1. Neuroscience

Normal cognitive and social development require posterior cerebellar activity

  1. Aleksandra Badura
  2. Jessica L Verpeut
  3. Julia M Metzger
  4. Talmo D Pereira
  5. Thomas J Pisano
  6. Ben Deverett
  7. Dariya E Bakshinskaya
  8. Samuel S-H Wang  Is a corresponding author
  1. Princeton University, United States
https://doi.org/10.7554/eLife.36401
Share this article
Cite this article
  1. Aleksandra Badura
  2. Jessica L Verpeut
  3. Julia M Metzger
  4. Talmo D Pereira
  5. Thomas J Pisano
  6. Ben Deverett
  7. Dariya E Bakshinskaya
  8. Samuel S-H Wang
(2018)
Normal cognitive and social development require posterior cerebellar activity
eLife 7:e36401.
https://doi.org/10.7554/eLife.36401
  2. Download BibTeX
  3. Download .RIS

Abstract

Cognitive and social capacities require postnatal experience, yet the pathways by which experience guides development are unknown. Here we show that the normal development of motor and nonmotor capacities requires cerebellar activity. Using chemogenetic perturbation of molecular layer interneurons to attenuate cerebellar output in mice, we found that activity of posterior regions in juvenile life modulates adult expression of eyeblink conditioning (paravermal lobule VI, crus I), reversal learning (lobule VI), persistive behavior and novelty-seeking (lobule VII), and social preference (crus I/II). Perturbation in adult life altered only a subset of phenotypes. Both adult and juvenile disruption left gait metrics largely unaffected. Contributions to phenotypes increased with the amount of lobule inactivated. Using an anterograde transsynaptic tracer, we found that posterior cerebellum made strong connections with prelimbic, orbitofrontal, and anterior cingulate cortex. These findings provide anatomical substrates for the clinical observation that cerebellar injury increases the risk of autism.

Data availability

Code and data for the main figures are available via the GitHub repository https://github.com/wanglabprinceton/behavioral-development.The complete raw data for this study are available from the corresponding author upon request (including behavioral videos and serial two-photon tomographic brain images of each mouse).

Article and author information

Author details

  1. Aleksandra Badura

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Jessica L Verpeut

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Julia M Metzger

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Talmo D Pereira

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9075-8365

  5. Thomas J Pisano

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Ben Deverett

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3119-7649

  7. Dariya E Bakshinskaya

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Samuel S-H Wang

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    For correspondence
    sswang@princeton.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0490-9786

Funding

Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Innovational Research Incentives Scheme VENI (NWO ZonMw))

  • Aleksandra Badura

Nancy Lurie Marks Family Foundation

  • Samuel S-H Wang

National Institutes of Health (R01 NS045193)

  • Samuel S-H Wang

New Jersey Commission on Brain Injury Research (CBIR16FEL010)

  • Jessica L Verpeut

National Science Foundation (Graduate Research Fellowship DGE-1148900)

  • Talmo D Pereira

Rutgers Robert Wood Johnson Medical School-Princeton University M.D.-Ph.D. Program

  • Thomas J Pisano
  • Ben Deverett

National Institutes of Health (R01 MH115750)

  • Samuel S-H Wang

National Institutes of Health (F30 MH115577)

  • Ben Deverett

National Institutes of Health (F31 NS089303)

  • Thomas J Pisano

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

Reviewing Editor

  1. Jennifer L Raymond, Stanford School of Medicine, United States

Ethics

Animal experimentation: Experimental procedures were approved by the Princeton University Institutional Animal Care and Use Committee (protocol number: 1943-16) and performed in accordance with the animal welfare guidelines of the National Institutes of Health. All mice were housed in Optimice cages (Animal Care Systems, Centennial, CO) containing blended bedding (The Andersons, Maumee, OH), paper nesting strips, and one heat-dried virgin pulp cardboard hut (Shepherd Specialty Papers, Milford, NJ). PicoLab Rodent Diet food pellets (LabDiet, St. Louis, MO) and drinking water (or CNO water in the developmental groups) were provided ad libitum. Mice were relocated to clean cages with new component materials every two weeks. All mice were group-housed in reverse light cycle to promote maximal performance during behavioral testing. All surgery was performed under isoflurane anesthesia (5% for induction, 1-2% in oxygen; 1 L/min) and daily monitoring was employed to minimize suffering.

Version history

  1. Received: March 5, 2018
  2. Accepted: September 15, 2018
  3. Accepted Manuscript published: September 18, 2018 (version 1)
  4. Accepted Manuscript updated: September 20, 2018 (version 2)
  5. Version of Record published: October 16, 2018 (version 3)

Copyright

© 2018, Badura 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

  • 8,026
    views
  • 1,064
    downloads
  • 138
    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. Aleksandra Badura
  2. Jessica L Verpeut
  3. Julia M Metzger
  4. Talmo D Pereira
  5. Thomas J Pisano
  6. Ben Deverett
  7. Dariya E Bakshinskaya
  8. Samuel S-H Wang
(2018)
Normal cognitive and social development require posterior cerebellar activity
eLife 7:e36401.
https://doi.org/10.7554/eLife.36401

Share this article

https://doi.org/10.7554/eLife.36401

Categories and tags

Research organism

Further reading

    1. Developmental Biology
    2. Neuroscience

    A unique multi-synaptic mechanism involving acetylcholine and GABA regulates dopamine release in the nucleus accumbens through early adolescence in male rats

    Melody C Iacino, Taylor A Stowe ... Mark J Ferris
    Research Article Updated

    Adolescence is characterized by changes in reward-related behaviors, social behaviors, and decision-making. These behavioral changes are necessary for the transition into adulthood, but they also increase vulnerability to the development of a range of psychiatric disorders. Major reorganization of the dopamine system during adolescence is thought to underlie, in part, the associated behavioral changes and increased vulnerability. Here, we utilized fast scan cyclic voltammetry and microdialysis to examine differences in dopamine release as well as mechanisms that underlie differential dopamine signaling in the nucleus accumbens (NAc) core of adolescent (P28-35) and adult (P70-90) male rats. We show baseline differences between adult and adolescent-stimulated dopamine release in male rats, as well as opposite effects of the α6 nicotinic acetylcholine receptor (nAChR) on modulating dopamine release. The α6-selective blocker, α-conotoxin, increased dopamine release in early adolescent rats, but decreased dopamine release in rats beginning in middle adolescence and extending through adulthood. Strikingly, blockade of GABAA and GABAB receptors revealed that this α6-mediated increase in adolescent dopamine release requires NAc GABA signaling to occur. We confirm the role of α6 nAChRs and GABA in mediating this effect in vivo using microdialysis. Results herein suggest a multisynaptic mechanism potentially unique to the period of development that includes early adolescence, involving acetylcholine acting at α6-containing nAChRs to drive inhibitory GABA tone on dopamine release.

    1. Neuroscience

    The scheduling of adolescence with Netrin-1 and UNC5C

    Daniel Hoops, Robert Kyne ... Cecilia Flores
    Short Report

    Dopamine axons are the only axons known to grow during adolescence. Here, using rodent models, we examined how two proteins, Netrin-1 and its receptor, UNC5C, guide dopamine axons toward the prefrontal cortex and shape behaviour. We demonstrate in mice (Mus musculus) that dopamine axons reach the cortex through a transient gradient of Netrin-1-expressing cells – disrupting this gradient reroutes axons away from their target. Using a seasonal model (Siberian hamsters; Phodopus sungorus) we find that mesocortical dopamine development can be regulated by a natural environmental cue (daylength) in a sexually dimorphic manner – delayed in males, but advanced in females. The timings of dopamine axon growth and UNC5C expression are always phase-locked. Adolescence is an ill-defined, transitional period; we pinpoint neurodevelopmental markers underlying this period.

    1. Neuroscience

    Cholinergic input to mouse visual cortex signals a movement state and acutely enhances layer 5 responsiveness

    Baba Yogesh, Georg B Keller
    Research Article

    Acetylcholine is released in visual cortex by axonal projections from the basal forebrain. The signals conveyed by these projections and their computational significance are still unclear. Using two-photon calcium imaging in behaving mice, we show that basal forebrain cholinergic axons in the mouse visual cortex provide a binary locomotion state signal. In these axons, we found no evidence of responses to visual stimuli or visuomotor prediction errors. While optogenetic activation of cholinergic axons in visual cortex in isolation did not drive local neuronal activity, when paired with visuomotor stimuli, it resulted in layer-specific increases of neuronal activity. Responses in layer 5 neurons to both top-down and bottom-up inputs were increased in amplitude and decreased in latency, whereas those in layer 2/3 neurons remained unchanged. Using opto- and chemogenetic manipulations of cholinergic activity, we found acetylcholine to underlie the locomotion-associated decorrelation of activity between neurons in both layer 2/3 and layer 5. Our results suggest that acetylcholine augments the responsiveness of layer 5 neurons to inputs from outside of the local network, possibly enabling faster switching between internal representations during locomotion.