Optogenetic tools to distinguish neuronal class in behaving non-human primates

光遗传学工具可区分非人类灵长类动物的神经元类别

• 批准号: 8771361
• 负责人: CORY T MILLER
• 金额: $ 30.7万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8771361
• 关键词: 6-Cyano-7-nitroquinoxaline-2,3-dione; AMPA Receptors; Action Potentials; Animals; Area; Attention deficit hyperactivity disorder; Autistic Disorder; Behavior; Biological Assay; Biological Models; Breeding; Callithrix; Callithrix jacchus jacchus; Cebidae; Cells; Cercopithecidae; Charge; Cortical Column; Data; Development; Disease; Electrodes; Foundations; Glutamates; Goals; Head; Homologous Gene; Interneurons; Label; Lasers; Light; Location; Membrane Potentials; Methodology; Methods; Modeling; Monkeys; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Opsin; Parvalbumins; Penetration; Physiologic pulse; Population; Primates; Relative (related person); Research; Response Latencies; Role; Schizophrenia; Sensory; Series; Serotyping; Site; Source; Stimulus; Subfamily lentivirinae; Surface; Synapsins; Syndrome; Target Populations; Techniques; Testing; Time; Transgenic Mice; Transgenic Organisms; Use of New Techniques; Visual; Visual Agnosias; area V2; area striata; awake; base; density; excitatory neuron; extracellular; extrastriate visual cortex; falls; genetic manipulation; interest; neglect; nervous system disorder; neural circuit; neuromechanism; neurophysiology; neuropsychological; nonhuman primate; novel; optogenetics; promoter; public health relevance; response; restraint; tool

DESCRIPTION (provided by applicant): A major obstacle to understanding the neural mechanisms underlying behavior is our inability to distinguish between neuronal classes in recordings from behaving animals. Mouse transgenic lines, including CRE lines, have made it possible to use optogenetic techniques to selectively activate different classes to determine their role in behavior. However, it remains a challenge to determine the neuronal identity based on optogenetic stimulation, as the latency of response to direct stimulation can overlap with strong but indirect disynaptic excitation. The proposed research will introduce novel methods for distinguishing direct from indirect stimulation in order to label neuronal identity. It will furthe develop these methods for extracellular recordings made with linear array electrodes and using current source density (CSD) analysis to identify laminar location. These methods will be validated in CRE mice, and then applied to the marmoset (Callithrix jacchus). The marmoset is a particularly interesting primate model because it offers opportunities for dissecting neural circuitry that are comparable to the mouse. It matures quickly and breeds well in captivity, so it is amenable to the kinds of genetic manipulation used in mice and has produced the first primate transgenic lines. It also has a lissencephalic (flat) cortex which aids in laminar recordings. Preliminary data show marmosets can perform visual tasks under head-restraint, making them suitable to awake neurophysiology. Establishing these methods will create opportunities to study cortical circuits at a mechanistic level, enabling the field to understand how aberrations in the cortical circuitry give rise to devastating disorders such as schizophrenia and autism.

描述（由申请人提供）：理解行为背后的神经机制的一个主要障碍是我们无法区分记录中的神经元类别和行为动物。小鼠转基因品系，包括 CRE 品系，使得利用光遗传学技术选择性激活不同类别以确定其 行为中的作用。然而，基于光遗传学刺激确定神经元身份仍然是一个挑战，因为对直接刺激的反应潜伏期可能与强烈但间接的突触激发重叠。拟议的研究将引入区分直接刺激和间接刺激的新方法，以标记神经元身份。它将进一步开发这些方法，用于使用线性阵列电极进行细胞外记录，并使用电流源密度（CSD）分析来识别层流位置。这些方法将在 CRE 小鼠中进行验证，然后应用于狨猴 (Callithrix jacchus)。狨猴是一种特别有趣的灵长类动物模型，因为它提供了与小鼠类似的解剖神经回路的机会。它成熟迅速，在圈养条件下繁殖良好，因此能够适应小鼠中使用的各种基因操作，并产生了第一个灵长类转基因品系。它还具有有助于层流录音的无脑（扁平）皮层。初步数据显示，狨猴可以在头枕下执行视觉任务，这使它们适合唤醒神经生理学。建立这些方法将为在机械层面上研究皮质回路创造机会，使该领域能够了解皮质回路的畸变如何导致精神分裂症和自闭症等破坏性疾病。