CACNA1C gene regulates behavioral strategies in operant rule learning

Behavioral experiments are usually designed to tap into a specific cognitive function, but animals may solve a given task through a variety of different and individual behavioral strategies, some of them not foreseen by the experimenter. Animal learning may therefore be seen more as the process of selecting among, and adapting, potential behavioral policies, rather than mere strengthening of associative links. Calcium influx through high-voltage-gated Ca2+ channels is central to synaptic plasticity, and altered expression of Cav1.2 channels and the CACNA1C gene have been associated with severe learning deficits and psychiatric disorders. Given this, we were interested in how specifically a selective functional ablation of the Cacna1c gene would modulate the learning process. Using a detailed, individual-level analysis of learning on an operant cue discrimination task in terms of behavioral strategies, combined with Bayesian selection among computational models estimated from the empirical data, we show that a Cacna1c knockout does not impair learning in general but has a much more specific effect: the majority of Cacna1c knockout mice still managed to increase reward feedback across trials but did so by adapting an outcome-based strategy, while the majority of matched controls adopted the experimentally intended cue-association rule. Our results thus point to a quite specific role of a single gene in learning and highlight that much more mechanistic insight could be gained by examining response patterns in terms of a larger repertoire of potential behavioral strategies. The results may also have clinical implications for treating psychiatric disorders.Author summary: To deal with an uncertain and complex world, animals have developed a large repertoire of behavioral heuristics and default strategies that spring into action in unknown situations. Building on this a priori repertoire, animals may find various ways to succeed on a given behavioral task. Therefore, determining the exact behavioral strategy followed during a task may be essential for understanding the cognitive processes involved. Using computational models to analyze behavior, we examined how a genetic variation in a gene that encodes a calcium channel and has been associated with learning deficits influences the way in which animals acted on a task in which a reward was associated with a specific behavior. We found that a knockout of the relevant gene does not lead to a general learning impairment but rather led animals to adopt a behavioral strategy different from the one employed by the control animals. Specifically, knockout animals managed to increase their reward returns by basing their responses more on the previous reward location rather than on reward-indicating stimuli, like the controls did. These findings may prove useful for behavioral therapy in the context of psychiatric disorders associated with this specific gene variation.