Shared and divergent alteration of whole-brain connectivity and sensory deficits in multiple autism mouse models.

Scientists studied brain connections in three different autism mouse models and found that while each genetic change caused different brain problems, all models had issues with the smell-processing part of the brain (piriform cortex). This brain region affects both smell detection and social behavior. All mouse models had trouble distinguishing smells, and when researchers changed activity in this brain area, it affected social behaviors. This suggests smell-processing problems might be common in autism.

This preclinical study used an AI-powered brain mapping platform to analyze connectivity patterns in three autism mouse models (Tbr1, Nf1, and Vcp mutations). Researchers found that while each genetic mutation caused distinct brain circuit abnormalities, all models showed consistent deficits in the piriform cortex, a brain region involved in smell processing and social behavior. The study revealed altered structural connectivity and reduced neurons in sensory regions, with visual and somatosensory cortices variably affected across models. All mouse models demonstrated olfactory discrimination impairments, and manipulating piriform cortex activity influenced social behaviors, suggesting this region plays a crucial role in autism-related circuit dysfunction.

Results suggest olfactory processing assessments might be valuable in autism diagnosis and monitoring. The piriform cortex represents a potential therapeutic target for addressing social difficulties. Findings support the need for sensory-focused interventions and highlight the importance of considering sensory processing differences in autism treatment approaches.

This is a preclinical mouse study, so findings may not directly translate to humans. Sample sizes not reported. The study examines only three genetic models, which may not represent the full spectrum of autism. Long-term effects and developmental trajectories were not assessed.

Autism spectrum disorder (ASD) is a heterogeneous developmental disconnection syndrome. Identifying circuit deficits is crucial for understanding ASD etiology, yet the involvement of multiple brain regions and genetic variations complicates this analysis. Here, using an AI-powered mapping platform, BM-auto (Brain Mapping with Auto-ROI correction), to analyze a Thy1-YFP reporter, we show that different ASD-associated mutations cause distinct circuit abnormalities but share common deficits in the piriform cortex, a region regulating olfactory discrimination and social behavior patterns. We analyzed the whole-brain distribution of the Thy1-YFP reporter in three ASD mouse models (Tbr1, Nf1, and Vcp).

YFP signals revealed altered axonal projections and structural connectivity. We also found that Thy1-YFPcell numbers varied across brain regions, revealing deficits in the differentiation or maintenance of projection neurons. While each mutation caused unique connectivity alterations, sensory regions-including the visual, somatosensory, and piriform cortices-were recurrently affected. However, effects on the visual and somatosensory cortices varied between models.

The piriform cortex was the only region consistently impaired, showing reduced YFP signals and fewer Thy1-YFPneurons across all three models. Furthermore, all three mutants exhibited common olfactory discrimination impairments. Manipulating piriform cortex activity altered social behavior patterns, highlighting its role in ASD-linked circuit dysfunction. These findings underscore the vulnerability of sensory regions-especially the piriform cortex-to ASD-related mutations, strengthening the notion that altered sensory experiences are common in ASD.