Understanding the relationship between behavior and underlying brain function constitutes one of the most complex intellectual challenges today. Functional neuroimaging represents an essential technology toward meeting this challenge. The large number of animal models of human brain disorders that have been established in rats and mice makes these species ideal candidates for brain mapping. A central dilemma, however, in conventional neuroimaging techniques is that immobilization of the subject, necessary to avoid movement artifact, extinguishes all but the simplest behaviors. The result is that brain function of such core animal behaviors as aggression, mating, feeding, and fear, remains poorly understood. To address the problem of immobilization, we have recently developed a miniature, self-contained, fully implantable infusion pump that in freely-moving animals allows intravenous bolus administration of imaging radiotracers by remote activation. Now with proof of principle demonstrated and a working model of the pump in use, a number of critical milestones remain necessary for widespread application and use of this technology in the scientific community. We now propose a novel microbolus infusion pump (MIP) that will allow greater flexibility of this tool in a broad range of experimental environments. For applications in small table-top experimental paradigms, we propose to power the MIP by a transcutaneous radiofrequency power link to an external resonating inductive coil driven by a novel Class E transmitter. This will allow the MIP to be powered and triggered remotely, and will make the device independent of finite battery power. For use of the MIP in open cage paradigms, we propose the use of a battery, rechargeable in the animal's homecage using the radiofrequency power link that enables the MIP to also operate independently when the animal is roaming free. A frequency-gated, optical controller in this design will allow transcutaneous triggering of the MIP from several meters distance, insensitive to ambient light. To miniaturize the MIP for use in mice, we propose to design a miniature, pressurized liquid reservoir and drug ejection chamber, and to develop and validate a miniature electrothermal valve. Application of the MIP to brain mapping in freely moving rats, as well as mice will be tested in a small table-top experimental paradigm (Conditioned Fear Response), as well as in an open cage study (Morris Water Maze). Cerebral blood flow related tracer distribution will be assessed using [14C]-iodoantipyrine injections followed by autoradiography. Research is conducted by an interdisciplinary team to develop a tool that can be applied not only to the brain mapping of basic neuronal circuits underlying normal and abnormal behavior, but also to behavioral pharmacology and in-vivo physiologic studies in small animal models. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050171-02
Application #
7033854
Study Section
Special Emphasis Panel (ZRG1-BDCN-K (10))
Program Officer
Pancrazio, Joseph J
Project Start
2005-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
2
Fiscal Year
2006
Total Cost
$348,163
Indirect Cost
Name
University of Southern California
Department
Psychiatry
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Meng, Ellis; Hoang, Tuan (2012) MEMS-enabled implantable drug infusion pumps for laboratory animal research, preclinical, and clinical applications. Adv Drug Deliv Rev 64:1628-38
Meng, Ellis; Hoang, Tuan (2012) Micro- and nano-fabricated implantable drug-delivery systems. Ther Deliv 3:1457-67
Sadler, Theodore R; Nguyen, Peter T; Yang, Jun et al. (2011) Antenatal maternal stress alters functional brain responses in adult offspring during conditioned fear. Brain Res 1385:163-74
Li, Po-Ying; Givrad, Tina K; Sheybani, Roya et al. (2010) A low power, on demand electrothermal valve for wireless drug delivery applications. Lab Chip 10:101-10
Givrad, Tina K; Maarek, Jean-Michel I; Moore, William H et al. (2010) Powering an implantable minipump with a multi-layered printed circuit coil for drug infusion applications in rodents. Ann Biomed Eng 38:707-13
Li, Po-Ying; Givrad, Tina K; Holschneider, Daniel P et al. (2009) A Parylene MEMS Electrothermal Valve. J Microelectromech Syst 18:1184-1197
Holschneider, D P; Maarek, J-M I (2008) Brain maps on the go: functional imaging during motor challenge in animals. Methods 45:255-61
Holschneider, D P; Scremin, O U; Chialvo, D R et al. (2008) Flattened cortical maps of cerebral function in the rat: a region-of-interest approach to data sampling, analysis and display. Neurosci Lett 434:179-84
Holschneider, D P; Yang, J; Guo, Y et al. (2007) Reorganization of functional brain maps after exercise training: Importance of cerebellar-thalamic-cortical pathway. Brain Res 1184:96-107
Yang, J; Sadler, T R; Givrad, T K et al. (2007) Changes in brain functional activation during resting and locomotor states after unilateral nigrostriatal damage in rats. Neuroimage 36:755-73

Showing the most recent 10 out of 12 publications