A novel approach to the assessment of higher-order rule learning in male mice.

Historically, the development of valid and reliable methods for assessing higher-order cognitive abilities (e.g., rule learning and transfer) has been difficult in rodent models. To date, limited evidence supports the existence of higher cognitive abilities such as rule generation and complex decision-making in mice, rats, and rabbits. To this end, we sought to develop a task that would require mice to learn and transfer a rule. We trained mice to visually discriminate a series of images (image set, six total) of increasing complexity following three stages: (1) learn a visual target, (2) learn a rule (ignore any new images around the target), and finally (3) apply this rule in abstract form to a comparable but new image set. To evaluate learning for each stage, we measured (1) days (and performance by day) to discriminate the original target at criterion, (2) days (and performance by day) to get back to criterion when images in the set were altered by the introduction of distractors (rule learning), and (3) overall days (and performance by day) to criterion when experienced versus naïve cohorts of mice were tested on the same image set (rule transfer). Twenty-seven wild-type male C57 mice were tested using Bussey-Saksida touchscreen operant conditioning boxes (Lafayette Instruments). Two comparable black-white image sets were delivered sequentially (counterbalanced for order) to two identical cohorts of mice. Results showed that all mice were able to effectively learn their initial target image and could recall it >80 d later. We also found that mice were able to quickly learn and apply a "rule" : Ignore new distractors and continue to identify their visual target embedded in more complex images. The presence of rule learning was supported because performance criterion thresholds were regained much faster than initial learning when distractors were introduced. On the other hand, mice appeared unable to transfer this rule to a new set of stimuli. This is supported because visual discrimination curves for a new image set were no better than an initial (naïve) learning by a matched cohort of mice. Overall results have important implications for phenotyping research and particularly for the modeling of complex disorders in mice.

Rapid auditory processing and medial geniculate nucleus anomalies in Kiaa0319 knockout mice.

Developmental dyslexia is a common neurodevelopmental disorder characterized by difficulties in reading and writing. Although underlying biological and genetic mechanisms remain unclear, anomalies in phonological processing and auditory processing have been associated with dyslexia. Several candidate risk genes have also been identified, with KIAA0319 as a main candidate. Animal models targeting the rodent homolog (Kiaa0319) have been used to explore putative behavioral and anatomic anomalies, with mixed results. For example after downregulation of Kiaa0319 expression in rats via shRNA, significant adult rapid auditory processing impairments were reported, along with cortical anomalies reflecting atypical neuronal migration. Conversely, Kiaa0319 knockout (KO) mice were reported to have typical adult auditory processing, and no visible cortical anomalies. To address these inconsistencies, we tested Kiaa0319 KO mice on auditory processing tasks similar to those used previously in rat shRNA knockdown studies. Subsequent neuroanatomic analyses on these same mice targeted medial geniculate nucleus (MGN), a receptive communication-related brain structure. Results confirm that Kiaa0319 KO mice exhibit significant auditory processing impairments specific to rapid/brief stimuli, and also show significant volumetric reductions and a shift toward fewer large and smaller neurons in the MGN. The latter finding is consistent with post mortem MGN data from human dyslexic brains. Combined evidence supports a role for KIAA0319 in the development of auditory CNS pathways subserving rapid auditory processing functions critical to the development of speech processing, language, and ultimately reading. Results affirm KIAA0319 variation as a possible risk factor for dyslexia specifically via anomalies in central acoustic processing pathways.