Fronto-Striatal Anatomy, Dependent-Behavior, and Neuronal Activity in a Rat Model of Fragile X Syndrome
Objectives: Studies on the Fmr1-KO rat have the potential to extend observations from existing mouse models on the role of Fmrp in the function of a PFC-related network and provide a better platform for development and evaluation of potential therapeutic strategies. Furthermore, since Fmrp is expressed throughout the brain and a loss of Fmrp may differentially affect brain regions, it is important to study circuits such as the fronto-striatal circuit. This study will aim to test whether insufficiency of Fmrp will cause disruption to the fronto-striatal cognitive network and lead to deficits in its morphology, activity, and dependent behaviors.
Methods: To test the effects of Fmrp loss on fronto-striatal circuit anatomy, this study will compare the regional volumes, dependent behaviors, and electrophysiological function of this circuit between Fmr1-KO rats and wild type (WT) littermates. Volumetric analyses will be conducted using Magnetic Resonance Imaging (MRI). The five-choice serial reaction time task (5-CSRTT), which tests the ability to correctly identify which of five ports has been briefly illuminated, will be used to test attention. Neuronal activity will be examined by recording local field potentials (LFP) of fronto-striatal regions, the PFC, anterior cingulate cortex, and nucleus accumbens, during the behavioral task.
Results: MRI data has been collected and analysis of these images using a pipeline, which performs automated nonbiased brain segmentation, is underway. Fmr1-KO rats display attentional deficits during training on the 5-CSRTT, as evidenced by preliminary data, which show a decrease in accuracy and an increase in omission rate (Figure 1). These deficits suggest that fronto-striatal-associated cognitive behavior is impaired in Fmrp-deficient rats. We are beginning to record LFPs during the 5-CSRTT.
Conclusions: This multi-level approach will allow for a better understanding of neural mechanisms affected in FXS, with the potential of discovering a new type of treatment target and providing an output measure for screening of potential therapies.