A novel, transient inactivation technique for studying the primate social brain

在本申请中，我们提出了一系列实验，如果成功，将永远改变我们评估非人类灵长类动物社会大脑的方法，并可能对行为神经科学产生更广泛的深远影响。电生理记录、脑损伤和功能性神经成像是用于识别和分离人类和动物脑结构功能的最常用方法。然而，侵入性神经记录或损伤可能导致意外的损伤和代偿性功能重组，这两者都使行为结果的解释复杂化。功能性神经成像虽然具有非侵入性和易于重复研究的优点，但可以表明大脑区域在特定行为期间是活跃的，但不能确定它对行为是必不可少的。还需要在动物模型中暂时操纵大脑功能的补充研究。然而，目前可用于非人灵长类动物短暂脑激活或失活的所有选择都需要重复注射到大脑和/或永久性颅骨植入物中，这两者都会导致身体创伤，并妨碍对清醒行为动物的长期研究。一项新技术，设计师受体专门由设计师药物激活（DREADDs），提供了一种微创手段来控制长期研究中的大脑功能。病毒载体通过DREADD基因在特定区域中阻断神经元。这些新的受体是通过静脉或口服一种称为氯氮平-N-氧化物（CNO）的无毒分子触发的。神经活动的激活或失活发生在CNO给药后15分钟内，并持续长达9小时。这项技术已成功地用于研究啮齿动物的复杂行为模式。我们的总体目标是在非人灵长类动物中实现基于DREADD的瞬时失活，这是研究社会脑的首选动物模型。在具体目标1中，我们将比较基于DREADD的一种社会性脑成分杏仁核的失活与已经以永久性杏仁核病变为特征的行为和代谢缺陷。在具体目标1A中，我们将使用高分辨率正电子发射断层扫描来测量CNO注入如何影响杏仁核和其他与之密切相关的大脑区域的代谢，我们还将研究基于DREADD的杏仁核失活如何影响恐惧学习（具体目标1B）和社会互动（具体目标1C）。一旦我们证实了DREADD方法可以可靠地抑制杏仁核功能，Specific Aim 2将测量杏仁核失活如何调节动物观看物种典型社会信号的图片或视频时的眼睛凝视模式。除了为非人类灵长类动物的微创瞬时失活研究提供一个强大的新工具外，这项研究还将促进我们对杏仁核如何促进社会信息处理的理解，以及杏仁核功能障碍如何导致许多人类精神疾病特征的深刻社会缺陷。

DESCRIPTION (provided by applicant): In this application, we propose a series of experiments that, if successful, will change forever our approaches to evaluating the nonhuman primate social brain, and could have a profound influence on behavioral neuroscience more broadly. Electrophysiological recordings, brain lesions and functional neuroimaging have been the most common methods used to identify and dissociate the function of brain structures in humans and animals. However, invasive neural recordings or lesions can result in unintended damage and compensatory functional reorganization, both of which complicate the interpretation of behavioral results. Functional neuro- imaging, while having the advantage of being noninvasive and amenable to repeated studies, can indicate that a brain region is active during a particular behavior, but cannot determine that it is essential for the behavior. Complementary studies that temporarily manipulate brain function in animal models are also needed. All options currently available for transient brain activation or inactivation in nonhuman primates, however, require repeated injections into the brain and/or permanent cranial implants, both of which cause physical trauma and preclude long-term study of awake, behaving animals. A new technique, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), offers a minimally-invasive means to control brain function during long-term studies. Viral vectors transfect neurons in specific areas with a DREADD gene. These novel receptors are triggered by intravenous or oral administration of a nontoxic molecule called clozapine-N-oxide (CNO). Activation or inactivation of neural activity occurs within 15 minutes after CNO administration and lasts for up to 9 hours. This technique has been successfully used to study complex behavioral patterns in rodents. Our overall objective is to implement DREADD-based transient inactivation in nonhuman primates, which is the animal model of choice for studying the social brain. In Specific Aim 1, we will compare DREADD-based inactivation of one social brain component, the amygdala, with behavioral and metabolic deficits already characterized with permanent amygdala lesions. In Specific Aim 1A, we will use high-resolution positron emission tomography to measure how CNO infusion affects metabolism in the amygdala and other brain areas that are heavily interconnected with it. We will also examine how DREADD- based amygdala inactivation affects fear learning (Specific Aim 1B) and social interactions (Specific Aim 1C). Once we have verified that the DREADD method can reliably inhibit amygdala function, Specific Aim 2 will measure how amygdala inactivation modulates eye gaze patterns as animals view pictures or videos of species-typical social signals. Beyond providing a powerful new tool for minimally-invasive transient inactivation studies with nonhuman primates, the proposed research will also advance our understanding of how the amygdala contributes to social information processing, and how amygdala dysfunction may contribute to the profound social deficits that characterize many human psychiatric disorders.