Normal Performance of Fmr1 Mice on a Touchscreen Delayed Nonmatching to Position Working Memory Task

Abstract

Fragile X syndrome is a neurodevelopmental disorder characterized by mild-to-severe cognitive deficits. The complete absence of Fmr1 and its protein product in the mouse model of fragile X (Fmr1 KO) provides construct validity. A major conundrum in the field is the remarkably normal performance of Fmr1 mice on cognitive tests in most reports. One explanation may be insufficiently challenging cognitive testing procedures. Here we developed a delayed nonmatching to position touchscreen task to test the hypothesis that paradigms placing demands on working memory would reveal robust and replicable cognitive deficits in the Fmr1 KO mouse. We first tested Fmr1 KO mice (Fmr1) and their wild-type (WT) littermates in a simple visual discrimination task, followed by assessment of reversal learning. We then tested Fmr1 and WT mice in a new touchscreen nonmatch to position task and subsequently challenged their working memory abilities by adding delays, representing a higher cognitive load. The performance by Fmr1 KO mice was equal to WTs on both touchscreen tasks. Last, we replicated previous reports of normal performance by Fmr1 mice on Morris water maze spatial navigation and reversal. These results indicate that, while the Fmr1 mouse model effectively recapitulates many molecular and cellular aspects of fragile X syndrome, the cognitive profile of Fmr1 mice generally does not recapitulate the primary cognitive deficits in the human syndrome, even when diverse and challenging tasks are imposed.

Touch-screen visual reversal learning is mediated by value encoding and signal propagation in the orbitofrontal cortex

“…Touch-screen automated paradigms have become increasingly utilized to screen rodent models of numerous neuropsychiatric disorders (Marquardt et al, 2014, Yang et al, 2015, Copping et al, 2016, Leach et al, 2016) as these paradigms closely model tools used in the clinical assessment and may increase translational potential of preclinical studies (Mar et al, 2013, Talpos and Steckler, 2013, Hvoslef-Eide et al, 2016). While previous studies have demonstrated that lesion and/or inactivation of the region is sufficient to disrupt visual touch-screen reversal, it has not yet been demonstrated that the rodent OFC mediates reversal of complex visual stimuli in an analogous manner to those seen in primates using visual stimuli (Clarke et al, 2008), or to more species-specific stimuli such as spatial, olfactory or tactile stimuli in rodents (Hamilton and Brigman, 2015b).…”

Trial-unique, delayed nonmatching-to-location (TUNL) touchscreen testing for mice: sensitivity to dorsal hippocampal dysfunction

“…Once mice acquire TUNL, further manipulations can be carried out by varying delay, spatial separation level and ITI (McAllister et al 2013 ). At least one other group has reported success training mice on this task in a similar, simplified manner (Leach and Crawley 2014 ). Note that although we had success with one method for the mouse, it may be that by varying other task parameters, alternative or additional improvements could be made.…”

Of Men and Mice: Modeling the Fragile X Syndrome

“…Although there are still two conserved parallel pathways between the cortex and the hippocampus in mice and men, which transfer object and context related information (reviewed in Ranganath and Ritchey, 2012 ), the finding of Bergmann and colleagues is of quiet some significance since cortical-hippocampal pathways are required for important brain functions including spatial working memory (studies in rodents and humans; reviewed in Sigurdsson and Duvarci, 2016 ), long-term memory (studies in rodents, primates and humans; reviewed in Sigurdsson and Duvarci, 2016 ), motivation and emotion (studies in rodents; reviewed in Sigurdsson and Duvarci, 2016 ), and social recognition (studies in rodents and humans; reviewed in Bicks et al, 2015 ). Indeed, weaknesses in working memory performance, in particular when requiring abstract item reasoning, are characteristic to FXS patients (Munir et al, 2000 ; Cornish et al, 2001 ; Kwon et al, 2001 ; Ornstein et al, 2008 ; Baker et al, 2011 ; Wang et al, 2013 ), but not to model mice (Leach et al, 2016 ). While Fmr1 −/y mice perform as well as their wildtype littermates even when their working memory is significantly challenged (Leach et al, 2016 ), individuals with FXS are unable to modulate activation of the prefrontal and parietal cortex in response to an increasing working memory load (Kwon et al, 2001 ), implying a lack of circuit control.…”