Temperature cues are integrated in a flexible circadian neuropeptidergic feedback circuit to remodel sleep-wake patterns in flies

PLoS Biology, Год журнала: 2024, Номер 22(12), С. e3002918 - e3002918

Опубликована: Дек. 2, 2024

Organisms detect temperature signals through peripheral neurons, which relay them to central circadian networks drive adaptive behaviors. Despite recent advances in Drosophila research, how circuits integrate cues with regulate sleep/wake patterns remains unclear. In this study, we used the FlyWire brain electron microscopy connectome map neuronal connections, identifying lateral posterior neurons LPNs as key nodes for integrating information into network. receive input from both and temperature-sensing promoting sleep behavior. Through analysis, genetic manipulation, behavioral assays, demonstrated that LPNs, downstream of thermo-sensitive anterior cells (ACs), suppress activity-promoting dorsal LNds via AstC pathway, inducing Disrupting LPN-LNd communication either AstCR1 RNAi or an mutant significantly impairs heat-induced reduction evening activity peak. Conversely, optogenetic calcium imaging assays revealed cold-activated subsequently stimulate NPF-NPFR signaling, establishing a negative feedback loop. This mechanism limits LNd activation appropriate levels, thereby fine-tuning peak increase at lower temperatures. conclusion, our study constructed comprehensive centered on identified novel peptidergic circuit coordinates signals, offering new insights regulation .

Язык: Английский

---

Dynamic neuronal instability generates synaptic plasticity and behavior: Insights from Drosophila sleep

Neuroscience Research, Год журнала: 2023, Номер 198, С. 1 - 7

Опубликована: Июнь 28, 2023

Язык: Английский

---

Conditional chemoconnectomics (cCCTomics) as a strategy for efficient and conditional targeting of chemical transmission

eLife, Год журнала: 2023, Номер 12

Опубликована: Дек. 19, 2023

Dissection of neural circuitry underlying behaviors is a central theme in neurobiology. We have previously proposed the concept chemoconnectome (CCT) to cover entire chemical transmission between neurons and target cells an organism created tools for studying it (CCTomics) by targeting all genes related CCT Drosophila . Here we lines conditional manner after modifying GFP RNA interference, Flp-out, CRISPR/Cas9 technologies. All three strategies been validated be highly effective, with best using chromatin-peptide fused Cas9 variants scaffold optimized sgRNAs. As proof principle, conducted comprehensive intersection analysis expression profiles clock neurons, uncovering 43 present neurons. Specific elimination each from revealed that loss neuropeptide CNMa two posterior dorsal (DN1ps) or its receptor (CNMaR) caused advanced morning activity, indicating suppressive role CNMa-CNMaR on anticipation, opposite promoting PDF-PDFR anticipation. These results demonstrate effectiveness CCTomics here establish antagonistic relationship signaling regulating

Язык: Английский

---

Identification of sleep and circadian alternative polyadenylation sites associated with APA-linked human brain disorders

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Янв. 18, 2024

Sleep and circadian rhythm disruptions are comorbid features of many pathologies can negatively influence numerous health conditions, including degenerative diseases, metabolic illnesses, cancer, various neurological disorders. Genetic association studies linking sleep disturbances with disease susceptibility have mainly focused on changes in gene expression due to mutations, such as single-nucleotide polymorphisms. Thus, associations between and/or alternative polyadenylation (APA), particularly the context other challenges, largely undescribed. APA is a process that generates transcript isoforms from same gene, resulting effects mRNA translation, stability, localization, subsequent function. Here, we identified unique APAs rat brain exhibit time-of-day-dependent oscillations well altered by deprivation recovery period. Genes affected usage include

Язык: Английский

---

Tob Regulates the Timing of Sleep Onset at Night inDrosophila

Journal of Neuroscience, Год журнала: 2024, Номер unknown, С. e0389232024 - e0389232024

Опубликована: Март 14, 2024

Sleep is regulated by homeostatic sleep drive and the circadian clock. While tremendous progress has been made in elucidating molecular components of core oscillator, output mechanisms which this robust oscillator generates rhythmic behaviour remain poorly understood. At cellular level, growing evidence suggests that subcircuits master pacemaker suprachiasmatic nucleus (SCN) mammals clock network Drosophila regulate distinct aspects sleep. Thus, to identify novel molecules regulating timing sleep, we conducted a large-scale screen mouse SCN-enriched genes . Here, show Tob (Transducer ERB-B2) regulates onset at night female fruit flies. Knockdown pan-neuronally, either constitutively or conditionally, advances night. We specifically required “evening neurons” (the LNds 5 th s-LNv) for proper onset. levels cycle clock-dependent manner these neurons. Silencing “evening” neurons results an advanced night, similar seen with knockdown. Finally, sharp intracellular recordings demonstrate amplitude kinetics LNd post-synaptic potentials (PSPs) between day cycling attenuated knockdown cells. Our data suggest acts as clock-output molecule subset potentiate their activity evening enable Significance Summary Well-timed, high quality critical human health function. Elucidating how may reveal targets intervening process. However, our understanding genetic underlying regulation limited. From high-throughput behavioral , identified gene tob ( transducer erb-b2 ) under control, facilitates potentiation specific population work mechanism potentiating function

Язык: Английский

---

Conditional chemoconnectomics (cCCTomics) as a strategy for efficient and conditional targeting of chemical transmission

eLife, Год журнала: 2024, Номер 12

Опубликована: Апрель 30, 2024

Dissection of neural circuitry underlying behaviors is a central theme in neurobiology. We have previously proposed the concept chemoconnectome (CCT) to cover entire chemical transmission between neurons and target cells an organism created tools for studying it (CCTomics) by targeting all genes related CCT Drosophila . Here we lines conditional manner after modifying GFP RNA interference, Flp-out, CRISPR/Cas9 technologies. All three strategies been validated be highly effective, with best using chromatin-peptide fused Cas9 variants scaffold optimized sgRNAs. As proof principle, conducted comprehensive intersection analysis expression profiles clock neurons, uncovering 43 present neurons. Specific elimination each from revealed that loss neuropeptide CNMa two posterior dorsal (DN1ps) or its receptor (CNMaR) caused advanced morning activity, indicating suppressive role CNMa-CNMaR on anticipation, opposite promoting PDF-PDFR anticipation. These results demonstrate effectiveness CCTomics here establish antagonistic relationship signaling regulating

Язык: Английский

---

Sleep and diurnal alternative polyadenylation sites associated with human APA-linked brain disorders

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Авг. 8, 2024

Disruption of sleep and circadian rhythms are a comorbid feature many pathologies, can negatively influence health conditions, including neurodegenerative disease, metabolic illness, cancer, various neurological disorders. Genetic association studies linking disturbances with disease susceptibility have mainly focused on changes in gene expression due to mutations, such as single-nucleotide polymorphisms. The interaction between and/or the use Alternative Polyadenylation (APA) has been largely undescribed, particularly context other APA is process that generates transcript isoforms same affecting its mRNA translation, stability, localization, subsequent function. Here we identified unique APAs expressed rat brain over time-of-day, immediately following deprivation, recovery period. From these data, performed secondary analysis sleep- or time-of-day associated PASs recently described APA-linked human disorder genes.

Язык: Английский

---

Sleep and diurnal alternative polyadenylation sites associated with human APA-linked brain disorders

Deleted Journal, Год журнала: 2024, Номер 1(1)

Опубликована: Ноя. 1, 2024

Disruption of sleep and circadian rhythms are a comorbid feature many pathologies, can negatively influence health conditions, including neurodegenerative disease, metabolic illness, cancer, various neurological disorders. Genetic association studies linking disturbances with disease susceptibility have mainly focused on changes in gene expression due to mutations, such as single-nucleotide polymorphisms. The interaction between and/or the use Alternative Polyadenylation (APA) has been largely undescribed, particularly context other APA generates transcript isoforms by utilizing polyadenylation sites (PASs) from same affecting its mRNA translation, stability, localization, subsequent function. Here we identified unique APAs expressed rat brain over time-of-day, immediately following deprivation, recovery period. From these data, performed secondary analysis sleep- or time-of-day associated PASs recently described APA-linked human disorder genes.

Язык: Английский

---

Ultrastructural correlates of circadian structural plasticity

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 7, 2024

In Drosophila, about 250 clock neurons in the brain form a network that orchestrates circadian rhythmicity. Among them, eight small Lateral ventral Neurons (s-LNvs) play critical role, synchronizing ensemble via neuropeptide Pigment-Dispersing Factor (PDF). Moreover, their neurites show daily variations morphology, PDF levels, synaptic markers and connectivity. This process, called structural plasticity, is ill-defined at subcellular level. Here, we present 3D volumes of s-LNv terminals generated by Serial Block-face Scanning Electron Microscopy (SBEM) three key time points, two hours before lights-ON, after lights-OFF. We report reduction number neuronal varicosities night, which reflects (and probably regulates) cycling components found therein. Indeed, morning observed more presynaptic sites increased accumulation release dense core vesicles. These rhythms were paralleled periodic changes mitochondrial structure suggest modulation activity. propose plasticity functionally relevant structures within cyclically modulates influence s-LNvs on network.

Язык: Английский

---

Contribution of membrane-associated oscillators to biological timing at different timescales

Опубликована: Июнь 26, 2023

Environmental rhythms such as the daily light-dark cycle selected for endogenous clocks. These clocks predict regular environmental changes and provide basis well-timed adaptive homeostasis in physiology behavior of organisms. Endogenous are oscillators that based on positive feedforward negative feedback loops. They generate stable even under constant conditions. Since weak interactions between allow autonomous synchronization, coupling/synchronization provides self-organized physiological timing. Amongst most thoroughly researched circadian clock neurons mammals insects. comprise nuclear clockworks transcriptional/translational loops (TTFL) ~24 h gene expression entrained to day-night cycle. It is generally assumed this TTFL clockwork drives all oscillations within cells, being any rhythm Instead current gene-based hierarchical model we here a systems view We suggest coupled system posttranslational loop (PTFL) oscillators/clocks run at multiple timescales governs adaptive, dynamic behavior. focus mammalian insect timescales. neuronal plasma membrane-associated signalosomes constitute specific PTFL localized but interlinked membrane potential intracellular messengers with frequencies. In each neuron multiscale form temporally structured oscillatory network common complex frequency-band comprising superimposed oscillations. Coupling oscillator/clock next level complexity an network. This systemic molecular cellular suggested cycles through homeostatic setpoints characteristic hallmark. propose mechanisms plasticity maintain stability these setpoints, whereas Hebbian enables switching via coupling factors, like biogenic amines and/or neuropeptides. reprogram new frequency, setpoint. Our novel hypothesis up experimental challenge.

Язык: Английский

---