Chemogenetic techniques, such as designer receptors exclusively activated by designer drugs (DREADDs), enable transient, reversible, and minimally invasive manipulation of neural activity in vivo. Their development in nonhuman primates is essential for uncovering neural circuits contributing to cognitive functions and their translation to humans. One key issue that has delayed the development of chemogenetic techniques in primates is the lack of an accessible drug-screening method. Here, we use resting-state fMRI, a noninvasive neuroimaging tool, to assess the impact of deschloroclozapine (DCZ) on brainwide resting-state functional connectivity in 7 rhesus macaques (6 males and 1 female) without DREADDs. We found that systemic administration of 0.1 mg/kg DCZ did not alter the resting-state functional connectivity. Conversely, 0.3 mg/kg of DCZ was associated with a prominent increase in functional connectivity that was mainly confined to the connections of frontal regions. Additional behavioral tests confirmed a negligible impact of 0.1 mg/kg DCZ on socio-emotional behaviors as well as on reaction time in a probabilistic learning task; 0.3 mg/kg DCZ did, however, slow responses in the probabilistic learning task, suggesting attentional or motivational deficits associated with hyperconnectivity in fronto-temporo-parietal networks. Our study highlights both the excellent selectivity of DCZ as a DREADD actuator, and the side effects of its excess dosage. The results demonstrate the translational value of resting-state fMRI as a drug-screening tool to accelerate the development of chemogenetics in primates.

SIGNIFICANCE STATEMENT Chemogenetics, such as designer receptors exclusively activated by designer drugs (DREADDs), can afford control over neural activity with unprecedented spatiotemporal resolution. Accelerating the translation of chemogenetic neuromodulation from rodents to primates requires an approach to screen novel DREADD actuators in vivo. Here, we assessed brainwide activity in response to a DREADD actuator deschloroclozapine (DCZ) using resting-state fMRI in macaque monkeys. We demonstrated that low-dose DCZ (0.1 mg/kg) did not change whole-brain functional connectivity or affective behaviors, while a higher dose (0.3 mg/kg) altered frontal functional connectivity and slowed response in a learning task. Our study highlights the excellent selectivity of DCZ at proper dosing, and demonstrates the utility of resting-state fMRI to screen novel chemogenetic actuators in primates.

化学遗传学技术，例如专门由设计药物激活的设计受体 (DREADD)，可以在体内对神经活动进行瞬时、可逆和微创操作. 它们在非人类灵长类动物中的发育对于揭示有助于认知功能的神经回路及其对人类的转化至关重要。延迟灵长类动物化学遗传学技术发展的一个关键问题是缺乏一种可用的药物筛选方法。在这里，我们使用静息态 fMRI（一种非侵入性神经影像学工具）来评估去氯氯氮平 (DCZ) 对 7 只没有 DREADD 的恒河猴（6 只雄性和 1 只雌性）全脑静息态功能连接的影响。我们发现 0.1 mg/kg DCZ 的全身给药不会改变静息状态功能连接。相反，0.3 mg/kg 的 DCZ 与主要局限于额叶区域连接的功能连接显着增加有关。额外的行为测试证实 0 的影响可以忽略不计。1 mg/kg DCZ 对社会情绪行为以及概率学习任务中的反应时间；然而，0.3 mg/kg DCZ 确实会减缓概率学习任务的反应，表明与额颞顶叶网络中的超连接相关的注意力或动机缺陷。我们的研究强调了 DCZ 作为 DREADD 致动器的出色选择性，以及其过量剂量的副作用。结果证明了静息态 fMRI 作为药物筛选工具的转化价值，可加速灵长类动物化学遗传学的发展。表明与额颞顶叶网络中的超连接相关的注意力或动机缺陷。我们的研究强调了 DCZ 作为 DREADD 致动器的出色选择性，以及其过量剂量的副作用。结果证明了静息态 fMRI 作为药物筛选工具的转化价值，可加速灵长类动物化学遗传学的发展。表明与额颞顶叶网络中的超连接相关的注意力或动机缺陷。我们的研究强调了 DCZ 作为 DREADD 致动器的出色选择性，以及其过量剂量的副作用。结果证明了静息态 fMRI 作为药物筛选工具的转化价值，可加速灵长类动物化学遗传学的发展。

意义声明化学遗传学，例如专门由设计药物激活的设计受体 (DREADD)，可以以前所未有的时空分辨率控制神经活动。加速化学遗传学神经调节从啮齿动物到灵长类动物的转化需要一种在体内筛选新型 DREADD 执行器的方法. 在这里，我们使用猕猴的静息态 fMRI 评估了全脑活动对 DREADD 致动器去氯氯氮平 (DCZ) 的反应。我们证明低剂量 DCZ (0.1 mg/kg) 不会改变全脑功能连接或情感行为，而较高剂量 (0.3 mg/kg) 会改变额叶功能连接并减缓学习任务中的反应。我们的研究强调了 DCZ 在适当剂量下的出色选择性，并证明了静息态 fMRI 在灵长类动物中筛选新型化学遗传致动器的效用。