Androgens Modulate Structure and Function of the Suprachiasmatic Nucleus Brain Clock

Abstract

Gonadal hormones can modulate circadian rhythms in rodents and humans, and androgen receptors are highly localized within the core region of the mouse suprachiasmatic nucleus (SCN) brain clock. Although androgens are known to modulate neural plasticity in other CNS compartments, the role of androgens and their receptors on plasticity in the SCN is unexplored. In the present study, we ask whether androgens influence the structure and function of the mouse SCN by examining the effects of gonadectomy (GDX) on the structure of the SCN circuit and its responses to light, including induction of clock genes and behavioral phase shifting. We found that after GDX, glial fibrillary acidic protein increased with concomitant decreases in the expression of the synaptic proteins synaptophysin and postsynaptic density 95. We also found that GDX exerts effects on the molecular and behavioral responses to light that are phase dependent. In late night [circadian time (CT)21], GDX increased light-induced mPer1 but not mPer2 expression compared with intact (INT) controls. In contrast, in early night (CT13.5), GDX decreased light induced mPer2 but had no effect on mPer1. At CT13.5, GDX animals also showed larger phase delays than did INT. Treatment of GDX animals with the nonaromatizable androgen dihydrotestosterone restored glial fibrillary acidic protein, postsynaptic density 95, and synaptophysin in the SCN and reinstated the INT pattern of molecular and behavioral responses to light. Together, the results reveal a role for androgens in regulating circuitry in the mouse SCN, with functional consequences for clock gene expression and behavioral responses to photic phase resetting stimuli.

Hippocampal gene expression induced by cold swim stress depends on sex and handling

“…Previous work has already demonstrated that handling can interact with the effects of ovarian hormones to impact hippocampus sensitive behaviors (Bohacek and Daniel, 2007), so the effect of ovarian hormones on Per1 expression needs to be explored in future experiments. Indeed, Per1 expression in the suprachiasmatic nucleus brain clock has been shown to be sensitive to circulating androgen levels (Karatsoreos et al, 2011), raising the possibility that steroid hormones can have modulatory effects on Per1 expression in different brain regions, possibly in concert with stress-hormones. Importantly, the present work used naturally cycling females, without controlling for the hormonal fluctuations occurring across the estrous cycle that may affect the responsiveness to stress (Figueiredo et al, 2002).…”

Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales

“…The existence of an essentially parallel literature on reproductive hormones and clock genes (Nakamura et al, 2008;Nakamura et al, 2010;Karatsoreos et al, 2011) again demonstrate the present minimal awareness of the functionally important adjacent positions of sex hormones and TNF in the same regulatory pathway. Certain clock genes have been demonstrated to undergo insulin-dependent regulation (Tahara et al, 2011), and to control adult neurogenesis, including in the hippocampus (Moriya et al, 2007;Borgs et al, 2009;Kimiwada et al, 2009), as well as endothelial cell (Wang et al, 2008) and cartilage (Mengatto et al, 2011) progenitors.…”

Time for Testosterone: The Suprachiasmatic Nucleus Gets Sexy

“…This relationship became more provocative as they demonstrated that androgen administration in male mice can affect the molecular responses to time cues within the SCN, including immediate early gene expression (27), and in the current study, the induction of clock genes and structural plasticity (9). Finally, in this current study, they find that androgens are able to alter a potential physiological correlate of oscillator coupling, the proliferation of glial cells (9). This finding is consistent with their earlier behavioral results, indicating that androgens enhance rhythm precision (27) because models suggest that rhythm precision benefits from enhanced oscillator coupling.…”

“…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.…”

“…Using this information, they demonstrated that androgens (testosterone, dihydrotestosterone) were able not only to alter the endogenous period of behavioral rhythms in male mice (29) but also to alter rhythm properties that are closely associated with the function of the core of the SCN: phase shifting in response to environmental time cues, entrained phase, and rhythm precision (9,27,28). This relationship became more provocative as they demonstrated that androgen administration in male mice can affect the molecular responses to time cues within the SCN, including immediate early gene expression (27), and in the current study, the induction of clock genes and structural plasticity (9). Finally, in this current study, they find that androgens are able to alter a potential physiological correlate of oscillator coupling, the proliferation of glial cells (9).…”