Neuromodulation of Brain States

大脑状态的神经调节

• 批准号: 10311052
• 负责人: LIQUN LUO
• 金额: $ 66.21万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311052
• 关键词: Address; Anatomy; Anxiety; Architecture; Axon; Behavior; Behavioral; Behavioral Paradigm; Biological Assay; Brain; Brain Diseases; Brain Stem; Brain region; Cell Nucleus; Cells; Complex; Data; Disease; Dopamine; Dorsal; Foundations; Frequencies; Future; Genetic; Glutamate Transporter; Heterogeneity; Human; Hunger; Hypothalamic structure; Impulsivity; Link; Location; Mammals; Mediating; Mental Depression; Midbrain structure; Modernization; Moods; Mus; Neurons; Neurotransmitters; Norepinephrine; Output; Parkinson Disease; Pattern; Phenotype; Physiological; Physiology; Population; Prosencephalon; Rabies; Regulation; SLC17A8 gene; Schizophrenia; Serotonergic System; Serotonin; Societies; Synapses; System; Techniques; Thirst; Transgenic Mice; Water; base; behavioral study; dopaminergic neuron; drinking; excitatory neuron; experimental study; gamma-Aminobutyric Acid; inhibitory neuron; locus ceruleus structure; monoamine; motivated behavior; neuroregulation; optogenetics; preoptic nucleus; tool; unpublished works; virus genetics

PROJECT SUMMARY The monoamines, which include dopamine, norepinephrine, and serotonin, are evolutionarily conserved neurotransmitters that modulate the activity of excitatory and inhibitory neurons throughout the entire brain, and are thus essential for diverse aspects of physiology and behavior. Abnormalities of monoamine systems contribute to numerous brain disorders including schizophrenia, depression, and Parkinson's disease. We recently developed viral-genetic tools to determine the input, output, and input–output relationships of a given neuronal population at the scale of the entire mouse brain, and discovered contrasting input–output architectures between locus coeruleus norepinephrine neurons and midbrain dopamine neurons. Here, we apply these tools to study the organization and function of the dorsal raphe (DR) serotonin system, which provides major serotoninergic input to the forebrain to regulate diverse . functions and brain states including mood, impulsivity, anxiety, as well as hunger and thirst. Using rabies-mediated trans-synaptic tracing, we previously defined the input architecture to the entire populations of DR-serotonin and DR-GABA neurons However, our unpublished work revealed considerable heterogeneity within the DR serotonin system and suggests that it consists of parallel sub- systems that differ in input, output, and neurotransmitter phenotypes. We propose that each DR serotonin sub-system may carry out a specific subset of the diverse functions ascribed to the DR-serotonin neurons. We plan to complete our characterization of the anatomical organization of the DR serotonin sub- systems, addressing the questions of how axons of each sub-system divide up the projections of the entire DR serotonin system, and what is the input–output relationship for each DR serotonin sub-system. These will lay a foundation for all future studies of DR-serotonin neurons. We also propose to identify behavioral functions of a subset of these sub-systems by manipulating and recording serotonin neuron subtypes in anxiety- and depression-like states known to involve serotonin, as well as new behavioral paradigms. Finally, because previous studies and our own unpublished data suggest a strong link between serotonin and thirst, we will explore the circuit and cellular mechanisms by which serotonin regulates thirst-motivated behavior using quantitative and sensitive assays we have established based on a technique we developed to gain genetic access of thirst-activated neurons. The integration of anatomical, physiological, and behavioral studies on genetic-, projection-, and activity-defined neuronal populations proposed here will help dissect the complex serotonin system into specific sub-systems and advance our understanding of how serotonin modulates diverse physiological functions and behaviors.

项目概要 单胺，包括多巴胺、去甲肾上腺素和血清素，在进化上是保守的 调节整个大脑兴奋性和抑制性神经元活动的神经递质， 因此对于生理学和行为的各个方面都至关重要。单胺异常 系统会导致许多脑部疾病，包括精神分裂症、抑郁症和帕金森氏症 疾病。我们最近开发了病毒遗传工具来确定输入、输出和输入-输出 整个小鼠大脑范围内给定神经元群的关系，并发现 蓝斑去甲肾上腺素神经元和中脑之间的对比输入输出结构 多巴胺神经元。在这里，我们应用这些工具来研究中缝背侧的组织和功能 (DR) 血清素系统，为前脑提供主要的血清素能输入，以调节多种 。 功能和大脑状态，包括情绪、冲动、焦虑以及饥饿和口渴。 使用狂犬病介导的跨突触追踪，我们之前定义了整个系统的输入架构 然而，我们未发表的工作揭示了 DR-5-羟色胺和 DR-GABA 神经元的群体 DR 血清素系统内存在相当大的异质性，并表明它由平行的子系统组成 输入、输出和神经递质表型不同的系统。我们建议每个 DR 血清素 子系统可以执行归因于 DR-5-羟色胺神经元的不同功能的特定子集。 我们计划完成 DR 血清素亚组解剖结构的表征 系统，解决每个子系统的轴突如何划分整个系统的投影的问题 DR 血清素系统，以及每个 DR 血清素子系统的输入输出关系是什么。这些 将为未来所有 DR-5-羟色胺神经元的研究奠定基础。我们还建议识别行为 通过操纵和记录血清素神经元亚型来控制这些子系统的子集的功能 已知与血清素有关的焦虑和抑郁样状态，以及新的行为模式。 最后，因为之前的研究和我们自己未发表的数据表明血清素之间存在密切的联系 和口渴，我们将探索血清素调节口渴的回路和细胞机制 使用我们基于我们开发的技术建立的定量和灵敏测定的行为 获得口渴激活神经元的遗传通路。解剖学、生理学和 这里提出的关于遗传、投射和活动定义的神经元群体的行为研究将 帮助将复杂的血清素系统分解为特定的子系统，并加深我们对 血清素如何调节不同的生理功能和行为。

项目成果

Thirst-associated preoptic neurons encode an aversive motivational drive.

• DOI: 10.1126/science.aan6747
• 发表时间: 2017-09-15
• 期刊: Science (New York, N.Y.)
• 作者: Allen WE;DeNardo LA;Chen MZ;Liu CD;Loh KM;Fenno LE;Ramakrishnan C;Deisseroth K;Luo L
• 通讯作者: Luo L

Genetic Dissection of Neural Circuits: A Decade of Progress.

• DOI: 10.1016/j.neuron.2018.03.040
• 发表时间: 2018-04-18
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Luo L;Callaway EM;Svoboda K
• 通讯作者: Svoboda K

Generation of a DAT-P2A-Flpo mouse line for intersectional genetic targeting of dopamine neuron subpopulations.

生成 DAT-P2A-Flpo 小鼠品系，用于多巴胺神经元亚群的交叉遗传靶向。

• DOI: 10.1016/j.celrep.2021.109123
• 发表时间: 2021-05-11
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Kramer DJ;Aisenberg EE;Kosillo P;Friedmann D;Stafford DA;Lee AY;Luo L;Hockemeyer D;Ngai J;Bateup HS
• 通讯作者: Bateup HS

The Temporal Association Cortex Plays a Key Role in Auditory-Driven Maternal Plasticity.

• DOI: 10.1016/j.neuron.2020.05.004
• 发表时间: 2020-08-05
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Tasaka GI;Feigin L;Maor I;Groysman M;DeNardo LA;Schiavo JK;Froemke RC;Luo L;Mizrahi A
• 通讯作者: Mizrahi A

Differential encoding in prefrontal cortex projection neuron classes across cognitive tasks.

• DOI: 10.1016/j.cell.2020.11.046
• 发表时间: 2021-01-21
• 期刊: Cell
• 影响因子: 64.5
• 作者: Lui JH;Nguyen ND;Grutzner SM;Darmanis S;Peixoto D;Wagner MJ;Allen WE;Kebschull JM;Richman EB;Ren J;Newsome WT;Quake SR;Luo L
• 通讯作者: Luo L