2014 — 2017 |
Cowen, Stephen Heien, Michael |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Brain Eager: Integrated Measurement of Dopamine Release and Large-Scale Ensemble Activity in Behaving Animals
This award is jointly made by two programs: the Instrument Development for Biological Research program (IDBR) and Emerging Frontiers (EF) in the Directorate of Biological Sciences (BIO).
The neurotransmitter dopamine plays a central role in learning, decision making, motivation, and the control of movement. It is assumed that dopamine influences these functions by modulating the capacity of individual neurons to form brief or lasting connections with other neurons. This assumption, however, has not been tested as no instrument exists for the real-time measurement of both dopamine release and the activities of groups of individual neurons in freely-moving animals. To build such a device the following will be combined: fast-scan cyclic voltammetry, the current state-of-the-art technology for measuring dopamine release, and high-density extracellular electrode arrays for the real-time measurement of large groups of individual neurons. The instrument will be designed for recording in freely-behaving animals, giving scientists the unprecedented opportunity to address questions such as: Is communication between neurons in distant brain regions enhanced by dopamine release? Does such enhanced communication correspond with improvements in learning, decision making, or motor control? Does dopamine release during sleep coordinate the reactivation of neurons involved in a recent learning experience? Is such reactivation important for the formation of long-term memories? The societal impact of addressing questions such as these would be in the fundamental advances answers would bring to the understanding of the brain as an integrated system, how this system works during learning and decision making, and what goes wrong when components of this system break down due to neurological disease or injury.
No tool exists that enables researchers to investigate the link between the activities of large groups of individual neurons and dopamine release in freely-behaving animals. The goal of this project is to build an instrument capable of measuring dopamine release and the activity of 100s of simultaneously active neurons in awake and behaving animals. The instrument integrates state-of-the-art technologies for measuring dopamine (fast-scan cyclic voltammetry) and neural activity (high-density ensemble recording). These technologies have not been integrated due to technical limitations. For example, electrical pulses created during voltammetry interfere with neural recording. Our methods are 1) adapt a recently-developed multi-channel headstage amplifier into our recording system that rapidly adapts to electrical artifacts, and 2) develop a novel carbon-film coating for metal electrodes, permitting dopamine recordings from electrode arrays. Our approach is to identify technical hurdles by troubleshooting and collecting scientific data from the system in anesthetized and freely-behaving rats. The two-year scope of this study is to collect and publish scientific and technical data from fully functional prototypes. These data will support funding efforts to build and distribute a commercial product. The theoretical foundation inspiring this work is that dopamine modulates decision making, learning, and motor control through its ongoing regulation of plasticity and neural activity in neuronal groups. According to the reinforcement-learning theory of dopamine function, dopamine release following unexpected rewards triggers associative learning and plasticity in networks of neurons. The question of how activity and connectivity are regulated by dopamine in behaving animals is unanswered and the proposed instrument will help fill this gap in understanding.
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0.915 |
2014 — 2015 |
Heien, Michael L |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Direct Measurements of Neurotransmitter Concentrations in Vivo
DESCRIPTION (provided by applicant): Where two neurons meet they can form a synapse and chemical communication can occur. This is the functional unit of the brain, and it is at this level where changes equate to learning. The proposed research will develop and then use electrochemical methods to measure the absolute concentrations of easily oxidized neurotransmitters in vivo - something not possible with current methodology. Fast changes in the extracellular concentration of neurotransmitters can arise from phasic neuronal firing. For this reason, chemical sensors should be able to operate on a wide range of time scales. An ideal sensor for the detection of neurotransmitters has high sensitivity, can distinguish between compounds, and has a fast response time. Electrochemical approaches offer a way to accomplish this for easily oxidized neurotransmitters by using an electrode next to sites where the neurotransmitter is released. Background-subtracted cyclic voltammetry, one widely used method is capable of measuring changes in neurotransmitter concentrations on a sub-second timescale. This methodology has proved to be a valuable tool to measure the concentrations; however, it cannot measure the absolute concentrations of neurotransmitters. The absolute concentration is of critical importance as it affects the receptor occupancy and can change the effect of released neurotransmitters on the receptors. A novel method to measure the absolute concentrations of easily oxidizable neurotransmitters on a single-second timescale will be developed. This method relies on the adsorption of these molecules to the sensing surface. Background-subtracted cyclic voltammetry is typically performed in a kinetically limited regime. In this experiment, we allow the amount adsorbed to the surface to vary by changing detection parameters. By allowing the system to come close to equilibrium, and then pushing it farther away, the absolute concentration of neurotransmitter present can be measured. The method will be validated by using well-characterized drugs. The effects of cocaine and methylphenidate (Ritalin), a psychostimulant drug on the absolute dopamine concentration in the rat striatum will be determined. Methylphenidate is approved for the treatment of attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome, and narcolepsy. Methylphenidate, like other stimulants, increases the concentration of dopamine in the brain; however how methylphenidate changes these concentrations has not been measured with exquisite temporal resolution.
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1 |
2021 |
Heien, Michael L |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Neuroanalytical Core
Summary ? Neuroanalytial Core The Neuroanalytical Core develops and applies methods to measure electroactive neurotransmitters in vivo. The core will develop and then use electrochemical methods to measure the absolute concentrations of easily oxidized neurotransmitters in vivo ? something not possible with other methodology. Fast changes in the extracellular concentration of neurotransmitters can arise from phasic neuronal firing. For this reason, chemical sensors should be able to operate on a wide range of time scales. An ideal sensor for the detection of neurotransmitters has high sensitivity, can distinguish between compounds, and has a fast response time. Electrochemical approaches offer a way to accomplish this for easily oxidized neurotransmitters by using an electrode next to sites where the neurotransmitter is released. The core can monitor rapid, phasic changes using FSCV or slow, tonic changes using FSCAV. Making simultaneous measurements of dopamine and serotonin on multiple timescales has the potential to further understanding of the interactions between the two systems. It is important to note that in vivo experimentation will require informed selection of the brain regions of interest. This instrument allows for the investigation of the interdependence of the dopaminergic and serotonergic systems and the role they play in learning and disease states. Excitingly, this core has been designed to allow additional methods to be incorporated. This core can be used to further behavioral neuroscience and our current understanding of the links between neurochemical systems. We couple the methodologies to neuroscience to ensure that we will continue to advance the impact of the NIDA research community.
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