CACNA1C gene regulates behavioral strategies in operant rule learning.

Georgia Koppe,Anne Stephanie Mallien,Dusan Bartsch,Peter Gass,Daniel Durstewitz,Stefan Berger,Barbara Vollmayr,Jozsef Csicsvari

doi:10.1371/journal.pbio.2000936

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.

Highlights

The ability to learn, to adapt one’s own behavior in order to optimize positive and avoid negative feedback, is central to all living beings
We studied learning in terms of behavioral strategies on a 2-choice operant cue discrimination task in 2 groups of mice, a group with a genetic modification associated with severe learning deficits [22], namely, a selective knockout (KO) of the Cacna1c gene coding for the α subunit of Cav1.2 L-type highvoltage-dependent calcium channels (Cav1.2NesCre), and matched controls with intact gene
To examine potential learning deficits caused by selective ablation of the Cav1.2 L-type calcium channel subunit, a cue discrimination task consisting of 3 different task phases was set up (Fig 1)

Summary

Introduction

The ability to learn, to adapt one’s own behavior in order to optimize positive and avoid negative feedback, is central to all living beings. Animals like humans are constantly seeking to infer the (causal) structure of their environment and to predict the outcomes of their actions [1,2], sometimes to a degree that “superstitial beliefs” about environmental contingencies may form [3]. Animals like humans rely on heuristics, strategies, and ecological biases that favor certain types of environmental contingencies over others and narrow down the search space [5,6]. The upshot here is that animal learning may rely on a large variety of different previously acquired or predisposed strategies, rather than on a uniform mechanism, like SR strengthening, that could either be enabled or disabled

Methods

Results

Conclusion