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Genetically encoded indicators for large-scale sensing of neuromodulatory signaling in behaving animals

用于大规模感知行为动物神经调节信号的基因编码指标

基本信息

批准号：
9767296
负责人：
Axel Nimmerjahn
金额：
$ 96.08万
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：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9767296
关键词：
Acetylcholine Acute Address Affect Affinity Amino Acids Anatomy Animal Behavior Animals Arousal Arrestins Attention Behavior Behavioral Biological Assay Body Regions Brain Brain region Calcium Catecholamines Cell Nucleus Cell Survival Cells Cognition Cognitive Color Communication Communities Computer Simulation Corpus striatum structure Cyclic AMP Dimensions Directed Molecular Evolution Disease Dopamine Dorsal Electric Stimulation Electrophysiology (science)Emotions Evolution Flow Cytometry G-Protein-Coupled Receptors GTP-Binding Proteins Generations Glutamates Health Human Image In Vitro Kinetics Lead Ligands Link Measurement Mental Depression Mental disorders Microdialysis Molecular Mus Nervous system structure Neurodegenerative Disorders Neuroglia Neuromodulator Neurons Neuropeptides Neurosciences Noise Norepinephrine Opioid Optics Output Parkinson Disease Pathway interactions Pattern Peptide Signal Sequences Perception Periodicity Pharmaceutical Preparations Play Population Process Property Proteins Reporting Research Personnel Resolution Role Scaffolding Protein Schizophrenia Sensitivity and Specificity Serotonin Signal Transduction Site Site-Directed Mutagenesis Slice Specificity Spinal Spinal cord injury Substantia nigra structure Surface Synapses Synaptic Transmission System Techniques Testing Time Validation Viral Whole-Cell Recordings Work addiction arrestin 2 base behavior influence behavior test beta-arrestin calcium indicator dorsal horn drug of abuse extracellular gamma-Aminobutyric Acid high throughput screening in vivo insight locus ceruleus structure minimally invasive monoamine mouse model multidisciplinary nano nervous system disorder neural circuit neuronal patterning neuroregulation novel operation recruit sensor spatiotemporal success temporal measurement trafficking two photon microscopy virtual voltage

项目摘要

Brain functions are executed by intricately coordinated networks of neurons, whose modes of operation are highly sensitive to a constellation of neuromodulators. More specifically, neuromodulators such as dopamine, norepinephrine, serotonin, and acetylcholine exert dramatic control over global brain processes such as arousal, attention, emotion, or cognitive perception. Altered neuromodulator signaling has been linked to neurological and psychiatric disorders such as Parkinson's disease, schizophrenia, depression and addiction. Similarly, opioid neuropeptides play important roles in the modulation of cognition and behavior. While the anatomical structures that produce neuromodulatory signals are well known, little is known about the spatial and temporal evolution of these signals in the innervated brain regions. This is because current measurement techniques, such as microdialysis or cyclic voltammetry, lack the spatial or temporal resolution (and often the molecular specificity) to resolve respective signals. This technical challenge has been a long-standing barrier to our understanding of how neuromodulation alters neural circuit function in order to influence behavior. To address this challenge, this project will develop, validate, and disseminate novel genetically encoded fluorescent proteins for large-scale optical measurement of monoamine neuromodulator and opioid neuropeptide signaling in behaving animals, by bringing together a multi-disciplinary team of investigators with unique and complementary expertise. These sensor proteins have the potential to revolutionize neuroscience in a way similar to genetically encoded indicators for calcium, glutamate, and voltage, which are now in widespread use. Combined with calcium and voltage imaging, neuromodulator sensors will reveal how these systems impinge on cellular and circuit function. In particular, proposed sensors will enable minimally invasive, high-resolution, long-term, and direct measurement of neuromodulator and neuropeptide signaling at synaptic, cellular, and system levels. Sensors for neuromodulatory signaling have remained elusive for a long time. Our team recently developed a first generation of genetically encoded indicators for serotonin (5-HT), norepinephrine (NE), and dopamine (DA) that can report nano- to micromolar concentration changes with high spatial and temporal resolution. Building on this work, the following specific aims are proposed: 1) Optimize and diversify genetically encoded sensors for the monoamines using computational modeling, directed evolution and high-throughput screening; 2) Develop and optimize genetically encoded sensors for opiate neuropeptides using novel protein scaffolds; and 3) Systematically validate the novel neuromodulator and neuropeptide sensors in acute brain slices and behaving animals. Together, this work will provide the neuroscience community with a wide range of well-characterized multi-color indicators for probing the functional role of neuromodulators and neuropeptides in regulating neural circuit function and behavior in both health and disease.

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