Multiplex interrogation of neuromodulatory signaling in behaving animals with enhanced depth and resolution

以增强的深度和分辨率对行为动物的神经调节信号进行多重询问

基本信息

批准号：
10166304
负责人：
Lin Tian
金额：
$ 86.96万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10166304
关键词：
Anatomy Animals Behavioral Binding Biology Brain Brain region Calcium Cells Collaborations Color Communication Communities Complex Computer Models Corpus striatum structure Development Directed Molecular Evolution Disease Dopamine Effectiveness Endorphins Engineering Ensure Environment Feedback Fiber Fishes G-Protein-Coupled Receptors Glutamates Goals Health Human Image Image Enhancement Knowledge Ligand Binding Location Machine Learning Measurement Measures Membrane Mental Depression Mental disorders Microscopic Microscopy Motivation Mus Neuromodulator Neurons Neurosciences Neurotransmitters Norepinephrine Opsin Optics Output Parkinson Disease Penetration Peptides Pharmaceutical Preparations Photometry Photons Property Regulation Reporting Resolution Robotics Role Schizophrenia Sensitivity and Specificity Serotonin Shapes Signal Transduction Specificity Structure Synapses Techniques Therapeutic Time Variant Work addiction base brain circuitry cell type design environmental change extracellular fly imaging modality improved in vivo interdisciplinary collaboration minimally invasive monoamine multiplexed imaging nerve supply nervous system disorder neural circuit neurochemistry neuroregulation neurotransmitter release novel novel therapeutic intervention operation optogenetics relating to nervous system response scaffold screening sensor spatiotemporal statistical and machine learning success tool two-photon virtual voltage

项目摘要

Project Summary The dynamic adaptability of the mammalian brain to environmental changes is remarkable, as it is the complexity of the networks of neurons underlying the operations that allow for such adaptations. Although we have some understanding of the anatomical and functional basis of this, we are still lacking a detailed picture of how the modulation of neuronal activity works. What is the timing and locations of these neuromodulator release and relationship with excitatory/inhibitory circuits? How does the neuromodulators circuitry accomplish the regulation of firing and synaptic properties of targeted neurons? Filling these gaps in knowledge would advance our understanding of all aspects of neuromodulator biology and allow discovery of new therapeutic strategies. To help close this gap, we have used creative approaches to the development of genetically encoded to directly report behaviorally triggered and modulated neuromodulator release including serotonin (5-HT), dopamine (DA) and norepinephrine (NE). We have disseminated these indicators to the neuroscience community and spurred major discoveries of novel mechanisms regulating neuromodulator release underlying motivation and addiction. Build on this initial success, we propose to further expand the effectiveness of this toolbox of NM sensors to enable imaging sparse release at depth and subcellular resolution. Our specific goals are to (1) improve the sensitivity of our current sensors to enable robust imaging of sparse neuromodulator release, push their spatial resolution to the subcellular level and increase linearity of response at lower concentrations; (2) expand their spectral range to red/far-red to enhance imaging depth, SNR and in vivo multiplex measurement and manipulation of multiple circuit components using two or three distinct colors, and (3) characterize the possible interference of current sensors with endogenous signaling and systematically validate emerging sensors with a wide-ranging microscopy approaches in vivo. Our strategy relies on a dynamic collaboration between the sensor design team and end users to obtain continuous feedback to implement efficient improvements to the sensors. It is our goal to rapidly disseminate a wide range of well-characterized, highly sensitive indicators for the neuroscience community to be employed to study behaving mice, fish, flies and worms, to enrich our knowledge on the functional roles of neuromodulators in the brain circuitry.

项目概要哺乳动物大脑对环境变化的动态适应性是显着的，因为它的复杂性允许这种适应的操作背后的神经元网络。虽然我们有一些尽管我们对其解剖学和功能基础的了解还不够深入，但我们仍然缺乏关于它如何进行的详细了解。神经元活动的调节起作用。这些神经调节剂释放的时间和位置是什么？与兴奋/抑制回路的关系？神经调节电路如何完成调节目标神经元的放电和突触特性？填补这些知识空白将促进我们了解神经调节生物学的各个方面并允许发现新的治疗策略。到为了缩小这一差距，我们使用了创造性的方法来开发基因编码以直接报告行为触发和调节的神经调节剂释放，包括血清素 (5-HT)、多巴胺 (DA) 和去甲肾上腺素（NE）。我们已将这些指标传播给神经科学界并刺激调节神经调节剂释放潜在动机和成瘾的新机制的重大发现。在此初步成功的基础上，我们建议进一步扩展该 NM 传感器工具箱的有效性能够在深度和亚细胞分辨率下对稀疏释放进行成像。我们的具体目标是 (1) 改进我们当前传感器的灵敏度能够对稀疏神经调节剂释放进行鲁棒成像，推动其空间分辨率达到亚细胞水平并增加较低浓度下的响应线性； (2) 扩大他们的光谱范围为红色/远红色，以增强成像深度、信噪比和体内多重测量使用两种或三种不同颜色操纵多个电路元件，以及（3）表征可能的电流传感器与内源信号的干扰，并系统地验证新兴传感器广泛的体内显微镜方法。我们的策略依赖于传感器之间的动态协作设计团队和最终用户获得持续的反馈，以对传感器进行有效的改进。我们的目标是快速传播一系列特征明确、高度敏感的指标神经科学界将被用来研究老鼠、鱼、苍蝇和蠕虫的行为，以丰富我们的知识关于神经调节剂在大脑回路中的功能作用。