Mutual Shaping of Circadian Body-Wide Synchronization by the Suprachiasmatic Nucleus and Circulating Steroids

Abstract

BackgroundSteroids are lipid hormones that reach bodily tissues through the systemic circulation, and play a major role in reproduction, metabolism, and homeostasis. All of these functions and steroids themselves are under the regulation of the circadian timing system (CTS) and its cellular/molecular underpinnings. In health, cells throughout the body coordinate their daily activities to optimize responses to signals from the CTS and steroids. Misalignment of responses to these signals produces dysfunction and underlies many pathologies.Questions AddressedTo explore relationships between the CTS and circulating steroids, we examine the brain clock located in the suprachiasmatic nucleus (SCN), the daily fluctuations in plasma steroids, the mechanisms producing regularly recurring fluctuations, and the actions of steroids on their receptors within the SCN. The goal is to understand the relationship between temporal control of steroid secretion and how rhythmic changes in steroids impact the SCN, which in turn modulate behavior and physiology.Evidence SurveyedThe CTS is a multi-level organization producing recurrent feedback loops that operate on several time scales. We review the evidence showing that the CTS modulates the timing of secretions from the level of the hypothalamus to the steroidogenic gonadal and adrenal glands, and at specific sites within steroidogenic pathways. The SCN determines the timing of steroid hormones that then act on their cognate receptors within the brain clock. In addition, some compartments of the body-wide CTS are impacted by signals derived from food, stress, exercise etc. These in turn act on steroidogenesis to either align or misalign CTS oscillators. Finally this review provides a comprehensive exploration of the broad contribution of steroid receptors in the SCN and how these receptors in turn impact peripheral responses.ConclusionThe hypothesis emerging from the recognition of steroid receptors in the SCN is that mutual shaping of responses occurs between the brain clock and fluctuating plasma steroid levels.

Parallel trajectories in the discovery of the SCN‐OVLT and pituitary portal pathways: Legacies of Geoffrey Harris

“…There is a vast literature from our lab and many others on the body-wide effects of each of these systems. [8][9][10][11]…”

“…In that case, the signal from the SCN reaches a target in the OVLT, which in turn communicates throughout the brain via the cerebrospinal fluid. There is a vast literature from our lab and many others on the body‐wide effects of each of these systems 8–11 …”

Connecting the Dots: Potential Interactions Between Sex Hormones and the Circadian System During Memory Consolidation

“…Within rodents, androgen receptors are localized to the core region of the SCN and are sensitive to light stimulation ( Karatsoreos et al, 2007 ). Unlike androgen receptors, estrogen receptors are expressed in both the shell and core of the SCN, with one type of receptor, estrogen receptor-β being expressed more frequently than estrogen receptor-α (for review see Hatcher et al, 2020 ; Yao and Silver, 2022 ). Progestin receptors are also present in the SCN, but very little has been characterized about their localization ( Kruijver and Swaab, 2002 ).…”

Nutrient-sensitive protein O-GlcNAcylation shapes daily biological rhythms

“…Brain and muscle Arnt-like protein-1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK) are the key transcriptional activators of the mammalian clock (Drosophila homologues are dCYCLE and dCLOCK (dCLK)), and as heterodimers, they drive the expression of thousands of clock-controlled genes including genes that encode their own transcriptional repressors, PERIOD1-3 (PER1-3) and CRYP-TOCHROME1-2 (CRY1-2) (dPER and dTIMELESS (dTIM) in Drosophila) (figure 3). The molecular oscillator is critical for generating daily rhythmicity of gene expression that manifest into a range of rhythmic biological processes (reviewed in [1][2][3][4][5][6][7][8][9][10]). PTMs, especially phosphorylation, have been established as essential mechanisms for maintaining the pace of the molecular oscillator [174][175][176].…”

“…In coordination with processes that are regulated by posttranscriptional mechanisms, clock-regulated rhythmic gene expression programs that are often tissue-and cell-specific produce daily rhythms in clock outputs. The outputs of animal circadian clocks are all-encompassing and include rhythmic processes such as sleep-wake cycles, feeding-fasting cycles, metabolism, hormone production and secretion, immune response, neuronal excitability and even permeability of the blood-brain barrier [3][4][5][6][7][8][9][10]. There is growing evidence that some clock outputs are themselves zeitgebers (i.e.…”