Abstract
Abnormal brain development manifests itself at different spatial scales. However, whether abnormalities at the cellular level can be diagnosed from network activity measured withfunctional magnetic resonance imaging (fMRI) is largely unknown, yet of high clinical relevance. Here we applied fMRI while using chemogenetics to increase the excitation-to-inhibition ratio (E:I) within cortical microcircuits of the mouse brain, thereby mimicking a putative mechanism of neurodevelopmental disorders including autism. Increased E:I caused a significant reduction of long-range connectivity, irrespective of whether excitatory neurons were facilitated or inhibitory Parvalbumin interneurons were suppressed. Training a classifier on fMRI signals, we were able to accurately classify cortical areas exhibiting increased E:I. This classifier was validated in an independent cohort of Fmr1y/- knock-out mice, a model for autism with well-documented loss of Parvalbumin neurons and chronic alterations of E:I. Our findings demonstrate a promising novel approach towards inferring microcircuit abnormalities from macroscopic fMRI measurements.
Footnotes
↵* V.Z and N.W share last authorship.
Abbreviations
- ASD
- autism spectrum disorder
- ASL
- arterial spin labelling
- BOLD
- blood-oxygen level dependent
- CAMKII
- alpha-calcium/calmodulin-dependent protein kinase II promoter
- CBF
- cerebral blood flow
- CP
- caudate putamen
- DREADD
- Designer Receptors Exclusively Activated by Designer Drugs
- FC
- functional connectivity
- Fmr1
- fragile X mental retardation 1 gene
- hM3Dq
- excitatory DREADD
- hM4Di
- inhibitory DREADD
- MOctx
- primary somatomotor cortex
- PV
- parvalbumin interneurons
- PVCre
- parvalbumin cre-dependant
- PVCre-hM4Di
- PVCre mice injected with hM4Di DREADD
- ReHo
- Regional Homogeneity
- rsfMRI
- resting-state functional Magnetic Resonance Imaging
- SSctx
- primary somatosensory cortex
- STR
- striatum
- TEa
- temporal association cortex
- TH
- thalamus
- VMHC
- Voxel-mirrored Homotopic Connectivity
- Wt-hM3Dq
- wildtype mice injected with hM3Dq DREADD