Parallel social information processing circuits are differentially impacted in autism

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, although to date direct evidence to support this hypothesis is lacking. Here we provide the first comprehensive characterization of magnocellular and parvocellular oxytocin neurons, validated across anatomical, projection target, electrophysiological, and transcriptional criteria. We next used 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 uniquely enriched in parvocellular 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.

Oxytocin administration in neonates shapes the hippocampal circuitry and restores social behavior in a mouse model of autism

“…Oxytocin deficiency, present in the Magel2-KO mouse model and in PWS, has also been frequently described in rodent models of ASD (2). Recently, evidences for a unifying role of oxytocin in pathogenic mechanisms responsible for social impairments across abroad range of autism etiologies have been provided (67, 68). Thus, our results demonstrate that peripheral OT-administration in a critical period of time, after birth, represents a viable therapeutic strategy for patients with SYS or PWS and possibly other neurodevelopmental disorders.…”

The Dopamine Hypothesis of Autism Spectrum Disorder Revisited: Current Status and Future Prospects

“…Given that participants with lower social motivation benefitted the most from the administered OXT [41], the gender bias could become a source of systematic error and needs to be considered when determining which subject would benefit from OXT treatment [42]. Second, Lewis et al [43] bring into question the appropriate therapeutic target in ASD. While supporting OXT as a feasible treatment, this study provides evidence that only certain oxytocinergic pathways could be truly relevant for autistic social reward behavior.…”

“…An explanation for the lack of a clear etiopathogenetic model of ASD resides in the approach researchers have used over the years, as theorized by Lewis et al [43]. They illustrate how ASD researchers have used the high heritability of the disorder in order to generate transgenic murine models.…”

“…While these models clarified how certain ASD genes might converge at the molecular and synaptic levels, this "bottom-up" approach has not led any closer to understanding how these disruptions produce the ASD behavioral phenotype. Thus, Lewis et al [43] propose instead a "top-down" approach which could generate an opportunity to merge the distinctiveness of the behavioral phenotype with the etiological diversity of ASD.…”

Neural circuitry for maternal oxytocin release induced by infant cries

“…Oxytocin signaling to the auditory cortex is important for promoting synaptic plasticity leading to enhanced detection of pup calls and retrieval behavior (Marlin et al, 2015; Carcea et al, 2019; Schiavo et al, 2020; Tasaka et al, 2020). PVN oxytocin neurons also send projections to a variety of other brain structures implicated in maternal care and social behavior (Dölen, 2015; Althammer and Grinevich, 2017; Grinevich et al, 2016; Lewis et al, 2020; Tang et al, 2020; Zhang et al, 2020). These include sensory, limbic, and motivational areas such as the ventral tegmental area (VTA), a brain region involved in rewarding aspects of maternal behavior, maternal motivation, and pup retrieval (Numan, 2006; Numan and Young, 2016; Fang et al, 2018; Kohl and Dulac, 2018; Rincón-Cortés and Grace, 2020).…”