Cross-Species analysis defines the conservation of anatomically-segregated VMH neuron populations

  1. Alison H Affinati
  2. Paul V Sabatini
  3. Cadence True
  4. Abigail J Tomlinson
  5. Melissa Kirigiti
  6. Sarah R Lindsley
  7. Chien Li
  8. David P Olson
  9. Paul Kievit
  10. Martin G Myers Jr  Is a corresponding author
  11. Alan C Rupp  Is a corresponding author
  1. University of Michigan, United States
  2. Oregon National Primate Research Center, United States
  3. Novo Nordisk Research Center, United States

Abstract

The ventromedial hypothalamic nucleus (VMH) controls diverse behaviors and physiologic functions, suggesting the existence of multiple VMH neural subtypes with distinct functions. Combing Translating Ribosome Affinity Purification with RNA sequencing (TRAP-seq) data with snRNA-seq data, we identified 24 mouse VMH neuron clusters. Further analysis, including snRNA-seq data from macaque tissue, defined a more tractable VMH parceling scheme consisting of 6 major genetically- and anatomically-differentiated VMH neuron classes with good cross-species conservation. In addition to two major ventrolateral classes, we identified three distinct classes of dorsomedial VMH neurons. Consistent with previously-suggested unique roles for leptin receptor (Lepr)-expressing VMH neurons, Lepr expression marked a single dorsomedial class. We also identified a class of glutamatergic VMH neurons that resides in the tuberal region, anterolateral to the neuroanatomical core of the VMH. This atlas of conserved VMH neuron populations provides an unbiased starting point for the analysis of VMH circuitry and function.

Data availability

Sequencing data have been deposited in GEO under accession code GSE172207

The following data sets were generated

Article and author information

Author details

  1. Alison H Affinati

    Internal Medicine, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  2. Paul V Sabatini

    Internal Medicine, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6613-566X
  3. Cadence True

    Oregon National Primate Research Center, Beaverton, United States
    Competing interests
    No competing interests declared.
  4. Abigail J Tomlinson

    Internal Medicine, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  5. Melissa Kirigiti

    Oregon National Primate Research Center, Beaverton, United States
    Competing interests
    No competing interests declared.
  6. Sarah R Lindsley

    Oregon National Primate Research Center, Beaverton, United States
    Competing interests
    No competing interests declared.
  7. Chien Li

    Obesity, Novo Nordisk Research Center, Seattle, United States
    Competing interests
    Chien Li, is an employee of Novo Nordisk A/S.
  8. David P Olson

    Internal Medicine, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  9. Paul Kievit

    Oregon National Primate Research Center, Beaverton, United States
    Competing interests
    No competing interests declared.
  10. Martin G Myers Jr

    Departments of Internal Medicine and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    For correspondence
    mgmyers@umich.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9468-2046
  11. Alan C Rupp

    Internal Medicine, University of Michigan, Ann Arbor, United States
    For correspondence
    ruppa@med.umich.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5363-4494

Funding

National Institutes of Health (dk056731)

  • Martin G Myers Jr

Novo Nordisk

  • Martin G Myers Jr

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 mice used in this study were maintained in accordance with University of Michigan Institutional Animal Care and Use Committee (IACUC), Association for the Assessment and Approval of Laboratory Animal Care (AAALAC) and National Institutes of Health (NIH) guidelines under protocol number PRO00007438 (PI Myers).Nonhuman primate tissue was obtained post-mortem from the Tissue Distribution Program at ONPRC. Animal care is in accordance with the recommendations described in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and animal facilities at the Oregon National Primate Research Center (ONPRC) are accredited by the American Association for Accreditation of Laboratory Animal Care International. ONPRC does not provide protocol numbers for security reasons.

Reviewing Editor

  1. Ana Domingos, University of Oxford, United Kingdom

Publication history

  1. Received: April 2, 2021
  2. Accepted: May 14, 2021
  3. Accepted Manuscript published: May 21, 2021 (version 1)
  4. Accepted Manuscript updated: May 24, 2021 (version 2)
  5. Version of Record published: June 7, 2021 (version 3)

Copyright

© 2021, Affinati 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

  • 1,292
    Page views
  • 173
    Downloads
  • 1
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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. Alison H Affinati
  2. Paul V Sabatini
  3. Cadence True
  4. Abigail J Tomlinson
  5. Melissa Kirigiti
  6. Sarah R Lindsley
  7. Chien Li
  8. David P Olson
  9. Paul Kievit
  10. Martin G Myers Jr
  11. Alan C Rupp
(2021)
Cross-Species analysis defines the conservation of anatomically-segregated VMH neuron populations
eLife 10:e69065.
https://doi.org/10.7554/eLife.69065

Further reading

    1. Neuroscience
    Andrea Merseburg et al.
    Research Article

    De novo mutations in voltage- and ligand-gated channels have been associated with an increasing number of cases of developmental and epileptic encephalopathies, which often fail to respond to classic antiseizure medications. Here, we examine two knock-in mouse models replicating de novo sequence variations in the HCN1 voltage-gated channel gene, p.G391D and p.M153I (Hcn1G380D/+ and Hcn1M142I/+ in mouse), associated with severe drug-resistant neonatal- and childhood-onset epilepsy, respectively. Heterozygous mice from both lines displayed spontaneous generalized tonic-clonic seizures. Animals replicating the p.G391D variant had an overall more severe phenotype, with pronounced alterations in the levels and distribution of HCN1 protein, including disrupted targeting to the axon terminals of basket cell interneurons. In line with clinical reports from patients with pathogenic HCN1 sequence variations, administration of the antiepileptic Na+ channel antagonists lamotrigine and phenytoin resulted in the paradoxical induction of seizures in both mouse lines, consistent with an effect to further impair inhibitory neuron function. We also show that these variants can render HCN1 channels unresponsive to classic antagonists, indicating the need to screen mutated channels to identify novel compounds with diverse mechanism of action. Our results underscore the necessity of tailoring effective therapies for specific channel gene variants, and how strongly validated animal models may provide an invaluable tool towards reaching this objective.

    1. Neuroscience
    Danilo Menicucci et al.
    Research Article

    Sleep and plasticity are highly interrelated, as sleep slow oscillations and sleep spindles are associated with consolidation of Hebbian-based processes. However, in adult humans, visual cortical plasticity is mainly sustained by homeostatic mechanisms, for which the role of sleep is still largely unknown. Here we demonstrate that non-REM sleep stabilizes homeostatic plasticity of ocular dominance induced in adult humans by short-term monocular deprivation: the counter-intuitive and otherwise transient boost of the deprived eye was preserved at the morning awakening (>6 hours after deprivation). Subjects exhibiting a stronger boost of the deprived eye after sleep had increased sleep spindle density in frontopolar electrodes, suggesting the involvement of distributed processes. Crucially, the individual susceptibility to visual homeostatic plasticity soon after deprivation correlated with the changes in sleep slow oscillations and spindle power in occipital sites, consistent with a modulation in early occipital visual cortex.