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.

项目摘要哺乳动物大脑对环境变化的动态适应能力是显着的，因为这是复杂性允许这种适应的操作的神经元网络的网络。虽然我们有一些了解这一点的解剖学和功能基础，我们仍然缺乏详细的了解神经元活动的调节作用。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？神经调节器电路如何完成调节靶向神经元的发射和突触特性？在知识中填补这些空白将促进我们的了解神经调节剂生物学的各个方面，并允许发现新的治疗策略。到帮助缩小这一差距，我们使用创新的方法来开发遗传编码的直接报告行为触发和调制的神经调节剂释放，包括5-羟色胺（5-HT），多巴胺（DA）和去甲肾上腺素（NE）。我们已经将这些指标传播给了神经科学社区，并刺激了调节神经调节剂释放基础动机和成瘾的新型机制的主要发现。以此最初的成功为基础，我们建议将此NM传感器工具箱的有效性进一步扩展到在深度和亚细胞分辨率下启用成像稀疏释放。我们的具体目标是（1）改善我们当前传感器的敏感性可以启用稀疏神经调节剂释放的鲁棒成像，推动空间在较低浓度下的亚细胞水平分辨率并增加响应的线性；（2）扩展他们的光谱范围至红色/远红色，以增强成像深度，SNR和体内多路复用测量和使用两种或三种不同的颜色操纵多个电路组件，（3）表征可能电流传感器干扰内源信号传导并系统地验证新兴传感器广泛的显微镜在体内接近。我们的策略依赖于传感器之间的动态合作设计团队和最终用户获得连续反馈，以实施对传感器的有效改进。我们的目标是快速传播广泛的特征良好，高度敏感的指标神经科学社区用于研究行为的老鼠，鱼类，苍蝇和蠕虫，以丰富我们的知识关于神经调节剂在脑电路中的功能作用。