Abstract
Gene transcription is essential for learning, but the precise role of transcription factors that control expression of many other genes in specific learning paradigms is yet poorly understood. Zif268 (Krox24/Egr-1) is a transcription factor and an immediate-early gene associated with memory consolidation and reconsolidation, and induced in the striatum after addictive drugs exposure. In contrast, very little is known about its physiological role at early stages of operant learning. We investigated the role of Zif268 in operant conditioning for food. Zif268 expression was increased in all regions of the dorsal striatum and nucleus accumbens in mice subjected to the first session of operant conditioning. In contrast, Zif268 increase in the dorsomedial caudate-putamen and nucleus accumbens core was not detected in yoked mice passively receiving the food reward. This indicates that Zif268 induction in these structures is linked to experiencing or learning contingency, but not to reward delivery. When the task was learned (5 sessions), Zif268 induction disappeared in the nucleus accumbens and decreased in the medial caudate-putamen, whereas it remained high in the lateral caudate-putamen, previously implicated in habit formation. In transgenic mice expressing green fluorescent protein (GFP) in the striatonigral neurons, Zif268 induction occured after the first training session in both GFP-positive and negative neurons indicating an enhanced Zif268 expression in both striatonigral and striatopallidal neurons. Mutant mice lacking Zif268 expression obtained less rewards, but displayed a normal discrimination between reinforced and non-reinforced targets, and an unaltered approach to food delivery box. In addition, their motivation to obtain food rewards, evaluated in a progressive ratio schedule, was blunted. In conclusion, Zif268 participates in the processes underlying performance and motivation to execute food-conditioned instrumental task.
Highlights
Animals adapt their behavior when they receive reward, leading to incentive learning and changes in motivation state [1]
To test if Zif268 expression could be altered by training for instrumental task, we subjected two groups of mice to a single or five sessions with a FR1 schedule (‘‘Active’’) and compared them to two control groups with 1 and 5 sessions, respectively (‘‘Control’’)
Previous studies have shown that green fluorescent protein (GFP)-negative medium-sized spiny neurons (MSNs) in the Drd1a::GFP transgenic mice express D2 receptors (D2Rs) [26], these results indicated that training to operant task induced Zif268 in both D1 receptor (D1R)- and D2R-expressing MSNs populations
Summary
Animals adapt their behavior when they receive reward, leading to incentive learning and changes in motivation state [1]. Learning processes are of two types, Pavlovian conditioning in which predictive associations of sensory stimuli with reward are memorized, and instrumental conditioning in which the consequences of motor acts are learned in relation with reward [2] In combination with these learning processes, elements of stimulusreward and action-reward associations acquire motivational values that greatly influence the animal willingness to perform the learned responses [3]. Considerable research has long suggested that these processes are controlled by the cerebral cortex and basal ganglia, the cortex being a major source of input to the basal ganglia through its topographical projections to the striatum [4] In both rodents and humans, different types of conditioning are controlled by specific parts of the striatal complex that are connected with specific cortical areas [5,6]. Medial CPu is critical for the formation of actionoutcome associations mediating goal-directed behaviors [8]
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