Functional role of dual neurotransmission in aggression

双重神经传递在攻击中的功能作用

• 批准号: 10586868
• 负责人: Sarah J Certel
• 金额: $ 35.65万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586868
• 关键词: Acetylcholine; Address; Adrenergic Receptor; Age; Aggressive behavior; Aging; Antibodies; Behavior; Behavioral; Biological Models; Biosensor; Communication; Cues; Data; Disease; Drosophila genus; Economic Burden; Epitopes; Equilibrium; Exhibits; Female; Functional Imaging; Funding; Genetic; Glutamate Transporter; Glutamates; Goals; Human; Image; Individual; Injury; Invertebrates; Mental disorders; Metabotropic Glutamate Receptors; Molecular; Nervous System; Neurodegenerative Disorders; Neuromodulator; Neurons; Neuropeptides; Neurosciences; Neurotransmitters; Norepinephrine; Octopamine; Phenotype; Physiological; Property; Regulation; Reproductive Behavior; Resources; Role; Sex Differences; Signal Transduction; Social Behavior; Societies; Specific qualifier value; System; Testing; Therapeutic; Violence; Visualization; Work; age related; analog; behavioral response; economic impact; flexibility; fly; gamma-Aminobutyric Acid; genome editing; insight; knock-down; male; monoamine; neurotransmission; neurotransmitter release; noradrenergic; novel strategies; postsynaptic; postsynaptic neurons; presynaptic; presynaptic neurons; receptor; receptor function; response; segregation; sex; sexual dimorphism; small molecule; socioeconomics; tool; transmission process

ABSTRACT Dual neurotransmission has the potential to transform the way we consider neuronal signaling and the transmission of information within circuits and networks. The importance of dual transmission is evident by the large and increasing number of identified dual transmitting neurons in every system. However we still have only limited insight into the regulation and functional effects of co-transmission. During our previous funding period, we established: 1) the majority of octopamine (OA, the invertebrate analogue of norepinephrine), neurons co-express glutamate, 2) OA and glutamate have overlapping, as well as distinct, roles in reproductive and aggressive behaviors, and 3) manipulation of a glutamate-OA neuronal subset leads to high intensity aggression. Although aggression is a critical component of social behavior observed across species, when expressed at elevated levels aggression in humans can threaten lives and incur economic burdens on society. Given the importance of maintaining a critical balance of aggression and understanding the implications of dual transmission signaling in general, in this proposal we are identifying the molecular and physiological mechanisms that constrain aggression as well as dynamically regulate the release of co-transmitters. Leveraging our deep understanding of aggression- promoting neurons, genetic tools, and functional imaging, we will test our hypothesis in three specific aims. First, using fluorescent biosensors to visualize neurotransmitter release and Ca2+ imaging to quantify neuron activity, we will test the hypothesis that glutamatergic and adrenergic receptors expressed by glutamate-OA neurons are required for the regulation of co-transmission. Second, using epitope-tagged vesicular transporters and antibodies we will test the hypothesis that sexually dimorphic glutamate-OA neurons exhibit dynamic age-related changes in VGLUT levels. Finally, we will determine if VMAT-VGLUT terminal phenotypes are dependent on external cues from postsynaptic neurons. The significance of our study is that it addresses a fundamental neuroscience question, namely the molecular and potentially sexually dimorphic regulation of the dual transmission phenomenon, as well as potentially leading to the targeting of the glutamatergic system within glutamate-monoamine neurons as a therapeutic strategy for unchecked aggression.

摘要 双重神经传递有可能改变我们考虑神经元信号传导和神经元信号传导的方式。 在电路和网络中传输信息。双重传输的重要性显而易见， 在每个系统中，识别出的双传递神经元的数量越来越多。然而，我们仍然 对共传播的调节和功能影响只有有限的了解。在我们之前的 资金期间，我们建立了：1）大多数章鱼胺（OA，无脊椎动物类似物， 去甲肾上腺素），神经元共表达谷氨酸，2）OA和谷氨酸有重叠，以及不同的， 在生殖和攻击行为中的作用，以及3）操纵谷氨酸-OA神经元亚群导联 高强度的攻击。虽然攻击性是社会行为的一个重要组成部分， 人类的侵略行为在高水平表达时，可能威胁生命并造成经济损失。 社会的负担。考虑到保持侵略性和侵略性之间的关键平衡的重要性， 为了理解一般双传输信令的含义，在本提案中， 确定限制攻击性的分子和生理机制， 动态调节共发射器的释放。利用我们对攻击性的深刻理解- 促进神经元，遗传工具和功能成像，我们将在三个具体目标测试我们的假设。 首先，使用荧光生物传感器可视化神经递质释放和Ca 2+成像来量化神经元 活性，我们将测试这一假设，即谷氨酸-OA表达的肾上腺素能和肾上腺素能受体 需要神经元来调节共传递。第二，使用表位标记的囊泡 转运蛋白和抗体，我们将测试的假设，性二型谷氨酸-OA神经元表现出 VGLUT水平的动态年龄相关变化。最后，我们将确定VMAT-VGLUT终端是否 表型依赖于来自突触后神经元的外部线索。我们研究的意义在于， 它解决了一个基本的神经科学问题，即分子和潜在的性别二态性， 管制双重传播现象，以及可能导致针对 谷氨酸单胺神经元内的谷氨酸能系统作为未经检查的 侵略