavage with corn oil vehicle or 2.5 mg/kg or 5 mg/kg of CPF on gestational days 12-15. Social preference, social and non-social conditioned place preference tasks were tested in adults. Expression of oxytocin transcripts in hypothalamus was measured by qPCR. RESULTS: Chlorpyrifos (5 mg/kg on GD 12-15) reduced the innate preference for a conspecific in a dose and sex dependent manner. Adult males exposed prenatally to 5 mg/kg CPF showed a reduction in social preference. Socially conditioned place preference was impaired in offspring of dams treated with either dose of CPF. Non-social appetitive place conditioning was impaired in offspring of dams exposed to 2.5 mg/kg, but not to 5 mg/kg chlorpyrifos. Prenatal chlorpyrifos treatment did not alter the expression of the oxytocin mRNA in the hypothalamus, although expression was significantly lower in females. CONCLUSIONS: Prenatal chlorpyrifos induced innate and learned social deficits and non-specific conditioning deficits in adult mice in a sex-dependent manner. Males showed specific social deficits following the higher dose whereas both males and females showed a more generalized conditioning deficit following the intermediate dose.

Questioning the predictive validity of the amphetamine-induced hyperactivity model for screening mood stabilizing drugs.

Animal models are critical for the study of disease mechanisms and the screening of potential novel treatments. In the context of bipolar disorder, amphetamine-induced hyperactivity (AIH) is a frequently used screening model for antimanic effects. Yet, the utility of screening models depends on their predictive (or pharmacological) validity and it is expected that such models will respond to effective treatments. Lithium is the prototypic mood stabilizer but previous data regarding the effects of lithium in the AIH model are not clear and most data comes from studies using acute lithium administration that is not relevant to the therapeutic regimen in patients. To evaluate the pharmacological validity of AIH as a model for mania-like behavior we tested the interaction between chronic oral administration of lithium and amphetamine in ICR (CD-1®) mice and in black Swiss mice. We conducted 4 different experiments where chronic lithium was followed by an acute injection of amphetamine and one experiment where chronic amphetamine was combined with chronic lithium. The results show that amphetamine result in hyperactivity (experiments 1-4) and that lithium has no effects. Moreover, chronic amphetamine (experiment 5) result in sensitization that is not attenuated by lithium. The results clearly show that the predictive validity of the AIH model in ICR or black Swiss mice is problematic and possibly cast doubt on the utilization of the AIH as a screening model for novel mood stabilizers in other strains of mice.

Prenatal chlorpyrifos leads to autism-like deficits in C57Bl6/J mice.

BACKGROUND: Children are at daily risk for exposure to organophosphate insecticides, of which the most common is chlorpyrifos (CPF). Exposure of pregnant women to CPF was linked to decreased birth weight, abnormal reflexes, reduction in IQ, as well as increased maternal reports of signs of pervasive developmental disorder. The aim of current study was to examine the long term effects of prenatal exposure to CPF in C57BL/6 J (B6) mice with specific focus on social and repetitive behavior. METHODS: B6 female mice were treated with vehicle, 2.5 mg/kg CPF or 5 mg/kg of CPF on gestational days 12-15 by oral gavage. On postnatal days (PND's) 6-12 early development and neuromotor ability were assessed by measuring 3 neonatal reflexes in the offspring. In adulthood, PND 90, social behavior was investigated using the social preference, social novelty and social conditioned place preference tasks. Object recognition and restricted interest, measured by the repetitive novel object contact task (RNOC), were also assessed on PN D 90. In order to rule out the possibility that CPF administration induced alterations in maternal care, the dams' behavior was evaluated via the maternal retrieval task. RESULTS: CPF treatment resulted in delayed development of neonatal reflexes on PND's 6-12. On PND 90, mice treated prenatally with the 5.0 mg/kg dose exhibited reduced preference towards an unfamiliar conspecific in the social preference test and reduced social conditioned place preference. In the RNOC task, mice exposed prenatally to 2.5 mg/kg dose of CPF showed enhanced restricted interest. CPF administration did not impair dams' behavior and did not cause memory or recognition deficit as was observed in the object recognition task. CONCLUSIONS: Our data indicate that gestational exposure to CPF has long-term deleterious effects on social behavior and limits exploration of novel objects.