Sex differences in variability across timescales in BALB/c mice.

BackgroundFemales are markedly underinvestigated in the biological and behavioral sciences due to the presumption that cyclic hormonal changes across the ovulatory cycle introduce excess variability to measures of interest in comparison to males. However, recent analyses indicate that male and female mice and rats exhibit comparable variability across numerous physiological and behavioral measures, even when the stage of the estrous cycle is not considered. Hormonal changes across the ovulatory cycle likely contribute cyclic, intra-individual variability in females, but the source(s) of male variability has, to our knowledge, not been investigated. It is unclear whether male variability, like that of females, is temporally structured and, therefore, quantifiable and predictable. Finally, whether males and females exhibit variability on similar time scales has not been explored.MethodsThese questions were addressed by collecting chronic, high temporal resolution locomotor activity (LA) and core body temperature (CBT) data from male and female BALB/c mice.ResultsContrary to expectation, males are more variable than females over the course of the day (diel variability) and exhibit higher intra-individual daily range than females in both LA and CBT. Between mice of a given sex, variability is comparable for LA but the inter-individual daily range in CBT is greater for males. To identify potential rhythmic processes contributing to these sex differences, we employed wavelet transformations across a range of periodicities (1-39 h).ConclusionsAlthough variability in circadian power is comparable between the sexes for both LA and CBT, infradian variability is greater in females and ultradian variability is greater in males. Thus, exclusion of female mice from studies because of estrous cycle variability may increase variance in investigations where only male measures are collected over a span of several hours and limit generalization of findings from males to females

Free-Living Humans Cross Cardiovascular Disease Risk Categories Due to Daily Rhythms in Cholesterol and Triglycerides

Cardiovascular disease risk assessment relies on single time-point measurement of risk factors. Although significant daily rhythmicity of some risk factors (e.g., blood pressure and blood glucose) suggests that carefully timed samples or biomarker timeseries could improve risk assessment, such rhythmicity in 'lipid' risk factors is not well understood in free-living humans. As recent advances in at-home blood testing permit lipid data to be frequently and reliably self-collected during daily life, we hypothesized that total cholesterol, HDL-cholesterol or triglycerides would show significant time-of-day variability under everyday conditions. To address this hypothesis, we worked with data collected by 20 self-trackers during personal projects. The dataset consisted of 1,319 samples of total cholesterol, HDL-cholesterol and triglycerides, and comprised timeseries illustrating intra and inter-day variability. All individuals crossed at least one risk category in at least one output within a single day. 90% of fasted individuals (n = 12) crossed at least one risk category in one output during the morning hours alone (06:00–08:00) across days. Both individuals and the aggregated group show significant, rhythmic change by time of day in total cholesterol and triglycerides, but not HDL-cholesterol. Two individuals collected additional data sufficient to illustrate ultradian (hourly) fluctuation in triglycerides, and total cholesterol fluctuation across the menstrual cycle. Short-term variability of sufficient amplitude to affect diagnosis appears common. We conclude that cardiovascular risk assessment may be augmented via further research into the temporal dynamics of lipids. Some variability can be accounted for by a daily rhythm, but ultradian and menstrual rhythms likely contribute additional variance

Neural substrates underlying rhythmic coupling of female reproductive and thermoregulatory circuits

Coordinated fluctuations in female reproductive physiology and thermoregulatory output have been reported for over a century. These changes occur rhythmically at the hourly (ultradian), daily (circadian), and multi-day (ovulatory) timescales, are critical for reproductive function, and have led to the use of temperature patterns as a proxy for female reproductive state. The mechanisms underlying coupling between reproductive and thermoregulatory systems are not fully established, hindering the expansion of inferences that body temperature can provide about female reproductive status. At present, numerous digital tools rely on temperature to infer the timing of ovulation and additional applications (e.g., monitoring ovulatory irregularities and progression of puberty, pregnancy, and menopause are developed based on the assumption that reproductive-thermoregulatory coupling occurs across timescales and life stages. However, without clear understanding of the mechanisms and degree of coupling among the neural substrates regulating temperature and the reproductive axis, whether such approaches will bear fruit in particular domains is uncertain. In this overview, we present evidence supporting broad coupling among the central circuits governing reproduction, thermoregulation, and broader systemic physiology, focusing on timing at ultradian frequencies. Future work characterizing the dynamics of reproductive-thermoregulatory coupling across the lifespan, and of conditions that may decouple these circuits (e.g., circadian disruption, metabolic disease) and compromise female reproductive health, will aid in the development of strategies for early detection of reproductive irregularities and monitoring the efficacy of fertility treatments

Continuous body temperature as a window into adolescent development

Continuous body temperature is a rich source of information on hormonal status, biological rhythms, and metabolism, all of which undergo stereotyped change across adolescence. Due to the direct actions of these dynamic systems on body temperature regulation, continuous temperature may be uniquely suited to monitoring adolescent development and the impacts of exogenous reproductive hormones or peptides (e.g., hormonal contraception, puberty blockers, gender affirming hormone treatment). This mini-review outlines how traditional methods for monitoring the timing and tempo of puberty may be augmented by markers derived from continuous body temperature. These features may provide greater temporal precision, scalability, and reduce reliance on self-report, particularly in females. Continuous body temperature data can now be gathered with ease across a variety of wearable form factors, providing the opportunity to develop tools that aid in individual, parental, clinical, and researcher awareness and education

Sex Differences in Pubertal Circadian and Ultradian Rhythmic Development Under Semi-naturalistic Conditions.

Biological rhythms in core body temperature (CBT) provide informative markers of adolescent development under controlled laboratory conditions. However, it is unknown whether these markers are preserved under more variable, semi-naturalistic conditions, and whether CBT may therefore prove useful in a real-world setting. To evaluate this possibility, we examined fecal steroid concentrations and CBT rhythms from pre-adolescence (p26) through early adulthood (p76) in intact male and female Wistar rats under natural light and climate at the Stephen Glickman Field Station for the Study of Behavior, Ecology and Reproduction. Despite greater environmental variability, CBT markers of pubertal onset and its rhythmic progression were comparable with those previously reported in laboratory conditions in female rats and extend actigraphy-based findings in males. Specifically, sex differences emerged in CBT circadian rhythm (CR) power and amplitude prior to pubertal onset and persisted into early adulthood, with females exhibiting elevated CBT and decreased CR power compared with males. Within-day (ultradian rhythm [UR]) patterns also exhibited a pronounced sex difference associated with estrous cyclicity. Pubertal onset, defined by vaginal opening, preputial separation, and sex steroid concentrations, occurred later than previously reported under lab conditions for both sexes. Vaginal opening and increased fecal estradiol concentrations were closely tied to the commencement of 4-day oscillations in CBT and UR power. By contrast, preputial separation and the first rise in testosterone concentration were not associated with adolescent changes to CBT rhythms in male rats. Together, males and females exhibited unique temporal patterning of CBT and sex steroids across pubertal development, with tractable associations between hormonal concentrations, external development, and temporal structure in females. The preservation of these features outside the laboratory supports CBT as a strong candidate for translational pubertal monitoring under semi-naturalistic conditions in females