Genetic sensors for biogenic amines

Summary

Principal Investigator: Lin Tian
UC Davis Neuroscience
Title: " Genetically encoded sensors for the biogenic amines: watching neuromodulation in action"
BRAIN Category: Large-Scale Recording-Modulation - New Technologies (RFA NS-14-007)

Dr. Tian and her colleagues will create sensors that will allow researchers to see how molecules like dopamine, norepinephrine and serotonin regulate activity of neural circuits and behavior in living animals.

Principal Investigator: Lin Tian
UC Davis Neuroscience
Title: ”¬†Genetically encoded sensors for the biogenic amines: watching neuromodulation in action”
BRAIN Category: Large-Scale Recording-Modulation РNew Technologies (RFA NS-14-007)

Dr. Tian and her colleagues will create sensors that will allow researchers to see how molecules like dopamine, norepinephrine and serotonin regulate activity of neural circuits and behavior in living animals.

NIH Webpages

Genetically encoded indicators of neural activity. Fluorescent protein based biosensors can transfer changes in neural state (e.g. membrane potential or essential ion flux or enzyme activity) to fluorescence observables. They are genetically encoded, and can thus be used to label large populations of defined cell types and/or sub-cellular compartments.

Genetically encoded indicators of neural activity.
Fluorescent protein based biosensors can transfer changes in neural state (e.g. membrane potential or essential ion flux or enzyme activity) to fluorescence observables. They are genetically encoded, and can thus be used to label large populations of defined cell types and/or sub-cellular compartments.

Project Description

The goal of this proposal is to develop a toolbox of genetically encoded indicators for biogenic amines, the most important family of neuromodulators. All nervous systems are subject to neuromodulation, which reconfigure the dynamics of neural circuitry by transforming the intrinsic firing properties of targeted neurons and regulating their synaptic plasticity. The altered dynamics of the neuromodulators have been implicated in a number of human neurological and psychiatric diseases, including Parkinson’s, schizophrenia and addiction. Biogenic amines are a group of neuromodulators used by all animal brains to regulate the development, structure and function of neural circuits. Although the anatomical characterization and functional significance of biogenic amine projections are understood to a moderate degree, the precise mechanisms by which these molecules exert control over behavior are not fully understood. To decipher the mechanisms by which these molecules exert their influence on the brain and behavior, we must perform sensitive and specific measurements of neuromodulator transients, both broadly (volume modulation) and locally (targeted modulation), with the requisite spatial and temporal resolution, ideally in intac circuits. Existing methods, encompassing microdialysis and cyclic voltammetry, are useful, but not adequate for this task at hand. One potential solution would be to develop genetically encoded indicators based on fluorescent proteins combined with modern microscopy allowing direct and specific measurement of diverse types of neuromodulators with enhanced spatial and temporal resolutions. Recently we have successfully established technology platform for the development of genetically encoded indicators of neural activity, which have led to several high-quality optical probes for simultaneous imaging of large-scale neuronal populations in living animals. Building upon highly optimized platform for sensor sensors and extensive experience in sensor characterization and application in neuroscience, we propose to develop a high-quality toolkit of optical sensors for the biogenic amine neuromodulators, especially for dopamine, the most behavioral pervasive neuromodulator. Our specific aims will start by designing and screening sensors for each of the biogenic amines using combined computational redesign and direct revolution. We will then develop synaptic targeting strategies to display the sensors in dendrites and axons to improve their utility for synaptic imaging. We will finally characterize the performance of these sensors in living neurons and in rat brain slices and demonstrate their capabilities of probing dynamics of dopamine transients in living animals. State-of-the-art sensors for these molecules will facilitate the non-invasive, precise, direct and continual measurement of released neuromodulators at both the synaptic and circuit levels in live model organisms. Such technology advance in optical recordings will facilitate neural circuitry mapping and paint a dynamic picture of neuromodulation systems in regulating neural circuitry and behavior. Given the clear relevance of the biogenic amines to the neurological diseases, these sensors are especially beneficial for long-term studies of human stem cell and animal disease models (specially the Parkinson’s disease) and evaluating the effects of candidate therapeutics.

Public Health Relevance Statement

The altered dynamics of the neuromodulators have been implicated in a number of human neurological and psychiatric diseases, including Parkinson’s, schizophrenia and addiction. Our goal is to develop ultrasensitive genetically encoded sensors of the biogenic amines, the most powerful neuromodulators in the mammalian brain. Imaging the anatomical and functional organization of neuromodulation with these sensors in living model organisms will deepen our understanding of human neurological and psychiatric disorders and may bring us one step closer to finding improved treatment strategies.

NIH Spending Category

Bioengineering; Biotechnology; Brain Disorders; Neurosciences

Project Terms

ddiction; Amines; Animal Disease Models; Animal Model; Animals; Axon; base; Behavior; Behavioral; Binding (Molecular Function); Biogenic Amines; Brain; brain behavior; calcium indicator; California; cell body (neuron); Cell membrane; cell type; cytotoxicity; Dendrites; Dendritic Spines; design; Detection; Development; Diffusion; directed evolution; Distant; Dopamine; Epinephrine; Event; experience; Family; Farming environment; Fishes; fly; Foundations; Glutamates; Goals; Head; high throughput screening; Histamine; Human; human stem cells; Image; improved; In Vitro; in vivo; Individual; Kinetics; Life; Longitudinal Studies; Mammalian Cell; Maps; Measurement; Mental disorders; Methods; Microdialysis; Microscopy; Midbrain structure; Molecular; Mus; Myosin ATPase; nervous system disorder; Nervous system structure; neural circuit; Neuromodulator; Neurons; neuroregulation; Neurosciences; Neurotransmitters; Noise; Norepinephrine; One-Step dentin bonding system; optical sensor; Optics; Paint; Parkinson Disease; Pattern; Performance; Periplasmic Binding Proteins; Population; Presynaptic Terminals; Property; Protein Engineering; Proteins; public health relevance; Rattus; relating to nervous system; Reporting; Resolution; response; Rodent; scaffold; Schizophrenia; screening; Sensitivity and Specificity; sensor; Serotonin; Signal Transduction; Slice; small molecule; Solid; Solutions; Specificity; Structure; success; Surface; Synapses; Synaptic plasticity; System; Technology; Testing; Therapeutic; Time; tool; treatment strategy; two-photon; Universities; Validation; Vertebral column

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