Time for testosterone: the suprachiasmatic nucleus gets sexy

Abstract

One mechanism that has evolved to support optimal survival and success is an endogenous daily timekeeping capability, or circadian system. This system coordinates the timing of physiology and behavior, including reproductive events such as hormone release, ovulation, mating, parturition, and offspring care (1, 2). Given the life history and physiological differences between males and females, it is not surprising that these daily patterns exhibit sex differences and sensitivity to reproductive hormones (3). Natural life events, such as puberty, reproductive cycles, pregnancy, and menopause, as well as artificial hormone administration can alter the pacing (period) of endogenous rhythms or the alignment of these rhythms with time cues from the external environment, such as the solar day (3–7). Some of these changes are due to the activational (or immediate, transient) effects of reproductive hormones on circadian rhythms, but hormones can also give rise to organizational (long term, permanent) effects during development, producing sexual differentiation of circadian rhythm parameters and physiology (3). Until recently there was substantial debate over whether these effects of reproductive hormones on circadian rhythms could be the consequence of direct modulation of the central mammalian circadian regulator [the suprachiasmatic nuclei of the hypothalamus (SCN)]. This dispute arose because early reports were contradictory regarding the presence of hormone receptors in the region (4), suggesting that hormones might instead act downstream from the SCN by altering specific output pathways. This suspicion was further reinforced by the rapidity of some of the hormonal effects on circadian rhythms (8) because rhythms in the SCN were viewed as being slow to adjust after perturbation. The paper by Karatsoreos et al. (9) in the current issue sheds light on this debate because it provided a clear example of reproductive hormones (androgens) altering key components of SCN organization and function in male mice. The discovery that reproductive hormones could alter SCN function was facilitated by several large breakthroughs in our understanding of circadian physiology. Researchers determined that the daily cycle underlying circadian rhythms is generated by a molecular negative feedback loop within individual pacemaker cells in the SCN. Within this feedback loop, proteins produced by particular clock genes inhibit their own transcription, leading to daily cellular oscillations (10). These pacemaker cells use reciprocal communication to amplify oscillation and maintain a specific alignment between rhythmic events, a function referred to as oscillator coupling. It has been argued that the abundance of nonneuronal cells, called glia, in the SCN may play an important role in this coupling by modulating intercellular communication (11). Oscillator coupling is crucial because pacemaker cells can be divided into functional subgroups, characterized by different neurotransmitter content and connectivity. This provides a division of labor within the SCN. One functional subgroup (frequently referred to as the core of the SCN) is highly sensitive to environmental time cues. At particular times of day, time cues (typically light) cause an induction of components of the clock gene feedback loop, producing an overall phase shift (or realignment) of clock gene rhythms relative to the outside world. Another functional subgroup (often referred to as the shell of the SCN) sustains strong endogenous oscillation in the absence of rhythmic cues (12). Thus, the circadian system is entrained to maintain a particular alignment with environmental time cues, such as the solar day, by a hierarchical shifting of endogenous rhythms, which begins in the core of the SCN, is then relayed to the shell and finally conveyed to rhythmic oscillators throughout the rest of the body (13). These phase shifts occur within the SCN via a series of molecular events previously associated with long-term memory systems, including immediate early gene expression and synaptic remodeling (14). This increased understanding of circadian physiology allowed for a new generation of studies regarding the influence of reproductive hormones on the integrated SCN signals that synchronize the individual with the external world. Through these studies, it is clear that reproductive hormones could alter everything from clock gene rhythms, to elements of the entrainment pathway and oscillator coupling (15–26) (Fig. 1). However, to our knowledge, the recent series of papers by the group of Silver and colleagues (4, 27, 28), including the current paper in this issue of Endocrinology (9), is the first to present a compelling story tracing the effects of reproductive hormones on SCN physiology through molecular mechanisms to functional organization and organismal outcome. Growing evidence suggests that reproductive hormones influence the functioning of the SCN in adult rodents (3, 4, 15, 29