title: Mediodorsal thalamus hypofunction impairs flexible goal-directed behavior.
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.
authors.affiliation: Departments of Psychiatry (SP, KT, SSB, RDW, PDB, CK), Columbia University, New York, New York; Department of Pharmacology, Columbia University, New York, New York.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Parnaudeau
authors.affiliation: Departments of Psychiatry (SP, KT, SSB, RDW, PDB, CK), Columbia University, New York, New York.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Taylor
authors.affiliation: Departments of Psychiatry (SP, KT, SSB, RDW, PDB, CK), Columbia University, New York, New York; Department of Pharmacology, Columbia University, New York, New York.
authors.forename: Scott S
authors.initials: SS
authors.lastname: Bolkan
authors.affiliation: Departments of Psychiatry (SP, KT, SSB, RDW, PDB, CK), Columbia University, New York, New York.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Ward
authors.affiliation: Departments of Psychiatry (SP, KT, SSB, RDW, PDB, CK), Columbia University, New York, New York.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Balsam
authors.affiliation: Departments of Psychiatry (SP, KT, SSB, RDW, PDB, CK), Columbia University, New York, New York; Department of Pharmacology, Columbia University, New York, New York.. Electronic address: ck491@columbia.edu.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kellendonk
mesh_terms: D000818:Animals; D003214:Conditioning, Classical / Q000502:physiology*; D003216:Conditioning, Operant / Q000502:physiology*; D003463:Cues; D004192:Discrimination, Psychological / Q000502:physiology; D005108:Extinction, Psychological / Q000502:physiology*; D006040:Goals; D008297:Male; D008810:Mice, Inbred C57BL; D012193:Reversal Learning / Q000502:physiology; D012201:Reward; D013788:Thalamus / Q000503:physiopathology*; D014163:Transfer, Psychology / Q000502:physiology*
keywords: Behavioral flexibility; DREADD system; Goal-directed behavior; Mediodorsal thalamus; Pavlovian-to-instrumental transfer; Schizophrenia