Oestradiol Exposure Early in Life Programs Daily and Circadian Activity Rhythms in Adult Mice

Abstract

Hormone signalling during critical periods organises the adult circadian timekeeping system by altering adult hormone sensitivity and shaping fundamental properties of circadian rhythmicity. However, the timing of when developmental oestrogens modify the timekeeping system is poorly understood. To test the hypothesis that alterations in postnatal oestrogenic signalling organise adult daily activity rhythms, we utilised aromatase knockout mice (ArKO), which lack the enzyme required for oestradiol synthesis. ArKO and wild-type (WT) males and females were administered either oestradiol (E) or oil (OIL) daily for the first 5 postnatal days (p1-5E and p1-5OIL , respectively) because this time encompasses the emergence of clock gene rhythmicity and light responsiveness in the suprachiasmatic nucleus, a bilateral hypothalamic structure regarded as the 'master oscillator'. After sexual maturation, gonadectomy and exogenous oestradiol supplementation, locomotor parameters were assessed. We determined that altered oestrogenic signalling in early life exerts organisational control over the expression of daily and circadian activity rhythms in adult mice. Specifically, p1-5E reduced total wheel running activity in male and female ArKO and female WT mice but had no effect on WT male activity levels. In females, wheel running was consolidated by p1-5E to the early versus late evening, a phenomenon characteristic of male mice. The time of peak activity was advanced by p1-5E in WT and ArKO females but not males. P1-5E shortened the length of the active phase (alpha) in WT males but had no effect on ArKO males or females of either genotypes. Finally, p1-5E altered the magnitude of photic-induced shifts, suggesting that developmental oestrogenic signalling impacts adult circadian functions. In the present study, we further define both a critical period of development of the adult timekeeping system and the role that oestrogenic signalling plays in the expression of daily and circadian activity rhythms throughout life.

Sex Differences in Photic Entrainment and Sensitivity to Ethanol‐Induced Chronodisruption in Adult Mice After Adolescent Intermittent Ethanol Exposure

“…Although sex differences in phase-resetting were not analyzed per se , it is clear when comparing saline-treated groups that the magnitude of phase-delay was similar between males and females (~1.5 h). This is consistent with another recent study showing no difference in photic phase-shifting between wildtype male and female mice at ZT14 (Royston et al, 2016). However, these and other authors (Blattner and Mahoney, 2013) also report evidence that estrogen modulates phase-resetting and other circadian measures (discussed above).…”

“…Stowie and Glass (2015) also noted longer alpha and greater bout duration and intensity in adolescent and young adult female C57BL6J mice compared to age-matched males (Stowie and Glass, 2015). Similarly, Royston et al (2016) observed more wheel-running activity in adult female, compared to adult male mice of the same strain, a difference which was enhanced by aromatase deletion and dampened by estradiol (Royston et al, 2016). Longer activity duration has also been observed during DD in young adult (2-3 month old) female Per2 Luc mice on a C57BL6J background (Kuljis et al, 2013).…”

Modulation of circadian rhythms through estrogen receptor signaling

“…An additional experiment with GDX male and female ArKO mice and their respective GDX WT littermates found that exposure to estradiol at postnatal day (PD) 1–5 is essential for programming of circadian locomotor rhythms (Royston, Bunick, & Mahoney, ). Here, they found that OVX females treated with the oil control, irrespective of genotype, were significantly more active than GDX males treated with the oil control.…”

“…Normally, exposure to light in the early subjective night (ZT16, 4 hr after lights‐off) results in a phase delay of activity onset on subsequent days, while exposure to light in the late dark phase (ZT22, 2 hr before lights‐on) results in a phase advance. Early life exposure to estradiol during PD1‐5 appears to organize how the SCN responds to light in the early night in females, but not males (Royston et al., ). Interestingly, OVX WT females treated with early postnatal estradiol had a more robust response to light pulses at ZT16 compared to OVX WT females treated with oil, while OVX ArKO females treated with postnatal estradiol exhibited a phase response similar to OVX WT females.…”

Juvenile hormone affects the development and strength of circadian rhythms in young bumble bee (Bombus terrestris) workers

“…In mammals, it is well-established that sex steroid hormones have various organizational effects regulating the development of the circadian neural network and the expression of estrogen and androgen receptors which underlie sexual dimorphism in circadian activity (Hagenauer et al, 2011a(Hagenauer et al, , 2011bHummer et al, 2012;Melo et al, 2010;Royston et al, 2016;Sellix et al, 2013; for a recent review see Hatcher et al, 2020). Our findings that a single acute manipulation of JH levels shortly after adult eclosion from the pupa, resulted in relatively long term effects on the power of circadian rhythms best fit with the forth hypothesis stating that the influence of JH on circadian rhythms is mostly organizational.…”