Pharmacogenetic tool for the manipulation of functional brain connectivity

用于操纵功能性大脑连接的药物遗传学工具

• 批准号: 8093846
• 负责人: CORNELIUS T GROSS
• 金额: $ 20.92万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-02 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8093846
• 关键词: Adult; Agonist; Animal Behavior; Animals; Anxiety; Axon; Behavior; Behavioral inhibition; Biological Assay; Brain; C-terminal; Cells; Chimera organism; Clozapine; Conflict (Psychology); Data; Dependovirus; Development; Engineering; Funding; Future; G Protein-Coupled Receptor Genes; Goals; Hippocampus (Brain); Human; In Vitro; Knowledge; Lesion; Ligands; Maps; Medial; Mediating; Methods; Mus; Muscarinics; Neural Pathways; Neurobiology; Neurons; Neurosciences; Outcome; Output; Oxides; Pharmacogenetics; Prefrontal Cortex; Presynaptic Terminals; Research; Role; Serotonin Receptor 5-HT1B; Structure; Synaptic Transmission; System; Technology; Testing; Tissues; Tomatoes; Transgenic Organisms; Validation; Viral Vector; Work; awake; base; frontal lobe; improved; in vivo; neural circuit; neuromechanism; neurotransmitter release; novel; receptor; receptor coupling; receptor expression; relating to nervous system; research study; response; tool; vector; voltage

DESCRIPTION (provided by applicant): The brain structures and neural circuits regulating anxiety behavior are poorly understood. The hippocampus is thought to contribute to anxiety via its role in resolving conflicting goal-directed behavior as part of the behavioral inhibition system. Projections from the hippocampus to the medial prefrontal cortex carry information about the anxiety state of the animal and are proposed to be a critical conduit for the anxiety-modulating function of the hippocampus. However, until now it has not been possible to dissect the contributions of the hippocampal projections to the frontal cortex because classical lesions and pharmacological manipulations of these structures interfere with the basal function of these structures. Here we propose the development and validation of a novel pharmacogenetic inhibition technology to selectively manipulate functional connections between brain structures in awake behaving animals. This novel tool is based on the selective targeting of an inhibitory GPCR to axon pre-terminals. Expression of this axonal inhibition tool in hippocampal projection neurons followed by tissue-specific delivery of the GPCR agonist into target tissues will allow disruption of selected hippocampal outputs without altering neural firing activity. We propose to develop and validate a human muscarinic M4 DREADD receptor/serotonin 1B receptor chimera in two specific aims. Aim 1 involves the construction of the receptor, and characterization of its cellular localization, as well as the construction of a viral vector capable of delivering the chimeric receptor to neurons in vivo. Aim 2 involves the use of this vector to test the effects on evoked and spontaneous neural transmission in the ventral hippocampus-medial prefrontal cortex network. Successful completion of these experiments will prepare the applicants to apply this tool to dissect the role of selected hippocampal ouputs in regulating anxiety and other hippocampal-dependent behaviors, and will become proof-of-concept data to support a larger, R01 funding application. In the long run this work promises to establish a new pharmacogenetic neural connectivity inhibition tool that is likely to find wide use in the neuroscience field. PUBLIC HEALTH RELEVANCE: Developing improved treatments for anxiety requires greater knowledge of the neurobiology underlying this devastating set of illnesses. The current project seeks to develop a tool that will permit us to test the role of specific neural pathways in anxiety-related behavior. In the future, such a tool would be invaluable in identifying which neural pathways are required for anxiety, facilitating the development of new treatments.

描述（由申请人提供）：人们对调节焦虑行为的大脑结构和神经回路知之甚少。海马体被认为是行为抑制系统的一部分，通过其在解决相互冲突的目标导向行为方面的作用而导致焦虑。从海马体到内侧前额叶皮层的投射携带有关动物焦虑状态的信息，并且被认为是海马体焦虑调节功能的关键管道。然而，到目前为止，还不可能剖析海马投射对额叶皮层的贡献，因为这些结构的经典损伤和药理学操作会干扰这些结构的基础功能。在这里，我们建议开发和验证一种新型药物遗传学抑制技术，以选择性地操纵清醒行为动物的大脑结构之间的功能连接。这种新颖的工具基于抑制性 GPCR 对轴突前末端的选择性靶向。这种轴突抑制工具在海马投射神经元中的表达，然后将 GPCR 激动剂组织特异性递送到靶组织中，将允许破坏选定的海马输出，而不改变神经放电活动。我们提议开发并验证人类毒蕈碱 M4 DREADD 受体/血清素 1B 受体嵌合体，以实现两个特定目标。目标 1 涉及受体的构建、其细胞定位的表征，以及能够将嵌合受体递送至体内神经元的病毒载体的构建。目标 2 涉及使用该向量来测试对腹侧海马-内侧前额叶皮层网络中诱发和自发神经传递的影响。成功完成这些实验将使申请者做好准备，应用该工具来剖析选定的海马输出在调节焦虑和其他海马依赖性行为中的作用，并将成为支持更大的 R01 资助申请的概念验证数据。从长远来看，这项工作有望建立一种新的药物遗传学神经连接抑制工具，该工具可能会在神经科学领域得到广泛应用。 公共卫生相关性：开发改进的焦虑疗法需要更多地了解这一系列毁灭性疾病背后的神经生物学知识。当前的项目旨在开发一种工具，使我们能够测试特定神经通路在焦虑相关行为中的作用。未来，这样的工具对于识别焦虑所需的神经通路将具有无价的价值，从而促进新疗法的开发。