Noninvasive hippocampal blood-brain barrier opening in Alzheimer's disease with focused ultrasound.

The blood-brain barrier (BBB) presents a significant challenge for treating brain disorders. The hippocampus is a key target for novel therapeutics, playing an important role in Alzheimer's disease (AD), epilepsy, and depression. Preclinical studies have shown that magnetic resonance (MR)-guided low-intensity focused ultrasound (FUS) can reversibly open the BBB and facilitate delivery of targeted brain therapeutics. We report initial clinical trial results evaluating the safety, feasibility, and reversibility of BBB opening with FUS treatment of the hippocampus and entorhinal cortex (EC) in patients with early AD. Six subjects tolerated a total of 17 FUS treatments with no adverse events and neither cognitive nor neurological worsening. Post-FUS contrast MRI revealed immediate and sizable hippocampal parenchymal enhancement indicating BBB opening, followed by BBB closure within 24 h. The average opening was 95% of the targeted FUS volume, which corresponds to 29% of the overall hippocampus volume. We demonstrate that FUS can safely, noninvasively, transiently, reproducibly, and focally mediate BBB opening in the hippocampus/EC in humans. This provides a unique translational opportunity to investigate therapeutic delivery in AD and other conditions.

Engaging undergraduate summer research students and faculty in a regional neuroscience network.

Students who engage in experiential research programs and who form communities of learning are more likely to persist in Science, Technology, Engineering, and Math (STEM) programs. Faculty who collaborate are more likely to publish and to stay engaged in their field. With funding from the Great Lakes Colleges Association (GLCA) Expanding Collaboration Initiative, we engaged in a series of summer seminars with neuroscience faculty and their research students at five regional institutions, the College of Wooster, Ohio Wesleyan University, Earlham College, Oberlin College and Kenyon College. Our goals were to provide an opportunity for faculty and students to learn about the methods used in the labs at these institutions, to increase collaborative relationships across these institutions, to develop a community of learning among participating students, and to provide students with professional development opportunities. Pre- and post-assessment data indicate knowledge gains in demonstrated methods and increased comfort performing the methods with supervision or collaboration. In addition, several collaborative relationships were formed and significant assistance with planning, materials, and/or apparatus was provided across institutions. In open-ended post-experience questions, students indicated valuing the relationships formed with other students in this community of learning. We will continue this program with continued funding through the GLCA Expanding Collaboration Initiative and submission of a multi-center National Science Foundation Research Experience for Undergraduates grant and encourage others to engage in similar practices at their own institutions.

4-chloro-3-hydroxyanthranilate reduces local quinolinic acid synthesis, improves functional recovery, and preserves white matter after spinal cord injury.

Inflammatory processes within the central nervous system (CNS) contribute significantly to the pathogenesis of a broad range of neurologic diseases, including spinal cord injury (SCI). One mechanism by which immune activation causes neurologic symptoms and tissue injury is via the production of neurotoxins by activated macrophages and microglia. In the present study, the role of the endogenous tryptophan metabolite and neurotoxin quinolinic acid (QUIN) in secondary pathology following traumatic SCI was investigated. Adult Hartley guinea pigs were injured by lateral compression of the spinal cord at the 12th thoracic segment (T12). QUIN had accumulated at the site of injury on day 12 post-injury in proportion to the severity of functional neurologic deficits (as assessed by the cutaneus trunci muscle reflex and motor function score at 5 h post-injury). Systemic administration of the 3-hydroxyanthranilate-3,4-dioxygenase (3-HAD) inhibitor, 4-chloro-3-hydroxyanthranilate (4Cl-3HAA; approximately 100 mg/kg every 12 h, beginning 5 h after injury) attenuated local QUIN production and reduced QUIN accumulation at the site of injury by approximately 50% at day 12, without enhanced accumulations of the neuroprotective metabolite kynurenic acid (KYNA). The severity of secondary functional deficits was also reduced by 4Cl-3HAA. In toluidine blue-stained spinal cord sections, the area of surviving intact white matter at the injury site was increased by approximately 100% in the 4Cl-3HAA-treated group. Sparing of both axons and myelin contributed to this increase. These results support the conclusion that QUIN accumulations at the site of injury contribute to secondary functional deficits and tissue damage following SCI.

Collaborative Research in Teaching: Collaboration between Laboratory Courses at Neighboring Institutions.

The concept of collaboration is central to many scientific endeavors. Here we present a model for collaborative research between laboratory courses in behavioral neuroscience at different institutions (or for that matter, multiple classrooms at a single institution). This course design engages undergraduate students in novel scientific research inside the classroom, and in discussion of that research between classrooms. In addition to exposing students to scientific collaboration, teaching these courses in tandem allows for the sharing of a number of resources while allowing collection of potentially publishable data and training students to conduct continuing independent research. For the 2003 and 2004 school years, we have run in collaboration the Laboratory in Brain and Behavior course at Colby College and the Laboratory in Behavioral Neuroscience: Learning and Memory course at Bowdoin College. The students enrolled in these courses have conducted primary, novel research projects designed by the instructors using animal subjects. Students learn experimental design, and surgery, behavioral testing, and histological techniques. Enrollments are limited in these courses, so having both groups of students perform the same protocols increases the number of subjects in these studies, and therefore, the statistical power of the experiment. The physical distance between the schools requires that technology be used to bring students in the two courses together. We have used threaded discussion groups accessible to students at both schools for everyday exchange of methodological information and have used videoconferencing for "lab meetings" addressing methodological issues and data analysis.