Biology subjects

Jagannath, A.

Publications and source records attributed to Jagannath, A..

13 recordsLinked to original sources

bioRxiv2026

Hyperglycaemia reversibly disrupts circadian behaviour in mice

Disrupted sleep and circadian rhythms are among the most common features of diabetes, and are known to raise the risk of developing the disease. Whether the relationship also runs the other way, with diabetes itself disrupting the clock, has remained unresolved. Using an inducible mouse model of diabetes, in which hyperglycaemia can be induced and then reversed within the same animal, we show that elevated blood glucose is a reversible cause of circadian disruption. Raising blood glucose reduced the amplitude of circadian rest-activity rhythms by 50%, in proportion to the degree of hyperglycaemia, and shortened the free-running period of the clock. Restoring normoglycaemia reversed both effects. Diabetic animals had a delayed phase of activity onset, i.e. later chronotype, and re-entrained more slowly after a simulated jet lag. However, phase shifting to nocturnal light pulses was intact, suggesting normal photic responses. Brain glucose and O-GlcNAcylation, a nutrient-sensitive protein modification, were both elevated in diabetic animals, showing that peripheral hyperglycaemia reaches the brain and alters its metabolic state, and providing a molecular readout of that exposure. Together, these findings establish that a peripheral metabolic state is a reversible determinant of circadian rest-activity behaviour, completing a bidirectional link between blood glucose and the clock and arguing that the two must be treated together rather than in isolation.

neuroscience↗

bioRxiv2026

Lithium drives coordinated changes in the mouse synaptic phosphoproteome

Lithium is the gold standard mood stabiliser used to treat cycling mania and depression in bipolar disorder. Despite seven decades of clinical use, the mechanisms of its mood stabilisation are incompletely understood, fundamentally limiting development of improved alternatives. Two established lithium targets, glycogen synthase kinase 3{beta} (GSK3{beta}) and inositol monophosphatase, both modulate phosphorylation, suggesting lithium may exert broad effects on neuronal phosphorylation networks. We performed a discovery-phase in vitro screen of 140 kinases at 10mM LiCl and demonstrated that lithium inhibits 17 kinases beyond GSK3{beta}. We therefore used untargeted quantitative phosphoproteomics to create a comprehensive map of lithiums neural phosphorylation signature in lithium-treated mouse synaptoneurosomes. Samples were collected at dawn and dusk to match the peaks in phosphorylation that are induced by the sleep/wake cycle. Pathway analysis revealed convergence on synaptic plasticity, neurotransmitter release, and chemical transmission. Critically, lithium-sensitive phosphoproteins are significantly enriched in bipolar disorder genome-wide association study (GWAS) loci, providing independent genomic evidence that the phosphorylation networks we identified are relevant to bipolar pathophysiology. We identified novel kinase targets and phosphorylation sites not previously associated with lithiums mechanism of action and tied them to bipolar pathology. We further refined existing models of lithiums action by showing that GSK3{beta} inhibition is temporally restricted to dawn, indicating cross talk with sleep/wake cycles of phosphorylation. Overall, our data demonstrate that lithiums pleiotropic effects result from coordinated multi-kinase network reorganisation rather than single-target inhibition -- a principle with direct implications for rational polypharmacology in mood stabiliser development.

neuroscience↗

bioRxiv2026

Measurement Method Influences the Interpretated Effect of Oral Gavage on Murine Circadian Activity

Historically, the primary method for measuring murine circadian activity in vivo has been monitoring voluntary wheel running. Recently, passive infrared (PIR) motion sensors have emerged as an alternative that is not reliant on voluntary behaviour. While research has examined the differences between the two methods for measuring circadian parameters, little focus has been placed on how these techniques may confound the assessment of therapeutic interventions. Here, we show that wheel running activity is disproportionately affected by daily oral gavage of saline compared to sham gavage treatment. In contrast, PIR-monitored activity indicates little difference between the two treatments. Both PIR and running-wheel-measured activity show a reduction in circadian amplitude and an increase in intradaily variability during both types of gavage, likely reflecting the stress of daily gavage, though the mice showed no weight loss. This finding indicates that pre- and post-intervention comparisons will misattribute gavage effects to the intervention unless appropriate sham and vehicle controls are included. More broadly, the choice of circadian measurement technique fundamentally shapes the interpretation of pharmacological interventions and must be considered in experimental design.

animal behavior and cognition↗

bioRxiv2024

The dynamic gene regulatory landscape of the mouse brain in response to sleep deprivation

Sleep deprivation (SD) negatively impacts nearly all brain functions including cognition, memory consolidation and metabolism. However, the gene regulatory networks that underlie these biological effects are not well understood. In order to identify these networks, we conducted a multiomic analysis to analyse how gene expression, chromatin accessibility, enhancer activity and DNA methylation change with acute SD in mice. By studying three brain regions involved in different aspects of sleep - the cortex (CTX), dentate gyrus (DG), and suprachiasmatic nucleus (SCN) - we found that the effects of SD on the multiome varied widely, impacting physiological processes specific to each area, from spine formation in the dentate gyrus to neuropeptide release in the SCN. Our integrated analysis showed that distinct brain region-specific networks of regulatory factors dynamically alter the epigenomic landscape in response to SD to orchestrate transcriptional responses. These findings provide new understanding of the regulatory grammar encoded within the genome, which enables a general physiological signal like SD to produce unique effects in a tissue-specific context.

neuroscience↗

bioRxiv2023

Adenosine Kinase regulates Sleep Timing and the Homeostatic Sleep Response through Distinct Molecular Pathways

Sleep behaviour is broadly regulated by two drives, the circadian (Process C), which is orchestrated by the suprachiasmatic nuclei (SCN), and controls sleep timing, and the homeostatic (Process S), which controls sleep amount and the response to sleep deprivation (Borbely et al., 2016). However, the molecular pathways that mediate their independent effects, and their interactions remain unclear. Adenosine is an important integrator of both processes (Bjorness & Greene, 2009; Jagannath et al., 2021, 2022), such that adenosine levels track and modulate wakefulness, whilst adenosine signalling inhibits the circadian response to light. Therefore, we studied the sleep/circadian behaviour, and cortical and SCN transcriptomic profiles of a mouse model overexpressing Adenosine Kinase (Adk-Tg) (Fedele et al., 2005), (Palchykova et al., 2010). We found that overall, the Adk-Tg mouse slept less and showed lower amplitude circadian rhythms with an altered sleep/wake distribution across the 24h day, which correlated with changes in transcription of synaptic signalling genes that would shift the excitatory/inhibitory balance. In addition, the Adk-Tg mouse showed a reduced level of ERK phosphorylation, and attenuation of DNA repair related pathways. After sleep deprivation, however, the Adk-Tg mouse significantly increased relative to wildtype, immediate early gene expression levels including of Arc, but paradoxically reduced ERK phosphorylation. Thus, baseline sleep levels and timing are regulated by ERK signalling, whereas the response to sleep loss is mediated by the alteration of the transcriptomic landscape independently of ERK.

molecular biology↗

bioRxiv2023

Sex specific regulation of the cortical transcriptome in response to sleep deprivation

Multiple studies have documented sex differences in sleep behaviour, however the molecular determinants of such differences remain unknown. Furthermore, most studies addressing molecular mechanisms have been performed only in males, leaving the current state of knowledge biased towards the male sex. To address this, we studied the differences in the transcriptome of the cerebral cortex of male and female C57Bl/6J mice after six hours of sleep deprivation. We found that several genes, including the neurotrophin growth factor Bdnf, immediate early genes Fosb and Fosl2, and the adenylate cyclase Adcy7 are differentially upregulated in males compared to females. We identified the androgen-receptor activating transcription factor EZH2 as the upstream regulatory element specifying sex differences in the sleep deprivation transcriptome. We propose that the pathways downstream of these transcripts, which impact on cellular re-organisation, synaptic signalling and learning may underpin the differential response to sleep deprivation in the two sexes.

molecular biology↗

bioRxiv2022

Sleep and circadian rhythm disruption alters the lung transcriptome to predispose to viral infection

Sleep and circadian rhythm disruption (SCRD), as encountered during shift work, increases the risk of respiratory viral infection including SARS-CoV-2. However, the mechanism(s) underpinning higher rates of respiratory viral infection following SCRD remain poorly characterised. To address this, we investigated the effects of acute sleep deprivation on the mouse lung transcriptome. Here we show that sleep deprivation profoundly alters the transcriptional landscape of the lung, causing the suppression of both innate and adaptive immune systems, disrupting the circadian clock, and activating genes implicated in SARS-CoV-2 replication, thereby generating a lung environment that promotes viral infection and associated disease pathogenesis. Our study provides a mechanistic explanation of how SCRD increases the risk of respiratory viral infections including SARS-CoV-2 and highlights therapeutic avenues for the prevention and treatment of COVID-19.

neuroscience↗

bioRxiv2021

Light-regulated SIK1 remodels the synaptic phosphoproteome to induce sleep

The sleep and circadian systems act in concert to regulate sleep-wake timing, yet the molecular mechanisms that underpin their interaction to induce sleep remain unknown. Synaptic protein phosphorylation, driven by the kinase SIK3, correlates with sleep pressure, however it is unclear whether these phosphoproteome changes are causally responsible for inducing sleep. Here we show that the light-dependent activity of SIK1 controls the phosphorylation of a subset of the brain phosphoproteome to induce sleep in a manner that is independent of sleep pressure. By uncoupling phosphorylation and sleep induction from sleep pressure, we establish that synaptic protein phosphorylation provides a causal mechanism for the induction of sleep under different environmental contexts. Furthermore, we propose a framework that details how the salt-inducible kinases regulate the synaptic phosphoproteome to integrate exogenous and endogenous stimuli, thereby providing the molecular basis upon which the sleep and circadian systems interact to control the sleep-wake cycle.

neuroscience↗

bioRxiv2021

Dystrophin regulates peripheral circadian SRF signalling

Dystrophin is a sarcolemmal protein essential for muscle contraction and maintenance, absence of which leads to the devastating muscle wasting disease Duchenne muscular dystrophy (DMD)[1, 2]. Dystrophin has an actin-binding domain [3-5], which specifically binds and stabilises filamentous (F)-actin[6], an integral component of the RhoA-actin-serum response factor (SRF)-pathway[7]. The RhoA-actin-SRF-pathway plays an essential role in circadian signalling whereby the hypothalamic suprachiasmatic nucleus, transmits systemic cues to peripheral tissues, activating SRF and transcription of clock target genes[8, 9]. Given dystrophin binds F-actin and disturbed SRF-signalling disrupts clock entrainment, we hypothesised that dystrophin loss causes circadian deficits. Here we show for the first time alterations in the RhoA-actin-SRF-signalling-pathway, in both dystrophin-deficient myotubes and dystrophic mouse models. Specifically, we demonstrate reduced F/G-actin ratios and nuclear MRTF, dysregulation of core clock and downstream target-genes, and down-regulation of key circadian genes in muscle biopsies from DMD patients harbouring an array of mutations. Further, disrupted circadian locomotor behaviour was observed in dystrophic mice indicative of disrupted SCN signalling, and indeed dystrophin protein was absent in the SCN of dystrophic animals. Dystrophin is thus a critically important component of the RhoA-actin-SRF-pathway and a novel mediator of circadian signalling in peripheral tissues, loss of which leads to circadian dysregulation.

cell biology↗

bioRxiv2021

Circadian regulation of SARS-CoV-2 infection in lung epithelial cells

The COVID-19 pandemic, caused by SARS-CoV-2 coronavirus, is a global health issue with unprecedented challenges for public health. SARS-CoV-2 primarily infects cells of the respiratory tract, via Spike glycoprotein binding angiotensin-converting enzyme (ACE2). Circadian rhythms coordinate an organisms response to its environment and can regulate host susceptibility to virus infection. We demonstrate a circadian regulation of ACE2 in lung epithelial cells and show that silencing BMAL1 or treatment with a synthetic REV-ERB agonist SR9009 reduces ACE2 expression and inhibits SARS-CoV-2 entry. Treating infected cells with SR9009 limits viral replication and secretion of infectious particles, showing that post-entry steps in the viral life cycle are influenced by the circadian system. Transcriptome analysis revealed that Bmal1 silencing induced a wide spectrum of interferon stimulated genes in Calu-3 lung epithelial cells, providing a mechanism for the circadian pathway to dampen SARS-CoV-2 infection. Our study suggests new approaches to understand and improve therapeutic targeting of SARS-CoV-2.

microbiology↗

bioRxiv2020

Cold induced chromatin compaction and nuclear retention of clock mRNAs resets the circadian rhythm

Cooling patients to sub-physiological temperatures is an integral part of modern medicine. We show that cold exposure induces temperature-specific changes to the higher-order chromatin and gene expression profiles of human cells. These changes are particularly dramatic at 18{degrees}C, a temperature synonymous with that experienced by patients undergoing controlled deep-hypothermia during surgery. Cells exposed to 18{degrees}C exhibit largely nuclear-restricted transcriptome changes. These include the nuclear accumulation of core circadian clock suppressor gene transcripts, most notably REV-ERB. This response is accompanied by compaction of higher-order chromatin and hindrance of mRNPs from engaging nuclear pores. Rewarming reverses chromatin compaction and releases the transcripts into the cytoplasm, triggering a pulse of suppressor gene proteins that resets the circadian clock. We show that cold-induced upregulation of REV-ERB alone is sufficient to trigger this resetting. Our findings uncover principles of the cellular cold-response that must be considered for current and future applications involving therapeutic deep-hypothermia.

molecular biology↗

bioRxiv2020

The role of the hypothalamus in cortical arousaland sleep homeostasis

Sleep and wakefulness are not simple homogenous all-or-none states, but instead are characterized by rich dynamics of brain activity across many temporal and spatial scales. Rapid global state transitions between waking and sleeping are believed to be controlled by hypothalamic circuits, but the contribution of the hypothalamus to within-state changes of sleep and wake "intensity" remains largely unexplored. Here we show that stimulation of inhibitory neurons in the preoptic hypothalamus does not merely trigger awakening from sleep, but the resulting awake state is also characterized by increased cortical activity. This activation is associated with a faster build-up of sleep pressure, proportional to the arousal level. These findings show that hypothalamic systems thought to exclusively control global state switching, also regulate within-state "intensity", which we propose as a key intrinsic variable in shaping the architecture of sleep/wake states across the 24h day.

neuroscience↗

bioRxiv2019

De novo transcriptome profiling of mustard aphid (Lipaphis erysimi) and differential expression of transcripts associated with developmental stages, feeding and non-feeding conditions

Lipaphis erysimi is a Brassicaceae specialist aphid, which causes significant losses in yield and/or reduction of oil content of vegetable and oilseed brassicas and is a major pest in the Indian subcontinent. This study reports the de novo transcriptome of L. erysimi for the first time. We also present a comparative analysis of nymphs and adult transcriptomes to study the differential expression profiles associated with different developmental stages as well as different feeding conditions. For this, RNA-seq was performed on three different biological samples adults, nymphs (with all nymph stages pooled) and adults starved for 3 hours (referred to as Adult Feeding, AF; Nymphs Feeding, NF, and Adult Starved_3 hr, ANF samples henceforth). A final transcriptome comprising 52,652 transcripts of 1064bp average length and N50 value of 1806 bp was generated. A total of 27,112 transcripts were annotated with insect proteins from SwissProt, of which 4128 transcripts were components of 165 KEGG pathways. A total of 17,296 transcripts were classified based on their Gene Ontology. Potential transcripts for host selection, detoxification, salivary proteins and effectors, molecular chaperones and developmental genes were identified. A total of 23,532 transcripts that remained unannotated were subjected to BLAST against aphid sequences available at AphidBase and a total of 3091 transcripts had hits with sequences of other aphids in the database, out of which 1380 had protein hits. A total of 20441 found to share no homology to any sequence available in the public domain and could therefore represent novel aphid genes or sequences that are unique to L. erysimi. This is an exploratory study with no biological replicates. However, the significant repertoire of feeding- and development-related genes and their differential expression profiles generated in this study adds to the limited data available on L. erysimi and it would facilitate studies on the molecular basis of aphid feeding and development. This could also allow identification of novel target genes for development of RNAi-based aphid control methods.

systems biology↗