Real-time biosensors for measuring multiple neuromodulators
A Grand Challenge for Neuroscience is to understand the neural circuitry that underlies brain health and disease. Neural circuit activity is dependent on the simultaneous actions of a bewildering array of chemical signaling molecules, often termed neuromodulators, yet the existing tools to measure these substances are primitive in that they lack the necessary chemical specificity, detection sensitivity, spatial resolution, and temporal resolution. To overcome this barrier to progress, we have assembled an interdisciplinary team of chemists, engineers, neuroscientists, and clinicians to create a transformative sensor technology to measure complex forms of chemical communication in the living brain, in real time. We will pursue two overarching goals. In PHASE I, we will focus on the development of the Real-Time Neurochemical “RTN” sensor that can simultaneously and precisely measure multiple signaling chemicals in specific brain targets in freely behaving animals. The performance of the RTN device will be rigorously tested first in brain slices and subsequently in rodent models. In PHASE II, we will utilize the RTN sensor to perform fundamental studies of how simultaneous changes in multiple neuromodulators in specific brain targets lead to the complex changes in neural circuit activity underlying adaptive and pathological behaviors. This will entail development of a second generation RTN sensor to enable expanded simultaneous measurement of additional neuromodulators and development of an implantable sensor with wireless circuitry to study freely moving subjects (rodents and non-human primates) without impeding their behavior. We will also explore using this technology for human clinical applications with the overall goal of advancing our understanding of brain disorder pathophysiology, identification of “drugable” targets, and implementation of novel precision therapeutic strategies. The successful development of the proposed technology will be transformative, as it will enable creation of “multidimensional maps” of neuromodulator action in the brain and can also be used to create multidimensional biomarker algorithms that will form the basis of the first laboratory-based diagnostic tests to detect brain diseases as well as used to monitor investigational drug efficacy and safety, critically, in real time.