Chemogenetic disconnection between the orbitofrontal cortex and the rostromedial caudate nucleus disrupts motivational control of goal-directed action

Abstract

The orbitofrontal cortex (OFC) and its major downstream target within the basal ganglia—the rostromedial caudate nucleus (rmCD)—are involved in reward-value processing and goal-directed behavior. However, a causal contribution of the pathway linking these two structures to goal-directed behavior has not been established. Using the chemogenetic technology of Designer Receptors Exclusively Activated by Designer Drugs with a crossed inactivation design, we functionally and reversibly disrupted interactions between the OFC and rmCD in two male macaque monkeys. We injected an adeno-associated virus vector expressing an inhibitory designer receptor (hM4Di) into the OFC and contralateral rmCD, the expression of which was visualized in vivo by positron emission tomography (PET) and confirmed by post-mortem immunohistochemistry. Functional disconnection of the OFC and rmCD resulted in a significant and reproducible loss of sensitivity to the cued reward value for goal-directed action. This decreased sensitivity was most prominent when monkeys had accumulated a certain amount of reward. These results provide causal evidence that the interaction between the OFC and the rmCD is needed for motivational control of action on the basis of the relative reward value and internal drive. This finding extends current understanding of the physiological basis of psychiatric disorders in which goal-directed behavior is affected, such as obsessive-compulsive disorder.Significance StatementIn daily life, we routinely adjust the speed and accuracy of our actions on the basis of the value of expected reward. Abnormalities in these kinds of motivational adjustments might be related to behaviors seen in psychiatric disorders such as obsessive-compulsive disorder. In the current study, we show that the connection from the orbitofrontal cortex to the rostromedial caudate nucleus is essential formotivational control of action in monkeys. This finding expands our knowledge about how the primate brain controls motivation and behavior and provides a particular insight into disorders like obsessive-compulsive disorder, in which altered connectivity between the orbitofrontal cortex and the striatum has been implicated.

Multimodal imaging for validation and optimization of ion channel-based chemogenetics in nonhuman primates

“…Chemogenetic tools using mutated muscarinic acetylcholine receptors, called Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), have been widely used in rodents and other small animals (Roth, 2016). DREADDs have also proven to be useful in nonhuman primates (NHPs), where they can manipulate neuronal activity in a specific cell type or neural pathway (Mimura et al, 2021;Oguchi et al, 2021;Perez et al, 2022) or simultaneously and discretely in multiple brain regions (Eldridge et al, 2016;Nagai et al, 2016Nagai et al, , 2020Raper et al, 2019;Hayashi et al, 2020;Hori et al, 2021;Oyama et al, 2021Oyama et al, , 2022Roseboom et al, 2021). As such, they provide an opportunity for identifying the regions and pathways that are causally responsible for cognitive/emotional functions.…”