1. Neuroscience

Dysfunctions of the paraventricular hypothalamic nucleus induce hypersomnia in mice

  1. Chang-Rui Chen  Is a corresponding author
  2. Yu-Heng Zhong
  3. Shan Jiang
  4. Wei Xu
  5. Lei Xiao
  6. Zan Wang
  7. Wei-Min Qu  Is a corresponding author
  8. Zhi-Li Huang  Is a corresponding author
  1. Fudan University, China
  2. The First hospital of Jilin University, China
https://doi.org/10.7554/eLife.69909
Share this article
Cite this article
  1. Chang-Rui Chen
  2. Yu-Heng Zhong
  3. Shan Jiang
  4. Wei Xu
  5. Lei Xiao
  6. Zan Wang
  7. Wei-Min Qu
  8. Zhi-Li Huang
(2021)
Dysfunctions of the paraventricular hypothalamic nucleus induce hypersomnia in mice
eLife 10:e69909.
https://doi.org/10.7554/eLife.69909
  2. Download BibTeX
  3. Download .RIS

Abstract

Hypersomnolence disorder (HD) is characterized by excessive sleep, which is a common sequela following stroke, infection or tumorigenesis. HD is traditionally thought to be associated with lesions of wake-promoting nuclei. However, lesions of a single wake-promoting nucleus, or even two simultaneously, did not exert serious HD. Therefore, the specific nucleus and neural circuitry for HD remain unknown. Here, we observed that the paraventricular nucleus of the hypothalamus (PVH) exhibited higher c-fos expression during the active period (23:00) than during the inactive period (11:00) in mice. Therefore, we speculated that the PVH, in which most neurons are glutamatergic, may represent one of the key arousal-controlling centers. By using vesicular glutamate transporter 2 (vglut2Cre) mice together with fiber photometry, multichannel electrophysiological recordings, and genetic approaches, we found that PVHvglut2 neurons were most active during wakefulness. Chemogenetic activation of PVHvglut2 neurons induced wakefulness for 9 h, and photostimulation of PVHvglut2→parabrachial complex/ventral lateral septum circuits immediately drove transitions from sleep to wakefulness. Moreover, lesioning or chemogenetic inhibition of PVHvglut2 neurons dramatically decreased wakefulness. These results indicate that the PVH is critical for arousal promotion and maintenance.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided at DRYAD (DOI: https://doi.org/10.5061/dryad.bg79cnpb6, https://doi.org/10.5061/dryad.x3ffbg7jw, https://doi.org/10.5061/dryad.r4xgxd2db)

The following data sets were generated

Article and author information

Author details

  1. Chang-Rui Chen

    Fudan University, Shanghai, China
    For correspondence
    changruichen@163.com
    Competing interests
    The authors declare that no competing interests exist.

  2. Yu-Heng Zhong

    Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  3. Shan Jiang

    Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  4. Wei Xu

    Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  5. Lei Xiao

    Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1640-9690

  6. Zan Wang

    The First hospital of Jilin University, Changchun, China
    Competing interests
    The authors declare that no competing interests exist.

  7. Wei-Min Qu

    Fudan University, Shanghai, China
    For correspondence
    quweimin@fudan.edu.cn
    Competing interests
    The authors declare that no competing interests exist.

  8. Zhi-Li Huang

    Fudan University, Shanghai, China
    For correspondence
    huangzl@fudan.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9359-1150

Funding

National Natural Science Foundation of China (81671317)

  • Zhi-Li Huang

National Natural Science Foundation of China (31530035)

  • Chang-Rui Chen

National Natural Science Foundation of China (81420108015)

  • Zhi-Li Huang

National Natural Science Foundation of China (31671099)

  • Zhi-Li Huang

National Natural Science Foundation of China (31871072)

  • Zhi-Li Huang

National Natural Science Foundation of China (31571103)

  • Chang-Rui Chen

National Natural Science Foundation of China (81701305)

  • Zhi-Li Huang

National Natural Science Foundation of China (81970727)

  • Lei Xiao

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were approved by the Medical Experimental Animal Administrative Committee of Shanghai. All experimental procedures involving animals were approved by the Animal Experiment and Use Committee of Fudan University (20150119 - 067).

Copyright

© 2021, Chen et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,834
    views
  • 635
    downloads
  • 45
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Chang-Rui Chen
  2. Yu-Heng Zhong
  3. Shan Jiang
  4. Wei Xu
  5. Lei Xiao
  6. Zan Wang
  7. Wei-Min Qu
  8. Zhi-Li Huang
(2021)
Dysfunctions of the paraventricular hypothalamic nucleus induce hypersomnia in mice
eLife 10:e69909.
https://doi.org/10.7554/eLife.69909

Share this article

https://doi.org/10.7554/eLife.69909

Categories and tags

Research organism

Further reading

    1. Neuroscience

    Visual routines for detecting causal interactions are tuned to motion direction

    Sven Ohl, Martin Rolfs
    Research Article

    Detecting causal relations structures our perception of events in the world. Here, we determined for visual interactions whether generalized (i.e. feature-invariant) or specialized (i.e. feature-selective) visual routines underlie the perception of causality. To this end, we applied a visual adaptation protocol to assess the adaptability of specific features in classical launching events of simple geometric shapes. We asked observers to report whether they observed a launch or a pass in ambiguous test events (i.e. the overlap between two discs varied from trial to trial). After prolonged exposure to causal launch events (the adaptor) defined by a particular set of features (i.e. a particular motion direction, motion speed, or feature conjunction), observers were less likely to see causal launches in subsequent ambiguous test events than before adaptation. Crucially, adaptation was contingent on the causal impression in launches as demonstrated by a lack of adaptation in non-causal control events. We assessed whether this negative aftereffect transfers to test events with a new set of feature values that were not presented during adaptation. Processing in specialized (as opposed to generalized) visual routines predicts that the transfer of visual adaptation depends on the feature similarity of the adaptor and the test event. We show that the negative aftereffects do not transfer to unadapted launch directions but do transfer to launch events of different speeds. Finally, we used colored discs to assign distinct feature-based identities to the launching and the launched stimulus. We found that the adaptation transferred across colors if the test event had the same motion direction as the adaptor. In summary, visual adaptation allowed us to carve out a visual feature space underlying the perception of causality and revealed specialized visual routines that are tuned to a launch’s motion direction.

    1. Neuroscience

    Serotonin modulates infraslow oscillation in the dentate gyrus during non-REM sleep

    Gergely F Turi, Sasa Teng ... Yueqing Peng
    Research Article

    Synchronous neuronal activity is organized into neuronal oscillations with various frequency and time domains across different brain areas and brain states. For example, hippocampal theta, gamma, and sharp wave oscillations are critical for memory formation and communication between hippocampal subareas and the cortex. In this study, we investigated the neuronal activity of the dentate gyrus (DG) with optical imaging tools during sleep-wake cycles in mice. We found that the activity of major glutamatergic cell populations in the DG is organized into infraslow oscillations (0.01–0.03 Hz) during NREM sleep. Although the DG is considered a sparsely active network during wakefulness, we found that 50% of granule cells and about 25% of mossy cells exhibit increased activity during NREM sleep, compared to that during wakefulness. Further experiments revealed that the infraslow oscillation in the DG was correlated with rhythmic serotonin release during sleep, which oscillates at the same frequency but in an opposite phase. Genetic manipulation of 5-HT receptors revealed that this neuromodulatory regulation is mediated by Htr1a receptors and the knockdown of these receptors leads to memory impairment. Together, our results provide novel mechanistic insights into how the 5-HT system can influence hippocampal activity patterns during sleep.

    1. Neuroscience

    Synaptic deregulation of cholinergic projection neurons causes olfactory dysfunction across five fly Parkinsonism models

    Ulrike Pech, Jasper Janssens ... Patrik Verstreken
    Research Article

    The classical diagnosis of Parkinsonism is based on motor symptoms that are the consequence of nigrostriatal pathway dysfunction and reduced dopaminergic output. However, a decade prior to the emergence of motor issues, patients frequently experience non-motor symptoms, such as a reduced sense of smell (hyposmia). The cellular and molecular bases for these early defects remain enigmatic. To explore this, we developed a new collection of five fruit fly models of familial Parkinsonism and conducted single-cell RNA sequencing on young brains of these models. Interestingly, cholinergic projection neurons are the most vulnerable cells, and genes associated with presynaptic function are the most deregulated. Additional single nucleus sequencing of three specific brain regions of Parkinson’s disease patients confirms these findings. Indeed, the disturbances lead to early synaptic dysfunction, notably affecting cholinergic olfactory projection neurons crucial for olfactory function in flies. Correcting these defects specifically in olfactory cholinergic interneurons in flies or inducing cholinergic signaling in Parkinson mutant human induced dopaminergic neurons in vitro using nicotine, both rescue age-dependent dopaminergic neuron decline. Hence, our research uncovers that one of the earliest indicators of disease in five different models of familial Parkinsonism is synaptic dysfunction in higher-order cholinergic projection neurons and this contributes to the development of hyposmia. Furthermore, the shared pathways of synaptic failure in these cholinergic neurons ultimately contribute to dopaminergic dysfunction later in life.