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: 8310938
• 负责人: CORNELIUS T GROSS
• 金额: $ 17.42万
• 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 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8310938
• 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; optogenetics; 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.

描述（由申请人提供）：对调节焦虑行为的大脑结构和神经回路的理解很少。海马被认为是由于行为抑制系统的一部分而在解决冲突目标指导行为中的作用中导致焦虑的。从海马到内侧前额叶皮层的投射携带有关动物焦虑状态的信息，并被认为是海马焦虑调节功能的关键渠道。但是，到目前为止，由于这些结构的经典病变和药理学操纵干扰了这些结构的基础功能，因此一直无法剖析海马投影对额叶皮层的贡献。在这里，我们提出了一种新型药物遗传学抑制技术的开发和验证，以选择性地操纵醒目的行为动物中大脑结构之间的功能联系。该新型工具基于抑制性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影神经元中的表达，然后将GPCR激动剂特异性递送到靶组织中，将允许破坏所选海马输出而不会改变神经发射活性。我们建议在两个特定的目标中开发和验证人类毒蕈碱M4 Dreadd受体/5-羟色胺1B受体嵌合体。 AIM 1涉及受体的构建及其细胞定位的表征，以及能够将嵌合受体传递到体内神经元的病毒载体的构造。 AIM 2涉及使用该矢量来测试对腹侧海马中性前额叶皮层网络中诱发和自发神经传播的影响。这些实验的成功完成将使申请人准备应用此工具，以剖析选定的海马欧普特人在调节焦虑和其他海马依赖性行为中的作用，并将成为概念验证数据，以支持更大的R01资金应用。从长远来看，这项工作有望建立一种新的药物神经连通性抑制工具，该工具可能在神经科学领域中发现广泛使用。

项目成果

Independent hypothalamic circuits for social and predator fear.

• DOI: 10.1038/nn.3573
• 发表时间: 2013-12
• 期刊: NATURE NEUROSCIENCE
• 影响因子: 25
• 作者: Silva, Bianca A.;Mattucci, Camilla;Krzywkowski, Piotr;Murana, Emanuele;Illarionova, Anna;Grinevich, Valery;Canteras, Newton S.;Ragozzino, Davide;Gross, Cornelius T.
• 通讯作者: Gross, Cornelius T.

The ventromedial hypothalamus mediates predator fear memory.

• DOI: 10.1111/ejn.13239
• 发表时间: 2016-06
• 期刊: The European journal of neuroscience
• 作者: Silva BA;Mattucci C;Krzywkowski P;Cuozzo R;Carbonari L;Gross CT
• 通讯作者: Gross CT