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Published on: May 12, 2015
Awake functional MRI detects neural circuit dysfunction in a mouse model of autism
Tomokazu Tsurugizawa1, Kota Tamada2, Nobukazu Ono3
1NeuroSpin, Commissariat à l'Energie Atomique et aux Energies Alternatives, CEA Saclay, Gif-sur-Yvette 91191, France.
Abstract:
MRI has potential as a translational approach from rodents to humans. However, given that mouse functional MRI (fMRI) uses anesthetics for suppression of motion, it has been difficult to directly compare the result of fMRI in "unconsciousness" disease model mice with that in "consciousness" patients. We develop awake fMRI to investigate brain function in 15q dup mice, a copy number variation model of autism. Compared to wild-type mice, we find that 15q dup is associated with whole-brain functional hypoconnectivity and diminished fMRI responses to odors of stranger mice. Ex vivo diffusion MRI reveals widespread anomalies in white matter ultrastructure in 15q dup mice, suggesting a putative anatomical substrate for these functional hypoconnectivity. We show that d-cycloserine (DCS) treatment partially normalizes these anormalies in the frontal cortex of 15q dup mice and rescues some social behaviors. Our results demonstrate the utility of awake rodent fMRI and provide a rationale for further investigation of DCS therapy.
Insights
Awake functional MRI in 15q dup mice reveals brain-wide hypoconnectivity and altered responses to social odors. D-cycloserine treatment partially restored function and social behaviors in this autism model.
Area of Science:
- Neuroscience
- Genetics
- Medical Imaging
Background:
- Functional MRI (fMRI) in mice typically requires anesthesia, hindering direct comparison with human studies.
- Investigating brain function in awake animal models is crucial for understanding neurological disorders.
Purpose of the Study:
- To develop and utilize awake fMRI in 15q dup mice, a model for autism spectrum disorder (ASD).
- To explore the functional and structural brain alterations associated with 15q duplication syndrome.
- To assess the therapeutic potential of d-cycloserine (DCS) in normalizing brain function and behavior.
Main Methods:
- Developed awake fMRI techniques for application in rodent models.
- Compared brain activity and connectivity in 15q dup mice and wild-type littermates using fMRI.
- Utilized ex vivo diffusion MRI to examine white matter microstructure.
- Administered d-cycloserine (DCS) to assess its effects on brain function and social behavior.
Main Results:
- 15q dup mice exhibited whole-brain functional hypoconnectivity compared to wild-type controls.
- Diminished fMRI responses to social odors (stranger mouse odors) were observed in 15q dup mice.
- Diffusion MRI revealed widespread white matter abnormalities in 15q dup mice.
- DCS treatment partially normalized frontal cortex function and improved some social behaviors in 15q dup mice.
Conclusions:
- Awake fMRI is a valuable tool for studying brain function in rodent models of neurological disorders.
- 15q duplication is associated with widespread functional and structural brain abnormalities.
- D-cycloserine shows promise as a potential therapeutic agent for aspects of 15q duplication syndrome.
