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

一种用于研究灵长类社交大脑的新型瞬时失活技术

• 批准号: 8401115
• 负责人: David G Amaral
• 金额: $ 26.89万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-29 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8401115
• 关键词: Acute; Affect; Agonist; Amygdaloid structure; Animal Model; Animals; Anxiety Disorders; Area; Association Learning; Attention; Autistic Disorder; Behavior; Behavioral; Bilateral; Brain; Brain Injuries; Brain region; Brothers; Chemosensitization; Clozapine; Complex; Conditioned Stimulus; Dependovirus; Designer Drugs; Development; Event; Exhibits; Eye; Face; Fright; Functional disorder; Funding; Genes; Glucose; Goals; Hour; Human; Image; Impairment; Infusion procedures; Injection of therapeutic agent; Laboratories; Learning; Lesion; Longitudinal Studies; Macaca mulatta; Measures; Mental disorders; Metabolic; Metabolism; Methods; Monitor; Monkeys; Neurons; Neurosciences; Oral Administration; Oxides; Patients; Pattern; Pharmacogenetics; Play; Positron-Emission Tomography; Posture; Primates; Reflex action; Relative (related person); Research; Resolution; Rest; Rodent; Role; Scanning; Series; Signal Transduction; Site; Social Behavior; Social Interaction; Stigmata; Stimulus; Structure; System; Techniques; Time; Trauma; Viral Vector; Visual; Visual attention; autism spectrum disorder; awake; base; behavior observation; drinking water; experience; gaze; glucose metabolism; information processing; intravenous administration; mind control; minimally invasive; neuroimaging; neurotransmitter agonist; nonhuman primate; novel; optogenetics; radiotracer; receptor; relating to nervous system; research study; skull implant; small molecule; social; social communication; social stigma; tool

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. PUBLIC HEALTH RELEVANCE: Many human psychiatric disorders, including autism spectrum disorder and select anxiety disorders, exhibit social behavior impairments. One way of studying the brain regions involved in social behavior is by turning them off in animal models. The goal of these studies is to demonstrate the feasibility of a new method of temporary neural inactivation to study the function of one social brain component, the amygdala, in a nonhuman primate animal model.

描述（由申请人提供）：在这份申请中，我们提出了一系列的实验，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识别和分离人类和动物大脑结构功能的最常用方法。然而，侵入性神经记录或损伤可导致意外损伤和代偿功能重组，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可重复研究的优点，但可以表明在特定行为中大脑区域是活跃的，但不能确定它对该行为是必要的。还需要在动物模型中临时操纵大脑功能的补充研究。然而，目前用于非人类灵长类动物的短暂脑激活或脑失活的所有选择都需要反复注射到大脑和/或永久性颅骨植入物，这两种方法都会造成身体创伤，并妨碍对清醒行为的动物进行长期研究。一项新技术，由设计药物独家激活的设计受体（DREADDs），提供了一种在长期研究中控制大脑功能的微创手段。病毒载体转染神经元的特定区域与一个DREADD基因。这些新的受体通过静脉或口服一种叫做氯氮平- n -氧化物（CNO）的无毒分子来触发。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。这项技术已经成功地用于研究啮齿类动物的复杂行为模式。我们的总体目标是在非人类灵长类动物中实现基于dreadd的短暂失活，这是研究社会大脑的首选动物模型。在Specific Aim 1中，我们将比较基于fdd的一种社会脑成分（杏仁核）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Specific Aim 1A中，我们将使用高分辨率正电子发射断层扫描来测量CNO输注如何影响杏仁核和其他与之紧密相连的大脑区域的代谢。我们还将研究基于DREADD的杏仁核失活如何影响恐惧学习（Specific Aim 1B）和社会互动（Specific Aim 1C）。一旦我们验证了DREADD方法可以可靠地抑制杏仁核功能，Specific Aim 2将测量当动物观看物种典型社交信号的图片或视频时，杏仁核失活是如何调节眼睛注视模式的。除了为非人类灵长类动物的微创短暂失活研究提供一个强大的新工具外，拟议的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可能导致许多人类精神疾病特征的深刻的社会缺陷。