Biology subjects

Nikhil, K. L.

Publications and source records attributed to Nikhil, K. L..

4 recordsLinked to original sources

bioRxiv2025

Fetoplacental circadian rhythms develop and then synchronize to the mother in utero

Circadian rhythms in gene expression and hormones are ubiquitous across species and differentiated cell types, yet their developmental origins remain poorly understood. This study aimed to determine if daily rhythms can be detected in utero and if they synchronize to the mother. We developed methods to longitudinally monitor PERIOD2 (PER2), a core circadian clock protein, from embryonic day (E)8.5 to E17.5 by restricting PER2::LUCIFERASE (PER2::LUC) expression to the mouse fetoplacental unit (fetus and fetal-derived tissues). In utero fetoplacental bioluminescence imaging showed that PER2 levels rose exponentially during pregnancy, with variable daily peak times that stabilized to dusk by E15.5. Interestingly, pregnancies that did not exhibit daily in utero PER2 variation were more likely to fail. Because maternal glucocorticoids have been implicated in fetal development and synchronizing other circadian tissues, we tested its capability to shift fetoplacental PER2 rhythms in utero. Daily subcutaneous glucocorticoid injections over five days of late pregnancy phase-dependently shifted the fetoplacental PER2 rhythms in utero. Blocking glucocorticoid signaling in vitro reduced synchrony between maternal and fetal placenta by [~]40%. We conclude that in utero daily rhythms gradually develop and synchronize with the mother prior to birth, potentially through glucocorticoid signaling.

developmental biology↗

bioRxiv2024

The Functional Connectome Mediating Circadian Synchrony in the Suprachiasmatic Nucleus

Circadian rhythms in mammals arise from the spatiotemporal synchronization of [~]20,000 neuronal clocks in the Suprachiasmatic Nucleus (SCN). While anatomical, molecular, and genetic approaches have revealed diverse cell types and signaling mechanisms, the network wiring that enables SCN cells to communicate and synchronize remains unclear. To overcome the challenges of revealing functional connectivity from fixed tissue, we developed MITE (Mutual Information & Transfer Entropy), an information theory approach that infers directed cell-cell connections with high fidelity. By analyzing 3447 hours of continuously recorded clock gene expression from 9011 cells in 17 mice, we found that the functional connectome of SCN was highly conserved bilaterally and across mice, sparse, and organized into a dorsomedial and a ventrolateral module. While most connections were local, we discovered long-range connections from ventral cells to cells in both the ventral and dorsal SCN. Based on their functional connectivity, SCN cells can be characterized as circadian signal generators, broadcasters, sinks, or bridges. For example, a subset of VIP neurons acts as hubs that generate circadian signals critical to synchronize daily rhythms across the SCN neural network. Simulations of the experimentally inferred SCN networks recapitulated the stereotypical dorsal-to-ventral wave of daily PER2 expression and ability to spontaneously synchronize, revealing that SCN emergent dynamics are sculpted by cell-cell connectivity. We conclude that MITE provides a powerful method to infer functional connectomes, and that the conserved architecture of cell-cell connections mediates circadian synchrony across space and time in the mammalian SCN. HighlightsO_LIWe developed MITE, an information theory method, to accurately infer directed functional connectivity among circadian cells. C_LIO_LISCN cell types with conserved connectivity patterns spatially organize into two regions and function as generators, broadcasters, sinks, or bridges of circadian information. C_LIO_LIOne-third of VIP neurons serve as hubs that drive circadian synchrony across the SCN. C_LIO_LIKey connectivity features mediate the generation and maintenance of intercellular synchrony and daily waves of clock gene expression across the SCN. C_LI

neuroscience↗

bioRxiv2023

Fetal daily rhythms develop during pregnancy and entrain to the maternal circadian system

Circadian rhythms in gene expression and hormones are ubiquitous across species and differentiated cell types. This study aimed to determine when daily rhythms begin in the fetus and synchronize to the mother. We developed methods to monitor the expression of fetal PERIOD2 (PER2), a core circadian clock protein, in mice longitudinally from embryonic day (E)8.5 to E17.5 through in utero bioluminescence imaging. We found that embryonic PER2 expression increased rapidly throughout pregnancy and exhibited day-night rhythms from the start of our recordings at E8.5. The daily peak time of PER2 varied between pregnancies until it reliably peaked at night and synchronized to the mother starting around E15.5. Loss of fetal circadian rhythms associated with pregnancies that ultimately failed. Because maternal glucocorticoids have been implicated in fetal development and synchronizing circadian tissues, we tested their sufficiency to shift fetal daily rhythms in utero. Daily glucocorticoids injections over five days of late pregnancy advanced fetal PER2 rhythms in utero and blocking glucocorticoid signaling in vitro reduced PER2 synchrony between the maternal and fetal placenta by [~]40%. We conclude that fetal daily rhythms arise early in pregnancy and then synchronize with the maternal rhythm prior to birth depending, in part, on glucocorticoid signaling.

developmental biology↗

bioRxiv2019

Circadian period-heterogeneity is governed by clonal inheritance of variable gene expression

A ubiquitous feature of circadian clocks across life forms is its organization as a network of coupled cellular oscillators. Individual cellular oscillators of the network often exhibit a considerable degree of heterogeneity in their intrinsic periods. While the interaction of coupling and heterogeneity in circadian clock networks is hypothesized to influence clocks entrainability, our knowledge of mechanisms governing network heterogeneity remains elusive. In this study, we aimed to explore the principles that underlie inter-cellular period variation in circadian clock networks (clonal period-heterogeneity). To this end, we employed a laboratory selection approach and derived a panel of 25 clonal cell populations exhibiting circadian periods ranging from 22 h to 28 h. We report that while a single parent clone can produce progeny clones with a wide distribution of circadian periods, heterogeneity is not entirely stochastically driven but has a strong heritable component. By quantifying the expression of 20 circadian clock and clock-associated genes across our panel, we found that inheritance of different expression patterns in at least three clock genes might govern clonal period-heterogeneity in circadian clock networks. Furthermore, we provide preliminary evidence suggesting that epigenetic variation might underlie such gene expression variation.

cell biology↗