This award supports a collaborative effort between PIs at Case Western Research University and Illinois State University to develop new instrumentation in support of neurobiology research. Monitoring neural activity in awake laboratory animals has proven to be a powerful tool for investigating how the brain ultimately controls behavior. Driving this approach are recent advances in microsensors for probing brain function very quickly and on microscopic scales as the behavior occurs. However, neuromonitoring at implanted microsensors remains particularly challenging, as the majority of available measurement systems are hampered by large size, high power requirements, and wired connections between animal and recording equipment. These technological limitations will be overcome by developing the next generation of ultra-small, low-power wireless devices for neurochemical and neuroelectrical monitoring and for neuromodulation using electrical stimulation in freely behaving animals.
State-of-the-art engineering methods called very-large-scale-integration (VLSI) and complementary-metal-oxide-semiconductor (CMOS) technologies will be employed to manufacture the proposed devices. This fabrication process will result in multichannel, multifunctional, wireless devices whose size and weight are suitable for implantation, freeing the animal from exposed, bulky instruments and cables that alter behavior, generate noise artifacts during movement, and limit experimental design. Power consumption will be dramatically reduced as well by the fabrication strategy, enabling the use of miniature batteries as a power source during operation. Once constructed, assembled and packaged into a chronically implantable form, and tested, these devices will be used in animal experiments to investigate the role of dopamine in motivated behavior. This important brain neurotransmitter has been implicated in responding to rewards or the cues that predict rewards, and in altering the long-term functioning of brain circuits involved in motivation.
By overcoming technical limitations of existing instrumentation, these new miniature wireless devices for will advance neurobiological investigations in the primary animal models used for the study of brain-behavior relationships and will extend this line of research to smaller animals whose size has previously limited inquiry. Such devices will ultimately be commercially viable driven by the needs of the larger neuroscience community. Through dissemination of these sensors and collaboration with users the sensor platform can evolve to meet emerging research needs. Additionally, this project will not only train undergraduate and graduate students in both science and engineering in the respective laboratories of the investigators, but it will also foster interdisciplinary training as the two laboratories will extensively and closely work together to develop and apply the new instrumentation. In a broader vein, the award will lead to establishing new working relationship between neurobiologists and engineers in support of both research and education.
in laboratory animals as a tool for advancing neuroscience research. While much progress has been made in understanding the brain, particularly how brain cells or neurons function in isolation, current technology has limited our ability to study how these neurons act during behavior. One critical hurdle for monitoring brain activity in awake animals is the physical connection to recording and stimulating equipment. This wired tether not only alters natural behavior but restricts the types of tests that can be performed and distorts measurements by adding noise during movement as well. A wireless link between animal and recording-stimulating equipment was proposed to obviate this problem. Devices were also proposed to be fabricated from integrated circuits ("chips"). Their small size offers the additional advantages of being less obtrusive to the animal and requiring less power than larger components. Thus, a major objective of this project was to combine an integrated circuit with a small battery to create a miniaturized device for minimal impact to the animal. The overall strategy for instrument development was a serial progression of integrated circuit functionality, culminating in a prototype miniaturized device. Three integrated circuits were successfully fabricated and tested. The first chip accommodated one chemical sensor for measuring dopamine, a neurotransmitter involved in motor control, motivation and cognition. The second chip expanded the number of recording channels to 16 and enabled both chemical and electrical measurements. Neurons use both neurotransmitters and electrical signals called action potentials to communicate, and monitoring both signals provides the most comprehensive view of brain function at the neuronal level. The third chip further enhanced the capabilities of each channel by supporting combined chemical and electrical measurements at the same brain-implanted sensor. In this way, the release of a neurotransmitter by one neuron and its effect on another target neuron is assessed simultaneously. A stimulator was also added to the third chip enabling the control of brain neurons by electrical activation. Finally, the third chip was assembled into a battery-powered miniaturized device and established the first wireless measurement of dopamine in an awake laboratory animal using the integrated-circuit approach. Overall, this project both advanced instrumentation for investigating brain-behavior relationships as noted above and contributed to student training and learning. Ultimately, the devices developed in this project will benefit society by laying the foundational work for the development of future instruments with markedly expanded capabilities in support of basic neuroscience research and potentially in support of clinically relevant neuroprostheses to treat debilitating neuropathologies. Participating undergraduate and graduate students in neurobiology were exposed to device development and testing, whereas participating graduate students in engineering gained experience in integrated circuit design, development, and benchtop testing, and were exposed to "wet" testing in a neurobiology laboratory. Outreach activities included development of new teaching modules for a graduate engineering course and on-line neuroscience curricular directed towards high school biology teachers and undergraduate non-science majors. Finally, this project continued to nurture and cultivate a productive partnership between two researchers with respective expertise in the disciplines of neurobiology-analytical chemistry and electrical engineering-computer science. We submit that this collaboration will continue to enjoy success in the future for development of novel instruments for the neurosciences.
