Estrogen-mediated coupling in the central clock

• Applicant: Dr. Violetta Pilorz
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Cognitive, Systems and Behavioural Neurobiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 538741530

The timing of many behaviours and physiological functions is controlled by a central clock in the suprachiasmatic nucleus (SCN) of the hypothalamus. The individual cells of the SCN generate circadian rhythms with remarkable precision. This precision is facilitated by intrinsic coupling mechanisms such as neurotransmitters and gap junctions composed of connexins (CX). In female rodents, the presence of estrogen receptors (ERs) in the SCN suggests a potential feedback mechanism involving estrogen (E2) that could regulate circadian rhythm and coupling. In females, behavioural rhythms interact with estrogen (E2) variation over the estrous cycle. At the peak of E2, females show a high amplitude in their locomotor activity rhythm compared to females with low E2 levels. We recently discovered that female mice in proestrous, a phase of high E2 concentration, show accelerated adaptation of behavioural and molecular rhythms to a new light-dark (LD) cycle compared to females in metestrous. Interestingly, the phase of the SCN lagged behind the phase of the peripheral oscillators during the transition to a new LD cycle. This finding suggests that gonadal secretion directly influences coupling in the SCN, thereby modulating the SCN's response to environmental changes. We hypothesise that E2 influences cell coupling in the SCN and modulates responses to environmental changes such as changes in light. Furthermore, we intend to contrast the effects of E2 with those of progesterone (P4), given its opposing impact on estrogenic functions such as its inhibitory effect on ER and Cx expression. We will use female mice of the PER2::LUCIFERASE mouse strain to elucidate the effect of E2 and P4 on central clock coupling. The work programme will include ex vivo and in vivo experiments that will allow us to address the hypothesis from three perspectives: 1. recording circadian PER2 bioluminescence and conducting Ca2+ imaging to examine inter-cellular coupling. 2. Investigating the involvement of ERs and progesterone receptors (PRs) in the regulation of SCN circuitry. 3. Exploring the systemic coupling response to light mediated by sex hormones.

• DFG Programme: Research Grants