A novel automated behavioral test battery assessing cognitive rigidity in two genetic mouse models of autism

Abstract

Repetitive behaviors are a key feature of many pervasive developmental disorders, such as autism. As a heterogeneous group of symptoms, repetitive behaviors are conceptualized into two main subgroups: sensory/motor (lower-order) and cognitive rigidity (higher-order). Although lower-order repetitive behaviors are measured in mouse models in several paradigms, so far there have been no high-throughput tests directly measuring cognitive rigidity. We describe a novel approach for monitoring repetitive behaviors during reversal learning in mice in the automated IntelliCage system. During the reward-motivated place preference reversal learning, designed to assess cognitive abilities of mice, visits to the previously rewarded places were recorded to measure cognitive flexibility. Thereafter, emotional flexibility was assessed by measuring conditioned fear extinction. Additionally, to look for neuronal correlates of cognitive impairments, we measured CA3-CA1 hippocampal long term potentiation (LTP). To standardize the designed tests we used C57BL/6 and BALB/c mice, representing two genetic backgrounds, for induction of autism by prenatal exposure to the sodium valproate. We found impairments of place learning related to perseveration and no LTP impairments in C57BL/6 valproate-treated mice. In contrast, BALB/c valproate-treated mice displayed severe deficits of place learning not associated with perseverative behaviors and accompanied by hippocampal LTP impairments. Alterations of cognitive flexibility observed in C57BL/6 valproate-treated mice were related to neither restricted exploration pattern nor to emotional flexibility. Altogether, we showed that the designed tests of cognitive performance and perseverative behaviors are efficient and highly replicable. Moreover, the results suggest that genetic background is crucial for the behavioral effects of prenatal valproate treatment.

Measuring discrimination- and reversal learning in mouse models within 4 days and without prior food deprivation

“…Previous studies also showed that measures of learning can be collected in standardized automated home-cage environments without human interference (Galsworthy et al 2005;Mechan et al 2009;Gallistel et al 2010;Endo et al 2011;Balci et al 2013;Puścian et al 2014;Remmelink et al 2015); however, all these tasks restricted reinforcement schedules to specific times of the day. We here demonstrate that continuous testing is compatible with operant testing which allowed for the short duration of the reversal learning protocol as well as animal paced task participation.…”

Update of neurotrophic factors in neurobiology of addiction and future directions

“…The number of publications where IntelliCage has been applied as a tool for behavioral testing is growing, although we have not found references directly addressing the role of NTFs in behavior. However, the method has been valuable for investigating the links between neurogenesis and behavior (Vannoni et al, 2014), in characterization of mouse models for Huntington’s disease (Knapska et al, 2013; Knapska et al, 2006; Kobayashi et al, 2013), Alzheimer’s disease (Codita et al, 2010; Ryan et al, 2013; Weyer et al, 2011), Down syndrome (Faizi et al, 2011), autism (Puscian et al, 2014). In addition, IntelliCage has been used as either enriched or stressful environment and combined with measurement of changes in the levels of BDNF and glucocorticoids (Alboni et al, 2015; Branchi et al, 2013; Kulesskaya et al, 2014) provides an excellent ethological surrounding for modeling stress and depression-like behavior in mice.…”

Nucleus accumbens dopamine D2-receptor expressing neurons control behavioral flexibility in a place discrimination task in the IntelliCage

“…More recently, IntelliCage place discrimination tasks have been used to investigate higher-order cognitive functions in both normal and disease model mice. Acquisition and reversal of place discrimination was found to differ between various commonly used inbred mouse strains (Krackow et al 2010;Endo et al 2011), and valproatetreated C57BL/6 mice, used as a model of autism, displayed impairments in place learning associated with perseverative responding (Puscian et al 2014). However, little is known about the neural circuitry that mediates performance on this task.…”