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’ (DREADD) 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 non-rewarded cues nor 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. Conclusion MD hypofunction causes cognitive inflexibility reflected by an inability 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.

Chemogenetic Inactivation of Dorsal Anterior Cingulate Cortex Neurons Disrupts Attentional Behavior in Mouse

“…The utility of this approach is substantiated in accumulating studies that have applied technology to specific cell types and neural circuits in the context of behavioral assays of brain function following its inception (Urban and Roth, 2015). Human M4 muscarinic DREADD receptor coupled to Gi (hM4Di) has been used to silence neuronal firing in vivo (Ferguson et al, 2011;Krashes et al, 2011), and has successfully elucidated neural mechanisms mediating complex cognitive processes, such as goal-directed behavior (Parnaudeau et al, 2013;Parnaudeau et al, 2015). This powerful chemogenetic tool has not been employed to examine the neural basis of attention processes.…”

For Value or for Worth? Part 2: A Neuroeconomical Thought-Action-Mood-Space Modulated by (Un-)Certainty as Sign- or Goal-tracking

“…While lack of mental flexibility can lead to apparent CO, this usually comes with some loss of intelligence, which is not a feature of COs [1], but rather due to disturbances at the medio-dorsal thalamus [42]. The focus on such cognitive efforts presently rejuvenates psychiatry [43,44].…”

A Method for Remotely Silencing Neural Activity in Rodents During Discrete Phases of Learning

“…6. Perform fluorescence microscopy on brain tissue to verify AAV placement and protein expression 12,24 .…”

“…Figures 4C-D illustrate representative fluorescent labeling of reporter proteins in experimental (Expt; rats were infused with an AAV construct containing the designer receptor gene and the mcitrine gene) and control (Ctrl; rats were infused with a similar AAV construct containing the GFP gene but no sequence for the designer receptor) rats, respectively. Receptor levels can also be displayed as minimum, representative and maximal expression 24 . If labeling is detected in regions outside of the area of interest, exclude those data from the behavioral analyses.…”

“…Drug administration can occur repeatedly, which is advantageous for behavioral tasks that occur across successive days or weeks 12,24,26 . Furthermore, evidence indicates that the designer drug (CNO) does not interfere with locomotor behavior or appetite 27,28 .…”