Browsing by Author "Kimbrough, Ian F."
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- Disruption of astrocyte-vascular coupling and the blood-brain barrier by invading glioma cellsWatkins, Stacey; Robel, Stefanie; Kimbrough, Ian F.; Roldan, Stephanie M.; Ellis-Davies, Graham; Sontheimer, Harald (Nature Publishing Group, 2014-06-01)
- Spatially expandable fiber-based probes as a multifunctional deep brain interfaceJiang, Shan; Patel, Dipan C.; Kim, Jongwoon; Yang, Shuo; Mills, William A. II; Zhang, Yujing; Wang, Kaiwen; Feng, Ziang; Vijayan, Sujith; Cai, Wenjun; Wang, Anbo; Guo, Yuanyuan; Kimbrough, Ian F.; Sontheimer, Harald; Jia, Xiaoting (Nature Research, 2020)Understanding the cytoarchitecture and wiring of the brain requires improved methods to record and stimulate large groups of neurons with cellular specificity. This requires miniaturized neural interfaces that integrate into brain tissue without altering its properties. Existing neural interface technologies have been shown to provide high-resolution electrophysiological recording with high signal-to-noise ratio. However, with single implantation, the physical properties of these devices limit their access to one, small brain region. To overcome this limitation, we developed a platform that provides three-dimensional coverage of brain tissue through multisite multifunctional fiber-based neural probes guided in a helical scaffold. Chronic recordings from the spatially expandable fiber probes demonstrate the ability of these fiber probes capturing brain activities with a single-unit resolution for long observation times. Furthermore, using Thy1-ChR2-YFP mice we demonstrate the application of our probes in simultaneous recording and optical/chemical modulation of brain activities across distant regions. Similarly, varying electrographic brain activities from different brain regions were detected by our customizable probes in a mouse model of epilepsy, suggesting the potential of using these probes for the investigation of brain disorders such as epilepsy. Ultimately, this technique enables three-dimensional manipulation and mapping of brain activities across distant regions in the deep brain with minimal tissue damage, which can bring new insights for deciphering complex brain functions and dynamics in the near future.
- Using Drosophila Two-Choice Assay to Study Optogenetics in Hands-On Neurobiology Laboratory ActivitiesFu, Zhuo; Huda, Ainul; Kimbrough, Ian F.; Ni, Lina (Faculty for Undergraduate Neuroscience, 2023)Optogenetics has made a significant impact on neuroscience, allowing activation and inhibition of neural activity with exquisite spatiotemporal precision in response to light. In this lab session, we use fruit flies to help students understand the fundamentals of optogenetics through hands-on activities. The CsChrimson channelrhodopsin, a light-activated cation channel, is expressed in sweet and bitter sensory neurons. Sweet sensory neurons guide animals to identify nutrient-rich food and drive appetitive behaviors, while bitter sensory neurons direct animals to avoid potentially toxic substances and guide aversive behavior. Students use two-choice assays to explore the causality between the stimulation activation of these neurons and the appetitive and avoidance behaviors of the fruit flies. To quantify their observations, students calculate preference indices and use the Student’s t-test to analyze their data. After this lab session, students are expected to have a basic understanding of optogenetics, fly genetics, sensory perception, and how these relate to sensory-guided behaviors. They will also learn to conduct, quantify, and analyze two-choice behavioral assays.
- Vascular Amyloid in an Alzheimer's Mouse ModelStublen, Andrew; Mills, William; Sontheimer, Harald; Kimbrough, Ian F. (2018-08)Alzheimer disease accounts for ~80% of dementia cases worldwide. Traditionally, one of the pathological hallmarks of this disease is Amyloid beta (A ) plaques. A is a 36-43 amino acid peptide formed from improperly cleaved amyloid precursor protein (APP). When APP is cleaved incorrectly in the brain, it forms sticky monomers. These monomers can usually be cleared from the brain and do not pose any hazards to normal brain functioning. However, in cases of disease these monomers can clump together to form A oligomers, or plaques. In addition to plaques, incorrectly cleaved A can also aggregate on vessels in the brain. Previous research has shown that these amyloid aggregates can displace astrocytic endfeet from blood vessels. This can cause the blood brain barrier to leak and prevent proper regulation of the diameter of vessels in the brain. This regulatory ability of the vessels in the brain is called functional hyperemia, and it enables precise control of where nutrient- lled blood is directed. When vascular amyloid surrounds the vessel and displaces astrocytic endfeet, it has been shown to cause a loss of this ability. This inhibits the brain’s ability to direct nutrients to areas of need and could be a major contributor to the cognitive decline seen in patients with Alzheimer Disease. In addition, any leakage of the blood brain barrier is very unhealthy for the surrounding tissue, as the blood brain barrier exists for the purpose of keeping toxins separate from the brain parenchyma. We do not currently understand how exactly these vascular amyloid plaques cause blood brain barrier failure. However, we have found that areas of the vasculature laden with vascular amyloid do demonstrate a downregulation in expression of the tight junction proteins ZO1 and Claudin 5. These tight junction proteins are responsible for holding the endothelial cells of the vasculature together to seal the blood brain barrier. To demonstrate that this decreased expression of tight junction proteins was not just a failure of the antibodies to penetrate through the vascular amyloid, the tissue was also stained for vinculin, a component of the cytoskeleton found directly beside these tight junctions. There was no di erence in vinculin labeling between areas with and without an amyloid burden, indicating that the amyloid is not preventing antibody penetration and that there is a true loss of tight junction protein expression. Addionally, we studied whether these damaging vascular amyloid plaques display a preference for certain kinds of vessels in the brain, based either on vessel size or vessel type. We showed that vascular amyloid does have a preference for arterioles and venules over capillaries, arteries, and veins. However, we were unable to distinguish with certainty whether amyloid displayed a preference for either arterioles or venules due to shortcomings in our DIC imaging.