Linking function, structure, and molecular identity of lateral habenula neurons

外侧缰核神经元的功能、结构和分子特性的联系

• 批准号: 10206846
• 负责人: Steven Shabel
• 金额: $ 73.75万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10206846
• 关键词: Anatomy; Brain; Brain region; Cell physiology; Cells; Collection; Data; Disease; Dopamine; Dorsal; Feedback; Fluorescent in Situ Hybridization; Functional Imaging; Future; Genes; Goals; Habenula; Heterogeneity; Image; Individual; Knowledge; Label; Lateral; Learning; Letters; Link; Location; Mammals; Maps; Messenger RNA; Methods; Microscope; Midbrain structure; Molecular; Molecular Profiling; Mus; Nervous system structure; Neurons; Pattern; Phylogenetic Analysis; Population; Property; Public Health; Rabies virus; Research; Rewards; Role; Serotonin; Slice; Structure; System; Tegmentum Mesencephali; To specify; Training; Ventral Tegmental Area; base; calcium indicator; cell type; dopaminergic neuron; ex vivo imaging; experimental study; gamma-Aminobutyric Acid; image registration; imaging modality; in vivo; in vivo calcium imaging; in vivo imaging; lens; molecular marker; motivated behavior; multimodality; neural circuit; novel therapeutics; single-cell RNA sequencing; two-photon

ABSTRACT: The lateral habenula (LHb) impacts motivated behavior through dense direct and indirect projections to midbrain dopaminergic and serotonergic neurons. Some LHb neurons project directly to midbrain dopaminergic or serotonergic neurons; others project indirectly through one of multiple types of midbrain GABAergic neurons. Similar to dopaminergic neurons, the LHb encodes reward prediction error (RPE) - the discrepancy between expected and actual value – a powerful computation that guides learning from environmental feedback. However, there is a large amount of molecular and anatomical heterogeneity in the LHb, and it is unclear how reward encoding varies among LHb neurons with different projection targets, subnuclear location, and molecular profiles. Here we propose to develop methods that would link in vivo information encoding, projection target, subnuclear location, and molecular expression properties of individual LHb neurons – thus delineating functional, multimodal classes of LHb neurons to better understand the organization of the LHb. We hypothesize that a subset of functional classes of LHb neurons encodes RPE, and more generally, that distinct in vivo activity patterns map onto neurons with different projection targets, subnuclear location, and molecular profiles. In Aim 1, we will optimize our GRIN lens imaging methods to increase the number of LHb neurons that can be imaged simultaneously. We will also develop the use of a non-toxic rabies virus system for functionally imaging LHb neurons with different cell-type-specific midbrain projections in mice. In Aim 2, we will validate methods for identifying individual LHb neurons in brain slices that were imaged in vivo. These methods will allow us to specify the molecular class and subnuclear location of neurons that were functionally imaged in behaving mice, and together with Aim 1, link in vivo information encoding, projection target, subnuclear location, and molecular expression properties of individual LHb neurons. Moreover, the experiments proposed in Aim 2 would be proof- of-principle for other studies that aim to understand the function of different cell types (especially cell types that are defined by multiple molecular markers) – a critical step for making sense of the complexity of the nervous system.

摘要： 外侧缰核（LHb）通过向中脑的密集的直接和间接投射影响动机行为 多巴胺能和多巴胺能神经元。一些LHb神经元直接投射到中脑多巴胺能或多巴胺能神经元。 GABA能神经元;其他通过多种类型的中脑GABA能神经元之一间接投射。 与多巴胺能神经元类似，LHb编码奖励预测误差（RPE）-- 期望值和实际值-一个强大的计算，指导从环境反馈中学习。然而，在这方面， 在LHb中存在大量的分子和解剖异质性，目前还不清楚如何奖励 LHb神经元之间的编码因投射靶点、亚核位置和分子水平的不同而不同。 数据区.在这里，我们建议开发将体内信息编码，投影靶点， 亚核位置，和单个LHb神经元的分子表达特性-从而描绘功能， LHb神经元的多模态类，以更好地理解LHb的组织。我们假设 LHb神经元功能类别的子集编码RPE，且更一般地，编码不同的体内活性 模式映射到具有不同投射目标、亚核位置和分子谱的神经元上。在Aim中 1，我们将优化我们的GRIN透镜成像方法，以增加可以成像的LHb神经元的数量 同步我们还将开发一种无毒的狂犬病病毒系统用于功能成像LHb 神经元与不同类型的细胞特异性中脑投射在小鼠。在目标2中，我们将验证以下方法： 识别在体内成像的脑切片中的单个LHb神经元。这些方法将允许我们指定 在行为小鼠中功能成像的神经元的分子类别和亚核位置，以及 与Aim 1一起，将体内信息编码、投射靶点、亚核定位和分子生物学联系起来， 单个LHb神经元的表达特性。此外，目标2中提出的实验将证明- 对于其他旨在了解不同细胞类型（特别是 由多个分子标记物定义）-这是理解神经系统复杂性的关键一步。 系统