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: 8475662
• 负责人: David G Amaral
• 金额: $ 14.74万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8475662
• 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; 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; 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; 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.

描述（由申请人提供）：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深远的影响。电生理记录，脑部病变和功能性神经影像学已是用于识别和分离人类和动物脑结构功能的最常见方法。但是，侵入性神经记录或病变可能会导致意外损害和补偿功能重组，这两者都使行为结果的解释变得复杂。功能性神经成像具有无创和可重复研究的优势，但可以表明大脑区域在特定行为期间具有活性，但不能确定其对行为至关重要。还需要在动物模型中暂时操纵大脑功能的互补研究。然而，目前可用于瞬时大脑激活或非人类灵长类动物灭活的所有选项，都需要重复注射大脑和/或永久性颅骨植入物，这两者都会引起身体创伤，并排除对行为动物的长期研究。一种新技术，是由设计师药物（Dreadds）专门激活的设计器受体，提供了一种最小的侵入性手段，可以在长期研究中控制脑功能。病毒载体在特定区域中转染神经元，带有dreadd基因。这些新型受体是由静脉或口服给药的无毒分子触发的，称为氯氮平-N-氧化物（CNO）。神经活动的激活或灭活发生在CNO给药后的15分钟内，持续9小时。该技术已成功地用于研究啮齿动物中的复杂行为模式。我们的总体目标是在非人类灵长类动物中实施基于恐惧的瞬态灭活，这是研究社会大脑的首选动物模型。在特定目标1中，我们将比较一种基于Dreadd的社会大脑成分杏仁核的失活，以及已经以永久性杏仁核病变为特征的行为和代谢缺陷。在特定的目标1a中，我们将使用高分辨率正电子发射断层扫描来衡量CNO输注如何影响与之互联的杏仁核和其他大脑区域的新陈代谢。我们还将研究基于Dreadd的杏仁核如何影响恐惧学习（特定目标1B）和社交互动（特定的AIM 1C）。一旦我们验证了Dreadd方法可以可靠地抑制杏仁核功能，特定的目标2将衡量杏仁核的灭活方式如何调节眼睛凝视模式，因为动物查看物种典型的社会信号的图片或视频。除了为与非人类灵长类动物的最小侵入性短暂失活研究提供强大的新工具外，拟议的研究还将提高我们对杏仁核如何有助于社会信息处理的理解，以及amygdala功能障碍如何有助于对许多人类精神病患者表征的深刻社会赤字。