Modular, in-situ probes of brain chemistry

大脑化学的模块化原位探针

基本信息

批准号：
10227222
负责人：
Tod Edward Kippin
金额：
$ 52.34万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA BARBARA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10227222
关键词：
Affinity Animals Behavioral Blood Brain Brain Chemistry Brain region Chemicals Cocaine Complex Concentration measurement Data Development Disease Dopamine Dose Drug Kinetics Drug Monitoring Electrochemistry Electrodes Ensure Feedback Frequencies Genetic Hand Health Hour In Situ Intervention Measurement Measures Metabolic Methamphetamine Methods Microdialysis Molecular Molecular Analysis Monitor Morphine Abuse Neurons Neurotransmitters Noise Outcome Output Oxidation-Reduction Performance Pharmaceutical Preparations Pharmacodynamics Pharmacology Physiological Psychotropic Drugs Rattus Reporter Reporting Resolution Rodent Route Running Sensitivity and Specificity Serotonin Signal Transduction Specificity Techniques Technology Testing Time Translating Variant Vision Work aptamer awake base detection limit drug of abuse gamma-Aminobutyric Acid improved in vivo innovation insight mind control neurochemistry neuropeptide Y optogenetics particle psychobiology receptor response screening sensor success temporal measurement tool

项目摘要

Summary. While the established electrochemical and microdialysis-based techniques for measuring drugs and neurotransmitters in the brain have unimpeachably contributed to our understanding of brain function, they are not without limitations. For example, when the same dose of cocaine is infused over 5 s versus 90 s the behavioral, metabolic, and even genetic outcomes vary dramatically, suggesting that the 2 min resolution of the most highly resolved of prior in-brain cocaine measurements are poorly matched to timescale of the drug's psychobiology. More generally, no drugs and only a small number of neurotransmitters have been measured to date in the brain with the most behaviorally relevant seconds time resolution. In response, our vision is to adapt electrochemical aptamer-based (E-AB) sensors, an in-vivo measurement platform that does not rely on the chemical or enzymatic reactivity of its targets (thus ensuring generality), to the problem of simultaneously monitoring drugs of abuse and the neurotransmitters they modulate in situ in the brains of freely moving, normally behaving rodents. To this end, we have already demonstrated feasibility by performing the high frequency, multi-hour measurement of more than a half dozen molecules in the blood and brains of live rats. Leveraging these preliminary results we propose here the adaptation of E-AB sensors to the problem of studying of brain chemistry. If successful, the proposed work will greatly expand the number of neurochemically relevant molecules that can be measured in real time and with second resolution in the living brain, thus creating a new window into brain chemistry that provides unique capabilities for closed-loop study and intervention.

概括。虽然已建立的基于电化学和微透析的技术用于测量药物和大脑中的神经递质对我们对大脑功能的理解做出了无可挑剔的贡献，它们是并非没有限制。例如，当输注相同剂量的可卡因超过 5 秒而不是 90 秒时，行为、代谢甚至遗传结果差异很大，这表明 2 分钟的分辨率先前最高分辨率的脑内可卡因测量与药物的时间尺度不匹配心理生物学。更一般地说，没有药物和只有少量神经递质被测量到大脑中的日期与行为最相关的秒时间分辨率。作为回应，我们的愿景是适应基于电化学适体（E-AB）的传感器，一种不依赖于电化学适配体的体内测量平台其目标的化学或酶反应性（从而确保通用性），同时解决问题监测滥用药物及其在自由活动的大脑中原位调节的神经递质，正常行为的啮齿动物。为此，我们已经通过执行高频率，对活体老鼠血液和大脑中超过六个分子进行多小时测量。利用这些初步结果，我们在此建议采用 E-AB 传感器来解决以下问题：研究脑化学。如果成功，拟议的工作将大大增加可以在活体中以第二分辨率实时测量神经化学相关分子大脑，从而为大脑化学创造了一个新的窗口，为闭环研究提供了独特的能力和干预。