Prolonged partner separation erodes nucleus accumbens transcriptional signatures of pair bonding in male prairie voles

  1. Julie M Sadino
  2. Xander G Bradeen
  3. Conor J Kelly
  4. Liza E Brusman
  5. Deena M Walker
  6. Zoe R Donaldson  Is a corresponding author
  1. University of Colorado Boulder, United States
  2. Oregon Health and Science University Hospital, United States

Abstract

The loss of a spouse is often cited as the most traumatic event in a person's life. However, for most people, the severity of grief and its maladaptive effects subside over time via an understudied adaptive process. Like humans, socially monogamous prairie voles (Microtus ochrogaster) form opposite-sex pair bonds, and upon partner separation, show stress phenotypes that diminish over time. We test the hypothesis that extended partner separation diminishes pair bond-associated behaviors and causes pair bond transcriptional signatures to erode. Pairs were cohoused for 2 weeks and then either remained paired or were separated for 48hrs or 4wks before collecting fresh nucleus accumbens tissue for RNAseq. In a separate cohort, we assessed partner-directed affiliation at these time points. We found that these behaviors persist despite prolonged separation in both same-sex and opposite-sex paired voles. Opposite-sex pair bonding led to changes in accumbal transcription that were stably maintained while animals remained paired but eroded following prolonged partner separation. Eroded genes are associated with gliogenesis and myelination, suggesting a previously undescribed role for glia in pair bonding and loss. Further, we pioneered neuron-specific translating ribosomal affinity purification in voles. Neuronally-enriched transcriptional changes revealed dopaminergic-, mitochondrial-, and steroid hormone signaling-associated gene clusters sensitive to acute pair bond disruption and loss adaptation. Our results suggest that partner separation erodes transcriptomic signatures of pair bonding despite core behavioral features of the bond remaining intact, revealing potential molecular processes priming a vole to be able to form a new bond.

Data availability

All sequencing data is available on GEO (GSE192661). All lab specific code is available on the Donaldson Lab GitHub (https://github.com/donaldsonlab) and all metadata including comprehensive statistical analyses, animal information, differential gene expression, gene sets, and IPA analyses are available on the Donaldson lab Figshare (DOIs in Supplemental) . The vole optimized DIO-eGFP-RPL10a vector will be made available on Addgene.

The following data sets were generated

Article and author information

Author details

  1. Julie M Sadino

    Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Xander G Bradeen

    Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Conor J Kelly

    Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2410-7892
  4. Liza E Brusman

    Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Deena M Walker

    Department of Behavioral Neuroscience, Oregon Health and Science University Hospital, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Zoe R Donaldson

    Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States
    For correspondence
    zoe.donaldson@colorado.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6699-7905

Funding

National Institutes of Health (T32 GM008759-17/18)

  • Julie M Sadino

Dana Foundation

  • Zoe R Donaldson

Whitehall Foundation

  • Zoe R Donaldson

National Institutes of Health (DP2OD026143)

  • Zoe R Donaldson

National Institutes of Health (R01MH125423)

  • Zoe R Donaldson

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 procedures were performed in accordance with standard ethical guidelines (National Institutes of Health Guide for the Care and Use of Laboratory Animals) and approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Colorado Boulder (protocol #2435). For stereotaxic surgery, adult prairie voles were anesthetized using isoflurane (3% induction, 1-2.5% maintenance) and depth of anesthesia was monitored by breathing and toe pinch reflex.

Copyright

© 2023, Sadino 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.

Download links

Share this article

https://doi.org/10.7554/eLife.80517

Further reading

    1. Neuroscience
    2. Physics of Living Systems
    Moritz Schloetter, Georg U Maret, Christoph J Kleineidam
    Research Article

    Neurons generate and propagate electrical pulses called action potentials which annihilate on arrival at the axon terminal. We measure the extracellular electric field generated by propagating and annihilating action potentials and find that on annihilation, action potentials expel a local discharge. The discharge at the axon terminal generates an inhomogeneous electric field that immediately influences target neurons and thus provokes ephaptic coupling. Our measurements are quantitatively verified by a powerful analytical model which reveals excitation and inhibition in target neurons, depending on position and morphology of the source-target arrangement. Our model is in full agreement with experimental findings on ephaptic coupling at the well-studied Basket cell-Purkinje cell synapse. It is able to predict ephaptic coupling for any other synaptic geometry as illustrated by a few examples.

    1. Neuroscience
    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.