Chronic Behavioral Manipulation via Orally Delivered Chemogenetic Actuator in Macaques

Oyama, Kei; Hori, Yukiko; Nagai, Yuji; Miyakawa, Naohisa; Mimura, Koki; Hirabayashi, Toshiyuki; Inoue, Ken; Higuchi, Makoto; Minamimoto, Takafumi

doi:10.1523/jneurosci.1657-21.2021

Cited by 18 publications

(11 citation statements)

References 47 publications

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“…Rats were then trained and tested as shown in Figure 5A . Following the initial instrumental training and outcome devaluation testing ( Figure 5—figure supplement 1A–C for LC: vlOFC and Figure 5—figure supplement 2A–C for LC: A32 ), both groups were further divided into two according to their initial performance: one group that would receive vehicle (Veh; n=12 for OFC-injected rats; n=8 for A32-injected rats) and one group that would receive deschloroclozapine dihydrochloride (DCZ; n=13 for OFC-injected rats; n=9 for A32-injected rats), a high affinity and selective DREADDs agonist ( Nagai et al, 2020 ; Nentwig et al, 2021 ; Oyama et al, 2022 ), during the reversal training.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of noradrenergic signalling in rodent orbitofrontal cortex impairs the updating of goal-directed actions

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Piccin

Dehove

et al. 2023

eLife

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In a constantly changing environment, organisms must track the current relationship between actions and their specific consequences and use this information to guide decision-making. Such goal-directed behavior relies on circuits involving cortical and subcortical structures. Notably, a functional heterogeneity exists within the medial prefrontal, insular, and orbitofrontal cortices (OFC) in rodents. The role of the latter in goal-directed behavior has been debated, but recent data indicate that the ventral and lateral subregions of the OFC are needed to integrate changes in the relationships between actions and their outcomes. Neuromodulatory agents are also crucial components of prefrontal functions and behavioral flexibility might depend upon the noradrenergic modulation of the prefrontal cortex. Therefore, we assessed whether noradrenergic innervation of the OFC plays a role in updating action-outcome relationships in male rats. We used an identity-based reversal task and found that depletion or chemogenetic silencing of noradrenergic inputs within the OFC rendered rats unable to associate new outcomes with previously acquired actions. Silencing of noradrenergic inputs in the prelimbic cortex or depletion of dopaminergic inputs in the OFC did not reproduce this deficit. Together, our results suggest that noradrenergic projections to the OFC are required to update goal-directed actions.

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Section: Resultsmentioning

confidence: 99%

Inhibition of noradrenergic signalling in rodent orbitofrontal cortex impairs the updating of goal-directed actions

Cerpa

Piccin

Dehove

et al. 2023

eLife

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“…Figure 5A-C for LC: OFC and Suppl. Figure 6A-C for LC: mPFC ), they were divided in two groups according to their initial performance: one group that would receive vehicle (Veh, -) during reversal training and one group that would receive deschloroclozapine dihydrochloride (DCZ, +), a high affinity and selective agonist for hM4D (Nagai et al, 2020; Nentwig et al, 2021; Oyama et al, 2022).…”

Section: Resultsmentioning

confidence: 99%

Noradrenergic signaling in the rodent orbitofrontal cortex is required to update goal-directed actions

Cerpa

Piccin

Dehove

et al. 2022

Preprint

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In a constantly changing environment, organisms must track the current relationship between actions and their specific consequences and use this information to guide decision‐making. Such goal‐directed behavior relies on circuits involving cortical and subcortical structures. Notably, a functional heterogeneity exists within the medial prefrontal, insular, and orbitofrontal cortices (OFC) in rodents. The role of the latter in goal‐directed behavior has been debated, but recent data indicate that the ventral and lateral subregions of the OFC are needed to integrate changes in the relationships between actions and their outcomes. Neuromodulatory agents are also crucial components of prefrontal functions and behavioural flexibility might depend upon the noradrenergic modulation of prefrontal cortex. Therefore, we assessed whether noradrenergic innervation of the OFC plays a role in updating action-outcome relationships. We used an identity‐based reversal task and found that depletion or chemogenetic silencing of noradrenergic inputs within the OFC rendered rats unable to associate new outcomes with previously acquired actions. Silencing of noradrenergic inputs in the medial prefrontal cortex or depletion of dopaminergic inputs in the OFC did not reproduce this deficit. Together, our results indicate that noradrenergic projections to the OFC are required to update goal‐directed actions.

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“…Importantly, also as in previous reports 12 , 31 – 33 , we did not observe any discernible side effects on brain activity or animal behavior. In the current study, we administered DCZ intramuscularly, but it can also be administered orally and has been proven to activate hM4Di chronically for more than two weeks with repetitive doses 34 . Although further safety testing is needed before moving on to clinical trials, these characteristics suggest that DCZ may be a safe and effective DREADD actuator that might be used in future clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Chemogenetic attenuation of cortical seizures in nonhuman primates

et al. 2023

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Epilepsy is a disorder in which abnormal neuronal hyperexcitation causes several types of seizures. Because pharmacological and surgical treatments occasionally interfere with normal brain function, a more focused and on-demand approach is desirable. Here we examined the efficacy of a chemogenetic tool—designer receptors exclusively activated by designer drugs (DREADDs)—for treating focal seizure in a nonhuman primate model. Acute infusion of the GABAA receptor antagonist bicuculline into the forelimb region of unilateral primary motor cortex caused paroxysmal discharges with twitching and stiffening of the contralateral arm, followed by recurrent cortical discharges with hemi- and whole-body clonic seizures in two male macaque monkeys. Expression of an inhibitory DREADD (hM4Di) throughout the seizure focus, and subsequent on-demand administration of a DREADD-selective agonist, rapidly suppressed the wide-spread seizures. These results demonstrate the efficacy of DREADDs for attenuating cortical seizure in a nonhuman primate model.

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Chronic Behavioral Manipulation via Orally Delivered Chemogenetic Actuator in Macaques

Abstract: Oyama et al. Chronic behavioral manipulation via orally delivered chemogenetic actuator in macaques

Cited by 18 publications

References 47 publications

Inhibition of noradrenergic signalling in rodent orbitofrontal cortex impairs the updating of goal-directed actions

Inhibition of noradrenergic signalling in rodent orbitofrontal cortex impairs the updating of goal-directed actions

Noradrenergic signaling in the rodent orbitofrontal cortex is required to update goal-directed actions

Chemogenetic attenuation of cortical seizures in nonhuman primates

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