Chemogenetic sensory fMRI reveals behaviorally relevant bidirectional changes in primate somatosensory network

Hirabayashi, Toshiyuki; Nagai, Yuji; Hori, Yukiko; Inoue, Kazuaki; Aoki, Ichio; Suhara, Tetsuya; Higuchi, Makoto; Minamimoto, Takafumi

doi:10.1016/j.neuron.2021.08.032

Cited by 24 publications

(33 citation statements)

References 98 publications

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“…Importantly, low doses of DCZ exert chemogenetic effects with rapid onset that last several hours in both rodents and nonhuman primates ( Nagai et al, 2020 ). This indicates that DCZ is a promising chemogenetic actuator that can be used for a wide variety of objectives (e.g., Hirabayashi et al, 2021 ; Hori et al, 2021 ; Oyama et al, 2021 ). In particular, its superior efficacy and brain permeability permit its use for oral administration.…”

Section: Introductionmentioning

confidence: 99%

Chronic Behavioral Manipulation via Orally Delivered Chemogenetic Actuator in Macaques

et al. 2022

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Section: Introductionmentioning

confidence: 99%

Chronic Behavioral Manipulation via Orally Delivered Chemogenetic Actuator in Macaques

et al. 2022

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“…In this context, the present study provides valuable causal information about a specific neural network in primates. Future chemogenetic studies combined with functional MRI will provide a unique opportunity to link behavioral and network changes in monkeys (e.g., Hirabayashi et al, 2021), and directly compare these changes with those seen in human psychiatric disorders. As a component of this future research, it would be useful to assess obsessive-compulsive or other behaviors that are not addressed in the current study.…”

Section: Discussionmentioning

confidence: 99%

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

Oyama

Hori

Mimura

et al. 2022

Preprint

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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.

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“…Animals were only lightly anesthetized throughout the scan sessions so that the resting-state brain activity was preserved as closes to that of the awake state as possible [11,22]. We hypothesized that low-dose DCZ, which is functionally effective in chemogenetic experiments in non-human primates [5,28], would not affect resting-state functional connectivity in non-transfected animals. As we expected, low-dose DCZ did not alter brain-wide functional connectivity either in cortical or subcortical areas ( Figures 2 and 3 ).…”

Section: Discussionmentioning

confidence: 99%

Resting-state fMRI-based screening of deschloroclozapine in rhesus macaques predicts dosage-dependent behavioral effects

Fujimoto

Elorette

Fredericks

et al. 2021

Preprint

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BackgroundVirally-mediated chemogenetic techniques hold the promise of circuit-specific neuromodulation for human brain disorders. Their protracted development in primates and issues related to the specificity of the actuator drugs has significantly slowed their implementation. Here we took a multi-disciplinary approach to assessing the translational appropriateness of a newly identified actuator drug, deschloroclozapine (DCZ).MethodsResting-state functional MRI (rs-fMRI) data was acquired from seven rhesus macaques (6 males and 1 female) after administration of either vehicle, 0.1 or 0.3 mg/kg DCZ, the latter of which produce 80% and near 100% chemogenetic receptor occupancy, respectively. Seed-based comparative-connectome analysis and independent component analysis assessed dose dependent neural impact. Two subsets of subjects were tested on socio-emotional tasks (N = 4), and a probabilistic learning task (N = 3), assessing DCZ’s impact on unconditioned and conditioned affective responses, respectively.ResultsNeither vehicle nor 0.1 mg/kg DCZ changed overall functional connectivity, affective responses, or reaction times in the learning task. 0.3 mg/kg DCZ increased functional connectivity, particularly in frontal regions, and increased reaction times in the learning task. Notably, there was a positive correlation between changes in overall functional connectivity and reaction time.ConclusionsThese experiments show the utility of rs-fMRI for in-vivo drug screening and benchmarking. We found that low dose DCZ does not alter brain function or affective behavior. However, higher doses of DCZ impacts frontal connectivity and is associated with deficits in task execution. Implementation of these methods will accelerate the development of chemogenetic in primates for research and therapeutic approaches.

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Chemogenetic sensory fMRI reveals behaviorally relevant bidirectional changes in primate somatosensory network

Cited by 24 publications

References 98 publications

Chronic Behavioral Manipulation via Orally Delivered Chemogenetic Actuator in Macaques

Chronic Behavioral Manipulation via Orally Delivered Chemogenetic Actuator in Macaques

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

Resting-state fMRI-based screening of deschloroclozapine in rhesus macaques predicts dosage-dependent behavioral effects

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