CREATIVE DIRECTIONS IN IMAGING
Translational Imaging of Methylphenidate in Developing Animals
Susan L. Andersen, Ph.D.
[Slides not available]
Magnetic resonance imaging (MRI) is a powerful tool that can be used to show functional changes in the brain that may occur as a result of drug exposure. Due to the relatively noninvasive nature of MRI, multiple scans across the course of development can reveal how drug-induced changes in brain function emerge with maturation. Dr. Andersen presented data from rat studies that demonstrated how prepubertal exposure to methylphenidate produces enduring changes in regional cerebral blood volume (rCBV) later in life. Previous behavioral studies suggested that prepubertal methylphenidate exposure reduces the rewarding properties of cocaine in adulthood. For this study, drug-induced changes were detected with monocrystalline iron oxide nanoparticles (MION), which constitute a long-lasting, iron-based contrast agent that has high magnetic susceptibility and increases the contrast-to-noise ratio over blood oxygen level-dependent (BOLD) preparations. Upon challenge with methylphenidate in adulthood, averaged rCBV values were significantly enhanced in the cortical regions associated with executive function in juvenile methylphenidate-treated rats relative to controls. With further maturation, this relative percentage in blood volume increased even more. Rats with juvenile exposure to methylphenidate were also challenged with cocaine in adulthood. The magnitude and time course of rCBV changes in response to cocaine (1 mg/kg IV) in methylphenidate-treated animals were significantly less than in vehicle or naïve animals. Dr. Andersen posited that MRI can be applied to the study of developmental drug exposure and subsequent responsiveness later in life.
Multiscale Imaging as an Approach To Elucidate CNS Sites of Stimulus Action
Maryann E. Martone, Ph.D.
Dr. Maryann Martone explained that the ability to combine gross structural imaging with high-resolution microscopy on a large scale will significantly advance the ability to detect and analyze pathology across multiple brain regions. Dr. Martone’s presentation highlighted the work of the newly created Biomedical Informatics Research Network (BIRN) project, a program created to acquire and analyze large-scale multiresolution brain maps. The BIRN project is creating a high-bandwidth and large-capacity network for sharing multimodal and multiresolution data obtained at multiple centers concerned with human disease and associated animal models. As part of the BIRN project, researchers at Duke University and the University of California, San Diego are collaborating on a multiscale investigation of a dopamine transporter knockout mouse. These animals exhibit chronic elevated extracellular dopamine and exhibit motor abnormalities, such as hyperactivity. Dr. Marton’s research team is combining gross structural analysis using structural MRI along with correlated histology and higher resolution light and electron microscopic techniques.
MRI/PET Imaging of Fetal Development
Helene Benveniste, M.D., Ph.D.
[Slides not available]
An accurate understanding of maternal-fetal exchange, fetal receptor maturation, and fetal pharmacodynamics is of pivotal importance to understanding how the developing human brain is affected by molecular, genetic, and environmental factors. This has become increasingly important as epidemiological and experimental studies now indicate that diseases such as autism, schizophrenia, depression, addiction, obesity, and certain forms of degeneration may have their origin early in life. One way to capture such complex interactions would be to longitudinally and noninvasively characterize (a) the maturation of fetal brain receptors, (b) the changes that might occur following various stressors, and (c) how such changes link to specific behaviors in the progeny later in life. Dr. Helene Benveniste discussed a noninvasive multimodality PET and MRI imaging approach for visualization of maternal-fetal drug exchange in the macaca radiata species developed by her research team. She described how their method allows them to quantify dopamine transporter uptake binding sites in the maternal and fetal brain. The presentation concluded with a discussion of their current and future studies, which focused on examination of characterizing receptor processes in the 2nd and 3rd trimesters.
In Vivo Mammalian Brain Imaging Using One- and
Two-Photon Fluorescence Microendoscopy
Mark J. Schnitzer, Ph.D.
[Slides not available]
One of the major limitations in the current set of techniques available to neuroscientists is the fact that there is a dearth of methods for imaging individual cells deep within the brains of live animals. To overcome this limitation, Dr. Mark Schnitzer and his research team developed two minimally invasive fluorescence microendoscopy techniques and tested their abilities to image cells in vivo. Both one- and two-photon fluorescence microendoscopy are based on compound gradient refractive index lenses that range from 350° to 1,000° microns in diameter and provide micron-scale resolution. One-photon microendoscopy allows full-frame images to be viewed by the eye or with a camera and is well suited to fast frame-rate imaging. Two-photon microendoscopy is a laser-scanning modality that provides optical sectioning deep within tissue. Using in vivo microendoscopy, the research team acquired video-rate movies of thalamic and CA1 hippocampal red blood cell dynamics and still-frame images of CA1 neurons and dendrites in anesthetized rats and mice. Dr. Schnitzer predicted that microendoscopy will help meet the growing demand for in vivo cellular imaging that has been created by the rapid emergence of new synthetic and genetically encoded fluorophores, which can be used to label specific brain areas or cell classes.