Parallel Social Information Processing Circuits Are Differentially Impacted in Autism

Eastman M Lewis; Genevieve L Stein-O'Brien; Alejandra V Patino; Romain Nardou; Cooper D Grossman; Matthew Brown; Bidii Bangamwabo; Ndeye Ndiaye; Daniel Giovinazzo; Ian Dardani; Connie Jiang; Loyal A Goff; Gül Dölen

doi:10.1016/j.neuron.2020.10.002

Parallel Social Information Processing Circuits Are Differentially Impacted in Autism

Neuron. 2020 Nov 25;108(4):659-675.e6. doi: 10.1016/j.neuron.2020.10.002. Epub 2020 Oct 27.

Authors

Affiliations

¹ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; The Brain Science Institute, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; The Kavli Neuroscience Discovery Institute, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; The Wendy Klag Institute for Autism and Developmental Disabilities, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
² The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; The Kavli Neuroscience Discovery Institute, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, School of Medicine, Baltimore, MD 21205; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
³ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; The Brain Science Institute, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; The Kavli Neuroscience Discovery Institute, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; The Wendy Klag Institute for Autism and Developmental Disabilities, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
⁴ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; The Brain Science Institute, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; The Kavli Neuroscience Discovery Institute, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
⁵ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
⁶ Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷ Cell and Molecular Biology Group, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁸ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; The Kavli Neuroscience Discovery Institute, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA. Electronic address: loyalgoff@jhmi.edu.
⁹ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; The Brain Science Institute, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; The Kavli Neuroscience Discovery Institute, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; The Wendy Klag Institute for Autism and Developmental Disabilities, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA. Electronic address: gul@jhu.edu.

Abstract

Parallel processing circuits are thought to dramatically expand the network capabilities of the nervous system. Magnocellular and parvocellular oxytocin neurons have been proposed to subserve two parallel streams of social information processing, which allow a single molecule to encode a diverse array of ethologically distinct behaviors. Here we provide the first comprehensive characterization of magnocellular and parvocellular oxytocin neurons in male mice, validated across anatomical, projection target, electrophysiological, and transcriptional criteria. We next use novel multiple feature selection tools in Fmr1-KO mice to provide direct evidence that normal functioning of the parvocellular but not magnocellular oxytocin pathway is required for autism-relevant social reward behavior. Finally, we demonstrate that autism risk genes are enriched in parvocellular compared with magnocellular oxytocin neurons. Taken together, these results provide the first evidence that oxytocin-pathway-specific pathogenic mechanisms account for social impairments across a broad range of autism etiologies.

Keywords: Fmr1; Fragile X; autism; circuit; hypothalamus; nucleus accumbens; oxytocin; reward; single-cell RNA sequencing; social.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Autism Spectrum Disorder / physiopathology*
Disease Models, Animal
Fragile X Mental Retardation Protein / genetics
Fragile X Mental Retardation Protein / physiology*
Gene Knock-In Techniques
Male
Mice
Mice, Knockout
Neurons / physiology*
Object Attachment
Oxytocin / genetics
Oxytocin / physiology*
Social Behavior*

Substances

Fmr1 protein, mouse
Fragile X Mental Retardation Protein
Oxytocin

Abstract

Publication types

MeSH terms

Substances

Grants and funding