Mediodorsal Thalamus Hypofunction Impairs Flexible Goal-Directed Behavior

• Published in: Biological psychiatry (1969) 2015-03, Vol.77 (5), p.445-453
• Main Authors: Parnaudeau, Sébastien, Taylor, Kathleen, Bolkan, Scott S, Ward, Ryan D, Balsam, Peter D, Kellendonk, Christoph
• Format: Article
• Language: English
• Subjects: Animals; Behavioral flexibility; Conditioning, Classical - physiology; Conditioning, Operant - physiology; Cues; Discrimination (Psychology) - physiology; DREADD system; Extinction, Psychological - physiology; Goal-directed behavior; Goals; Life Sciences; Male; Mediodorsal thalamus; Mice, Inbred C57BL; Neurons and Cognition; Pavlovian-to-instrumental transfer; Psychiatry; Reversal Learning - physiology; Reward; Schizophrenia; Thalamus - physiopathology; Transfer (Psychology) - physiology
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2014.03.020

Abstract Background Cognitive inflexibility is a core symptom of several mental disorders including schizophrenia. Brain imaging studies in schizophrenia patients performing cognitive tasks have reported decreased activation of the mediodorsal thalamus (MD). Using a pharmacogenetic approach to model MD hypofunction, we recently showed that decreasing MD activity impairs reversal learning in mice. While this demonstrates causality between MD hypofunction and cognitive inflexibility, questions remain about the elementary cognitive processes that account for the deficit. Methods Using the Designer Receptors Exclusively Activated by Designer Drugs system, we reversibly decreased MD activity during behavioral tasks assessing elementary cognitive processes inherent to flexible goal-directed behaviors, including extinction, contingency degradation, outcome devaluation, and Pavlovian-to-instrumental transfer ( n = 134 mice). Results While MD hypofunction impaired reversal learning, it did not affect the ability to learn about nonrewarded cues or the ability to modulate action selection based on the outcome value. In contrast, decreasing MD activity delayed the ability to adapt to changes in the contingency between actions and their outcomes. In addition, while Pavlovian learning was not affected by MD hypofunction, decreasing MD activity during Pavlovian learning impaired the ability of conditioned stimuli to modulate instrumental behavior. Conclusions Mediodorsal thalamus hypofunction causes cognitive inflexibility reflected by an impaired ability to adapt actions when their consequences change. Furthermore, it alters the encoding of environmental stimuli so that they cannot be properly utilized to guide behavior. Modulating MD activity could be a potential therapeutic strategy for promoting adaptive behavior in human subjects with cognitive inflexibility.