Extinction of an instrumental response: a cognitive behavioral assay in Fmr1 knockout mice
Author(s)
Taylor, M.
Gisin, E.
Sidorov, Michael
Krueger, Dilja
Osterweil, Emily
Bear, Mark
Date Issued
April 2014
Journal
Genes, Brain and Behavior
Publisher
Wiley Blackwell
Citation
Sidorov, M. S., D. D. Krueger, M. Taylor, E. Gisin, E. K. Osterweil, and M. F. Bear. “Extinction of an Instrumental Response: a Cognitive Behavioral Assay in Fmr1 Knockout Mice.” Genes, Brain and Behavior (April 2014): n/a–n/a.
Version
Author's final manuscript
Abstract
Fragile X (FX) is the most common genetic cause of intellectual disability and autism. Previous studies have shown that partial inhibition of metabotropic glutamate receptor signaling is sufficient to correct behavioral phenotypes in a mouse model of FX, including audiogenic seizures, open-field hyperactivity and social behavior. These phenotypes model well the epilepsy (15%), hyperactivity (20%) and autism (30%) that are comorbid with FX in human patients. Identifying reliable and robust mouse phenotypes to model cognitive impairments is critical considering the 90% comorbidity of FX and intellectual disability. Recent work characterized a five-choice visuospatial discrimination assay testing cognitive flexibility, in which FX model mice show impairments associated with decreases in synaptic proteins in prefrontal cortex (PFC). In this study, we sought to determine whether instrumental extinction, another process requiring PFC, is altered in FX model mice, and whether downregulation of metabotropic glutamate receptor signaling pathways is sufficient to correct both visuospatial discrimination and extinction phenotypes. We report that instrumental extinction is consistently exaggerated in FX model mice. However, neither the extinction phenotype nor the visuospatial discrimination phenotype is corrected by approaches targeting metabotropic glutamate receptor signaling. This work describes a novel behavioral extinction assay to model impaired cognition in mouse models of neurodevelopmental disorders, provides evidence that extinction is exaggerated in the FX mouse model and suggests possible limitations of metabotropic glutamate receptor-based pharmacotherapy.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Picower Institute for Learning and Memory
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1111/gbb.12137
