CACNA1C gene regulates behavioral strategies in operant rule learning

Abstract

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.

Calcium channelopathies and intellectual disability: a systematic review

“…Acetazolamide could abolish stress-induced ataxia in mice [ 144 ] Apoptotic pathway in ataxia [ 152 ] CACNA1C Calcium voltage-gated channel subunit alpha1 C Cav1.2 L-type Genetic Cacna1c rat model [ 239 ]. Cacna1c knockout model [ 240 ]. Mouse line with an inactivation of the Cav1.2 gene in the hippocampus and neocortex (Cav1.2 (HCKO)) [ 241 ].…”

Phasic dopamine reinforces distinct striatal stimulus encoding in the olfactory tubercle driving dopaminergic reward prediction

“…In Q-PH models, the value of choosing an action a at state s is parametrized by the variable Q s,a . The Pearce–Hall update mechanism generalizes the classic Rescorla–Wagner rule by introducing an associability variable a , which tracks the uncertainty of the animal on the trial outcome and is proportional to its attention to CS 34 , 36 , 72 , 73 . The associability affects the action value Q s,a as a feedback-dependent dynamical learning rate.…”

Genetic Variation in the Psychiatric Risk Gene CACNA1C Modulates Reversal Learning Across Species

“…Cacna1c knockout mice did not show an overall behavioral deficit; however, detailed behavioral analysis showed that these animals gained reward based on an outcome-based strategy, rather than learning cue–reward associations, basing their responses more on the previous location of the reward. 55 Similarly, Temme et al 54 found that mice lacking forebrain Cacna1c could learn contextual and spatial associations normally but were impaired on more subtle tests of context discrimination and pattern completion. A recent study also demonstrated impacts of Cacna1c hemizygosity on social behavior and communication.…”

“…Our results are broadly consistent with previous studies on mice with forebrain-specific total knockout of Cacna1c . 54,55 Koppe et al 55 found forebrain-specific conditional Cacna1c knockout mice adopt different behavioral strategies during an operant reward-based learning task compared to controls. Cacna1c knockout mice did not show an overall behavioral deficit; however, detailed behavioral analysis showed that these animals gained reward based on an outcome-based strategy, rather than learning cue–reward associations, basing their responses more on the previous location of the reward.…”