Biology subjects

Ono, D.

Publications and source records attributed to Ono, D..

7 recordsLinked to original sources

bioRxiv2026

The slow-acting G-protein Gz defines the duration of circadian rest time

Duration of nightly rest is a trait that varies between individuals, influenced by a complex interplay between multiple genetic and environmental factors. The central circadian clock that orchestrates daily rhythm in behavior/sleep resides in the suprachiasmatic nucleus (SCN). Yet, how the SCN encodes the "length" of the circadian rest phase ({rho}) remains an open question. Here we demonstrate that the unique G-protein-subtype Gz contributes to this process by sculpting the waveform of the circadian cAMP-PKA activity rhythm within the SCN. Genetic deletion and subsequent rescue of Gz expression reversibly altered the {rho} duration, shifting it from [~]10 h in Gz+/+ mice to [~]7.5 h in Gz-/-; mice, accompanied by proportional changes in peak cAMP-PKA activity duration and transcriptome remodeling in the SCN. Notably, intra-SCN cAMP activation led to behavioral rest, with Gz specifically shaping this response without affecting 24-h rhythmicity. These findings suggest that the SCN is not merely a rhythm-generator, but actively allocates the {rho}-rest period via Gz signaling.

neuroscience↗

bioRxiv2026

A preoptic circuit triggers rewarming from torpor

Torpor is an adaptive hypometabolic state that enables homeotherm to survive periods of energetic challenge. This strategy ranges from short bouts of daily torpor to prolonged hibernation. During torpor, animals markedly suppress metabolic rate, body temperature, heart rate, and respiration, while retaining the ability to rewarm. Torpor therefore comprises two critical transitions -entry into a hypometabolic state and active rewarming-both essential for organismal viability. Although neural mechanisms controlling torpor entry have begun to emerge, the circuits that initiate active rewarming and restore euthermia remain poorly defined. Here we identify corticotropin-releasing hormone (Crh)-expressing neurons in the anterodorsal preoptic area (ADP) as a key population for rewarming from fasting-induced torpor in mice. These neurons become active around natural rewarming and are selectively required to limit the depth and duration of torpor. Unlike pathways mediating acute cold defence, stress hyperthermia, or LPS-induced fever, this circuit is dedicated to promoting timely recovery to euthermia. Closed-loop optogenetic activation of ADPCrh neurons during torpor entry rapidly initiates rewarming, and thermographic recordings show that brown adipose tissue (BAT) thermogenesis precedes locomotor arousal. ADPCrh neurons are predominantly GABAergic and project monosynaptically to the lateral preoptic area, whose terminal activation is sufficient to increase body temperature and locomotor activity. Finally, we find robust activation of ADPCrh neurons during rewarming in a hibernator, suggesting conserved logic for exiting deep torpor. Together, our results define a discrete preoptic circuit that drives recovery from torpor and provide a framework for understanding and potentially controlling timely rewarming from profound hypothermia.

neuroscience↗

bioRxiv2026

Diurnality reconfigures circadian network dynamics in the suprachiasmatic nucleus

Diurnal and nocturnal mammals occupy opposite temporal niches, but whether the suprachiasmatic nucleus (SCN), the central circadian pacemaker, follows the same intrinsic rules for timing adjustment and network coordination across species is unknown. Because SCN clock gene rhythms and population-level activity measurements look broadly similar across species, the prevailing interpretation in comparative studies has been that temporal niche differences are implemented upstream or downstream of the SCN. However, these coarse readouts do not test how clock resetting depends on circadian phase or how neuronal timing is coordinated across SCN space. Here, we combined long-duration ex vivo SCN recordings with optogenetic stimulation to compare SCN network dynamics in the nocturnal mouse (Mus musculus) and the diurnal four-striped grass mouse (Rhabdomys pumilio). Rhabdomys SCN molecular clock rhythms exhibited a longer intrinsic period and, under the same daily stimulation protocol, converged on a larger absolute phase angle relative to the stimulus. Molecular clock phase response curves differed in overall structure across circadian time between species, including pronounced early subjective day delays in Rhabdomys when Mus responses were minimal. Phase mapping of single-cell SCN calcium rhythms revealed species-specific spatial timing organization, with a graded dorsomedial-to-ventrolateral phase progression in Rhabdomys and a sharper transition in Mus. The Mus and Rhabdomys SCN can thus appear similar by coarse readouts yet diverge in phase-dependent molecular clock resetting and network timing organization. These results indicate that models placing temporal niche divergence solely outside the SCN are mechanistically incomplete.

neuroscience↗

bioRxiv2024

Chemogenetic activation of astrocytes modulates sleep/wakefulness states in a brain region-dependent manner

Study objectivesAstrocytes change their intracellular calcium (Ca2+) concentration during sleep/wakefulness states in mice. Furthermore, the Ca2+ dynamics in astrocytes vary depending on the brain region. However, whether alterations in intracellular Ca2+ concentration in astrocytes can affect sleep/wakefulness states and cortical oscillations in a brain region-dependent manner remain unclear. MethodsThe Ca2+ concentration in astrocytes was artificially increased using chemogenetics in mice. Astrocytes in the hippocampus and pons, which are 2 brain regions previously classified into different clusters based on their Ca2+ dynamics during sleep/wakefulness, were focused on to compare whether there are differences in the effects of astrocytes from different brain regions. ResultsThe activation of astrocytes in the hippocampus significantly decreased the total time of wakefulness and increased the total time of sleep. This had minimal effects on cortical oscillations in all sleep/wakefulness states. On the other hand, the activation of astrocytes in the pons substantially suppressed rapid eye movement (REM) sleep in association with a decreased number of REM episodes, indicating strong inhibition of REM onset. Regarding cortical oscillations, the delta wave component during non-REM sleep was significantly enhanced. ConclusionsThese results suggest that astrocytes modulate sleep/wakefulness states and cortical oscillations. Furthermore, the role of astrocytes in sleep/wakefulness states appears to vary among brain regions. Statement of SignificanceSleep is an instinctive behavior for many organisms. Recently, it has been reported that not only neurons, but also astrocytes, a type of glial cell, contribute to sleep/wakefulness states. Intracellular Ca2+ concentration, an indicator of astrocyte activity, fluctuates during sleep/wakefulness states. However, it is still unclear whether changes in Ca2+ concentration in astrocytes can affect sleep/wakefulness states. In this study, we utilized chemogenetics to activate astrocytes in mice. Our results showed that activation of astrocytes in the hippocampus causes decreased wakefulness, and that in the pons causes decreased REM sleep. Therefore, our findings demonstrate that the activation of astrocytes modulates sleep/wakefulness states in a brain region-dependent manner. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/597103v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@100a766org.highwire.dtl.DTLVardef@1ee1d21org.highwire.dtl.DTLVardef@1ba8044org.highwire.dtl.DTLVardef@13af766_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2019

Dual Orexin and MCH neuron-ablated mice display severe sleep attacks and cataplexy

Orexin/hypocretin-producing and melanin-concentrating hormone-producing (MCH) neurons are co-extensive in the tuberal hypothalamus and project throughout the brain to regulate sleep/wakefulness. Ablation of orexin neurons in mice decreases wakefulness and results in a narcolepsy-like phenotype, whereas ablation of MCH neurons increases wakefulness. Since it is unclear how orexin and MCH neurons interact to regulate sleep/wakefulness, we generated conditional transgenic mice in which both orexin and MCH neurons could be ablated. Double-ablated mice exhibited increased wakefulness and decreased both rapid eye movement (REM) and non-REM (NREM) sleep. The total time in cataplexy and the mean cataplexy bout duration increased significantly in double-ablated mice compared with orexin neuron-ablated mice, suggesting that MCH neurons normally suppress cataplexy and that compromised MCH neurons may exacerbate symptoms in some narcoleptic patients. Double-ablated mice also showed frequent sleep attacks with elevated spectral power in the delta and theta range during wakefulness, a state with EEG characteristics indistinguishable from the transition from NREM into REM sleep. Together, these results indicate a functional interaction between orexin and MCH neurons in vivo that suggests the synergistic involvement of these neuronal populations in the sleep/wakefulness cycle.

neuroscience↗

bioRxiv2019

Weak Coupling Between Intracellular Feedback Loops Explains Dissociation of Clock Gene Dynamics

Circadian rhythms are generated by interlocked transcriptional-translational negative feedback loops (TTFLs), the molecular process implemented within a cell. The contributions, weighting and balancing between the multiple feedback loops remain debated. Dissociated, free-running dynamics in the expression of distinct clock genes has been described in recent experimental studies that applied various perturbations such as slice preparations, light pulses, jet-lag, and culture medium exchange. In this paper, we provide evidence that this \"presumably transient\" dissociation of circadian gene expression oscillations may occur at the single-cell level. Conceptual and detailed mechanistic mathematical modeling suggests that such dissociation is due to a weak interaction between multiple feedback loops present within a single cell. The dissociable loops provide insights into underlying mechanisms and general design principles of the molecular circadian clock.

systems biology↗

bioRxiv2019

GABA neurons in the ventral tegmental area regulate non-rapid eye movement sleep in mice

The daily sleep/wakefulness cycle is regulated by coordinated interactions between sleep- and wakefulness-regulating neural circuitry. However, the detailed neural circuitry mediating sleep is far from understood. Here, we found that glutamic acid decarboxylase 67 (Gad67)-positive GABAergic neurons in the ventral tegmental area (VTAGad67+) are a key regulator of non-rapid eye movement (NREM) sleep in mice. VTAGad67+ neurons project to multiple brain areas implicated in sleep/wakefulness regulation such as the lateral hypothalamus (LH) and dorsal raphe nucleus. Chemogenetic activation of VTAGad67+ neurons promoted NREM sleep with higher delta power whereas optogenetic inhibition of these neurons induced prompt arousal from NREM sleep under highly somnolescent conditions, but not during REM sleep. In vivo fiber photometry recordings revealed that VTAGad67+ neurons showed the highest population activity in NREM sleep and the lowest activity in REM sleep. Acute brain slice electrophysiology combined with optogenetics revealed that VTAGad67+ neurons directly innervate and inhibit wake-promoting orexin/hypocretin neurons in the LH by releasing GABA. Taken together, we reveal that VTAGad67+ neurons play a crucial role in the regulation of NREM sleep.

neuroscience↗