Cued and contextual fear conditioning in BTBR mice is improved with training or atomoxetine

• The BTBTR T + tf/J (BTBR) mice have shown impaired cued and contextual fear conditioning.
• Increased training improved cued fear conditioning in the BTBR mice.
• Atomoxetine improved contextual fear conditioning in the BTBR mice.
• The performance of the BTBR mice may be improved with behavioral or pharmacological intervention.

The BTBR T + tf/J (BTBR) strain of mice is a model for autism spectrum disorders (ASDs). These mice display reduced social behavior, altered communication, and high levels of repetitive behavior. BTBR mice have shown a deficit in learning cued and contextual fear conditioning. In this study, experiments were conducted to determine if either changes in training or drug administration would improve learning in BTBR mice when compared to C57BL/6 (B6) mice in contextual and cued fear conditioning. The first experiment examined the effects of three conditioned stimulus-unconditioned stimulus (CS–US) training paradigms; a 1P (1 CS–US pairing), 4P (4 CS–US pairings), and 10P (10 CS–US pairings). Increasing the number of CS–US pairings to 10 caused an increase in freezing behavior by the BTBR mice in contextual and cued conditioning indicating that more training facilitated BTBR learning. B6 mice had a more complex reaction to the increased training; the mice increased freezing behavior in the cued fear conditioning but not contextual fear conditioning. The second experiment determined whether atomoxetine, a noradrenergic reuptake inhibitor that has been shown to improve attention and decrease hyperactivity, impulsivity, and social withdrawal, would enhance learning. There was a significant increase in freezing behavior in contextual fear conditioning following atomoxetine administration in BTBR mice but not in B6 mice. Our data demonstrates that contextual and cued learning in BTBR mice is facilitated by increased training. Furthermore, contextual learning is improved in BTBR mice with use of atomoxetine, which helps to improve attention. Both increased training and pharmacological intervention improved learning in the BTBR mice suggesting a role for the combination of the two.