bims-ciryme 2026-04-12 papers

Nat Commun. 2026 Apr 07.

A hypothalamic circuit for circadian regulation of corticosterone secretion.

Oscar D Ramirez-Plascencia, Roberto De Luca, Natalia L S Machado, Dominique Eghlidi, Mudasir A Khanday, Sathyajit S Bandaru, Francesca Raffin, Nina Vujovic, Elda Arrigoni, Clifford B Saper.

There is a strong circadian rhythm of corticosteroid secretion in animals and humans, but the circuit for translating the suprachiasmatic (SCN) clock light-dark cycle rhythm into an increase in corticosteroid secretion beginning several hours before the active period is not known. We show here that in male mice, this rhythm depends upon input from the SCN to the subparaventricular zone (SPZ), and then to the dorsomedial nucleus of the hypothalamus (DMH). Both glutamatergic and GABAergic DMH neurons are required for the daily surge of corticosteroid secretion in anticipation of the active period. Glutamatergic DMH neurons directly excite paraventricular nucleus corticotrophin-releasing hormone (PVH-CRH) neurons, whereas DMH GABA neurons disinhibit PVH-CRH neurons via a relay in GABAergic neurons in the caudoventral PVH. This circuit underlies the daily surge in corticosteroid secretion that is temporally linked but phase advanced compared to the SCN activity cycle.

DOI: https://doi.org/10.1038/s41467-026-71482-0

Aging Cell. 2026 Apr;25(4): e70479

A Circadian Trough in Glucocorticoid Signaling Is Essential for Bone Health in Mice.

Annelies E Smit, Kaiming Yue, Sander Kooijman, Salwa Afkir, Maaike Schilperoort, Marijke Koedam, Bram C J van der Eerden, Jan Kroon, Onno C Meijer, Elizabeth M Winter.

We previously demonstrated that flattening circadian glucocorticoid (GC) rhythmicity without increasing overall GC exposure induces an osteoporotic phenotype in mice. Here, we aimed to further elucidate the importance of the amplitude and timing of circadian GC oscillations for bone health. C57Bl/6J mice were implanted with vehicle or corticosterone slow-releasing pellets to flatten the circadian GC rhythm. To differentiate between the importance of circadian GC peaks or troughs, mice with flattened GC rhythm received daily CORT injections at the time of the natural GC peak, or glucocorticoid receptor (GR) antagonist (RU486) injections at the time of the trough. One week of flattened GC rhythm reduced serum bone formation marker P1NP levels. Reinstating a trough with RU486 rescued this loss, whereas reinstating a GC peak did not. In an experiment in which mice with flattened GC rhythm received prolonged treatment for 7 weeks with RU486 at Zeitgeber time (ZT) 1 versus 11, we found that P1NP levels peaked with RU486 regardless of time of injection, altogether suggesting that bone formation depends on transient withdrawals from GCs. Seven weeks of flattened CORT rhythm reduced total lean mass and induced cortical bone thinning and trabecular bone loss. RU486 injection at either timepoint prevented cortical bone decline. Notably, trabecular bone volume was only preserved when RU486 was injected at the time of the natural GC trough at ZT1. In conclusion, reinstating a trough in GR signaling at its natural time of the day suffices to prevent osteoporosis in mice under conditions of flattened GC rhythm.

Keywords: aging; circadian rhythm; glucocorticoids; osteoporosis; translational research

DOI: https://doi.org/10.1111/acel.70479

bioRxiv. 2026 Mar 31. pii: 2026.03.27.714759. [Epub ahead of print]

Genetic Identification of Dopamine Neurons Required for Circadian Food Anticipatory Activity in Mice.

Andrew P Villa, Jacqueline Trzeciak, Damien Wolfe, David E Ehichioya, Jeffrey Falkenstein, Justine T Wong, Lauren Dimalanta, Wyatt Kaiban, Jaskaran Dhanoa, Gregory Stevens, Fernando Garcia, Lori Scarpa, Chris Chalfoun, Larry S Zweifel, Rajeshwar Awatramani, Richard D Palmiter, Martin Darvas, Shin Yamazaki, Andrew D Steele.

Anticipating daily food availability is a conserved circadian behavior that persists even in animals lacking the suprachiasmatic nucleus, yet the neural substrates of this behavior remain poorly defined. Striatal dopamine signaling through D1 receptors promotes food anticipatory activity (FAA), but the dopaminergic neurons responsible are unknown. Here, we conditionally deleted tyrosine hydroxylase ( Th ) from genetically defined dopaminergic neuronal populations in mice. Broad deletion of Th in dopamine transporter-expressing neurons nearly abolished FAA, while viral restoration of Th in substantia nigra neurons was sufficient to rescue anticipatory locomotion. Surprisingly, deletion of Th from several large molecularly defined dopamine neuron populations had little effect on FAA. In contrast, Th deletion using Calb1 Cre , affecting a relatively small subset (25%) of substantia nigra dopamine neurons, produced a profound FAA deficit. Notably, these mice retained anticipatory food-seeking behavior but failed to express anticipatory locomotion. These findings identify a small Calbindin1 + dopamine population that is required for the motor expression, but not the timekeeping, of food anticipation, revealing a genetic dissociation between circadian prediction and behavioral output.

DOI: https://doi.org/10.64898/2026.03.27.714759

J Biol Rhythms. 2026 Apr 10. 7487304261427042

Daily Rhythms in Clock Gene mRNA Expression in Serotonergic Brain Regions of Adult Male Rats.

Helen K Strnad, Robert L Spencer.

Dysregulation of the serotonergic system is consistently noted in cases of psychiatric pathology. Circadian rhythm dysregulation is also a common comorbidity in psychiatric populations, and the circadian and serotonergic systems have a long history of coregulation. Despite this, it is not yet known whether serotonergic neurons house circadian molecular clocks, the transcription and translation feedback loops that drive circadian rhythms at the cellular level. To investigate this, brain tissue was extracted from adult male rats every 4 h throughout the light-dark cycle. Radiolabeled in situ hybridization was used to quantify clock gene expression in the dorsal and median raphe, the two nuclei responsible for providing the majority of serotonin to the brain. We discovered oscillatory rhythms in the expression of clock genes Bmal1, Per1, and Per2 with a period of approximately 24 h, and confirmed via fluorescent in situ hybridization that serotonergic (positive for Tph2, the rate-limiting enzyme in serotonin synthesis) neurons do express clock genes. The roughly antiphasic relationship between Bmal1 and the Per genes supports the existence of a circadian molecular clock in these cells. We next measured clock gene expression in neighboring brainstem regions that were not serotonergic, and found that although they all had similar daily clock gene expression profiles, the dorsal and median raphe had higher amplitude Bmal1 expression, and trending higher amplitude Per1 expression. This study adds to the growing list of extra-SCN (suprachiasmatic nucleus) molecular clocks reported in the brain. The prevalence of this circadian machinery, especially in regions of the brain so relevant to psychiatric health, underscores the importance of circadian rhythms to well-being. A greater understanding of the unique nature of circadian rhythms in discrete brain regions is a fruitful frontier for improving psychiatric treatment outcomes and overall health.

Keywords: Bmal1; Per1; Per2; dorsal raphe nucleus; median raphe nucleus

DOI: https://doi.org/10.1177/07487304261427042

Curr Biol. 2026 Apr 07. pii: S0960-9822(26)00325-8. [Epub ahead of print]

The impact of self-selected light on activity rhythms in the diurnal striped mouse.

Rebecca B Hughes, Beatriz Bano-Otalora, Martha Davey, Franck P Martial, Aadhithyan Babu, Jonathan Wynne, Timothy M Brown, Robert J Lucas.

Access to self-selected light (SSL) breaks the ancient relationship between light and time of day and can disrupt sleep and circadian rhythms in humans. Such disruptions have been explained in terms of established features of circadian photosensitivity and positive associations between arousal and light. We address the potential of such intrinsic relationships to recapitulate the disruptive effects of SSL in a day-active rodent (Rhabdomys pumilio [R. pumilio]) that lacks the additional human drivers to consume light for work, care, and leisure. R. pumilio learns to SSL spontaneously and expresses a circadian rhythm in light intensity preference (choosing darkness and brightest available light for inactive and active phases, respectively), which feeds back to modify circadian period (τ) and extend active phase (α). Under imposed light:dark (LD) cycles, SSL can lead to increased dark phase activity and disrupted entrainment when SSL irradiance is ≥ imposed light. SSL does not exacerbate aberrant phase angles of entrainment in simulated social jet lag but can substantially delay re-entrainment to shifts in the external LD cycle. Our findings establish bright light as an innate preference in R. pumilio and are consistent with intrinsic relationships between light, arousal, and the clock being an origin for the disruptive effects of SSL.

Keywords: Rhabdomys pumilio; arousal; circadian clock; day-active; four-striped grass mouse; light preference; light:dark cycle; locomotor activity; phase response curve; sensory feedback

DOI: https://doi.org/10.1016/j.cub.2026.03.036