HHMI Janelia Research Campus

Ashburn, VA, United States

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Ashburn, VA, United States
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News Article | April 10, 2017
Site: www.medicalnewstoday.com

Biomedical engineers have developed a way to deliver drugs to specific types of neurons in the brain, providing an unprecedented ability to study neurological diseases while also promising a more targeted way to treat them. Drugs are the tool of choice for studying the connections between neurons, and continue to be the mainstream treatment for neurological disease. But a major drawback in both endeavors is that the drugs affect all types of neurons, complicating the study of how cell receptors in the synapse - the gap between neurons - work in an intact brain, and how their manipulation can lead to clinical benefits and side effects. A new method named DART (Drugs Acutely Restricted by Tethering) may overcome these limitations. Developed by researchers at Duke University and the Howard Hughes Medical Institute, DART offers researchers the first opportunity to test what happens when a drug is targeted exclusively to one cell type. In its inaugural study, DART reveals how movement difficulties in a mouse model of Parkinson's Disease are controlled by the AMPA receptor (AMPAR) - a synaptic protein that enables neurons to receive fast incoming signals from other neurons in the brain. The results reveal why a recent clinical trial of an AMPAR-blocking drug failed, and offer a new approach to using the pharmaceutical. The paper appeared online in the journal Science. "This study marks a major milestone in behavioral neuropharmacology," said Michael Tadross, assistant professor of biomedical engineering, who is in the process of moving his laboratory from the HHMI Janelia Research Campus to Duke. "The insights we gained in studying Parkinson's mice were unexpected and could not have been obtained with any previous method." DART works by genetically programming a specific cell type to express a sort of GPS beacon. The "beacon" is an enzyme borrowed from bacteria that is inert - it does nothing more than sit on the cell surface. Nothing, that is, until researchers deliver drugs loaded with a special homing device. Researchers administer these drugs at such low doses that they do not affect other cells. Because the homing system is so efficient, however, the drug is captured by the tagged cells' surface, accumulating within minutes to concentrations that are 100 to 1,000 times higher than anywhere else. In an experiment using a mouse model of Parkinson's disease, Tadross and colleagues attached the homing signal beacon to two types of neurons found in the basal ganglia - the region of the brain responsible for motor control. One type, referred to as D1 neurons, are believed to give a "go" command. The other, referred to as D2 neurons, are thought to do just the opposite, providing commands to stop movements. Using DART, Tadross delivered an AMPAR-blocking pharmaceutical to only D1-neurons, only D2-neurons, or both. When delivered to both cell types simultaneously, the drugs improved only one of several components of motor dysfunction - mirroring the lackluster results of recent human clinical trials. The team then found that delivering the drug to only the D1/"go" neurons did absolutely nothing. Surprisingly, however, by targeting the same drug to D2/"stop" neurons, the mice's movements became more frequent, faster, fluid and linear - in other words, much closer to normal. While the drug stops neurons from receiving certain incoming signals, it does not completely shut them down. This nuance is particularly important for a subset of the D2 neurons that have two prominent forms of firing. With DART, these components could be separately manipulated, providing the first evidence that Parkinson's motor deficits are attributable to the AMPAR-based component of firing in these cells. Tadross said this level of nuance could not have been obtained with prior cell type-specific methods that completely shut neurons down. "Already in our first use of DART, we've learned something new about the synaptic basis of circuit dysfunction in Parkinson's disease," said Tadross. "We've discovered that targeting a specific receptor on specific types of neurons can lead to surprisingly potent improvements." Tadross is already looking into how this discovery might translate into a new therapy by delivering drugs to these neurons through an emerging viral technique. He is also beginning work to develop a version of DART that does not need the genetically added homing beacon to work. Both efforts will require years of research before seeing fruition - but that's not stopping Tadross. "All too often in basic science, approaches are developed that may 'one day' make a difference to human health," he said. "At Duke, there's a palpable emphasis on providing new treatments to people as quickly as possible. I'm very excited that in this environment, my lab can work collaboratively with scientists, physicians, and biotech to solve the real-world challenges involved." This research was funded by the Howard Hughes Medical Institute.


Dyakova O.,Uppsala University | Lee Y.-J.,Uppsala University | Longden K.D.,HHMI Janelia Research Campus | Kiselev V.G.,Albert Ludwigs University of Freiburg | And 2 more authors.
Nature Communications | Year: 2015

Animal sensory systems are optimally adapted to those features typically encountered in natural surrounds, thus allowing neurons with limited bandwidth to encode challengingly large input ranges. Natural scenes are not random, and peripheral visual systems in vertebrates and insects have evolved to respond efficiently to their typical spatial statistics. The mammalian visual cortex is also tuned to natural spatial statistics, but less is known about coding in higher order neurons in insects. To redress this we here record intracellularly from a higher order visual neuron in the hoverfly. We show that the cSIFE neuron, which is inhibited by stationary images, is maximally inhibited when the slope constant of the amplitude spectrum is close to the mean in natural scenes. The behavioural optomotor response is also strongest to images with naturalistic image statistics. Our results thus reveal a close coupling between the inherent statistics of natural scenes and higher order visual processing in insects. © 2015 Macmillan Publishers Limited.


Parag T.,HHMI Janelia Research Campus | Ciresan D.C.,University of Applied Sciences and Arts Southern Switzerland | Giusti A.,University of Applied Sciences and Arts Southern Switzerland
Proceedings of the IEEE International Conference on Computer Vision | Year: 2016

The prospect of neural reconstruction from Electron Microscopy (EM) images has been elucidated by the automatic segmentation algorithms. Although segmentation algorithms eliminate the necessity of tracing the neurons by hand, significant manual effort is still essential for correcting the mistakes they make. A considerable amount of human labor is also required for annotating groundtruth volumes for training the classifiers of a segmentation framework. It is critically important to diminish the dependence on human interaction in the overall reconstruction system. This study proposes a novel classifier training algorithm for EM segmentation aimed to reduce the amount of manual effort demanded by the groundtruth annotation and error refinement tasks. Instead of using an exhaustive pixel level groundtruth, an active learning algorithm is proposed for sparse labeling of pixel and boundaries of superpixels. Because over-segmentation errors are in general more tolerable and easier to correct than the under-segmentation errors, our algorithm is designed to prioritize minimization of false-merges over false-split mistakes. Our experiments on both 2D and 3D data suggest that the proposed method yields segmentation outputs that are more amenable to neural reconstruction than those of existing methods. © 2015 IEEE.


Hao X.,HHMI Janelia Research Campus | Hao X.,Zhejiang University | Martin-Rouault L.,HHMI Janelia Research Campus | Cui M.,HHMI Janelia Research Campus
Scientific Reports | Year: 2014

Controlling the propagation of electromagnetic waves is important to a broad range of applications. Recent advances in controlling wave propagation in random scattering media have enabled optical focusing and imaging inside random scattering media. In this work, we propose and demonstrate a new method to deliver optical power more efficiently through scattering media. Drastically different from the random matrix characterization approach, our method can rapidly establish high efficiency communication channels using just a few measurements, regardless of the number of optical modes, and provides a practical and robust solution to boost the signal levels in optical or short wave communications. We experimentally demonstrated analog and digital signal transmission through highly scattering media with greatly improved performance. Besides scattering, our method can also reduce the loss of signal due to absorption. Experimentally, we observed that our method forced light to go around absorbers, leading to even higher signal improvement than in the case of purely scattering media. Interestingly, the resulting signal improvement is highly directional, which provides a new means against eavesdropping.


Bogovic J.A.,HHMI Janelia Research Campus | Hanslovsky P.,HHMI Janelia Research Campus | Wong A.,HHMI Janelia Research Campus | Saalfeld S.,HHMI Janelia Research Campus
Proceedings - International Symposium on Biomedical Imaging | Year: 2016

Multi-modal image registration is a challenging task that is vital to fuse complementary signals for subsequent analyses. Despite much research into cost functions addressing this challenge, there exist cases in which these are ineffective. In this work, we show that (1) this is true for the registration of in-vivo Drosophila brain volumes visualizing genetically encoded calcium indicators to an nc82 atlas and (2) that machine learning based contrast synthesis can yield improvements. More specifically, the number of subjects for which the registration outright failed was greatly reduced (from 40% to 15%) by using a synthesized image. © 2016 IEEE.


Cui M.,HHMI Janelia Research Campus
Frontiers in Optics, FiO 2014 | Year: 2014

We developed a super-penetration microscope that effectively compensates the wavefront distortion encountered in scattering biological systems. We report high-resolution in vivo imaging of mouse cerebral cortex at large depth and noninvasive imaging through intact mouse skull.


Hanslovsky P.,HHMI Janelia Research Campus | Bogovic J.A.,HHMI Janelia Research Campus | Saalfeld S.,HHMI Janelia Research Campus
Proceedings - International Symposium on Biomedical Imaging | Year: 2015

Serial section Microscopy is an established method for volumetric anatomy reconstruction. Section series imaged with Electron Microscopy are currently vital for the reconstruction of the synaptic connectivity of entire animal brains such as that of Drosophila melanogaster. The process of removing ultrathin layers from a solid block containing the specimen, however, is a fragile procedure and has limited precision with respect to section thickness. We have developed a method to estimate the relative z-position of each individual section as a function of signal change across the section series. First experiments show promising results on both serial section Transmission Electron Microscopy (ssTEM) data and Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) series. We made our solution available as Open Source plugins for the TrakEM2 software and the ImageJ distribution Fiji. © 2015 IEEE.


Apostolides P.F.,HHMI Janelia Research Campus | Milstein A.D.,HHMI Janelia Research Campus | Grienberger C.,HHMI Janelia Research Campus | Bittner K.C.,HHMI Janelia Research Campus | Magee J.C.,HHMI Janelia Research Campus
Neuron | Year: 2016

In CA1 pyramidal neurons, correlated inputs trigger dendritic plateau potentials that drive neuronal plasticity and firing rate modulation. Given the strong electrotonic coupling between soma and axon, the >25 mV depolarization associated with the plateau could propagate through the axon to influence action potential initiation, propagation, and neurotransmitter release. We examined this issue in brain slices, awake mice, and a computational model. Despite profoundly inactivating somatic and proximal axon Na+ channels, plateaus evoked action potentials that recovered to full amplitude in the distal axon (>150 μm) and triggered neurotransmitter release similar to regular spiking. This effect was due to strong attenuation of plateau depolarizations by axonal K+ channels, allowing full axon repolarization and Na+ channel deinactivation. High-pass filtering of dendritic plateaus by axonal K+ channels should thus enable accurate transmission of gain-modulated firing rates, allowing neuronal firing to be efficiently read out by downstream regions as a simple rate code. CA1 pyramidal neurons generate unique spike bursts known as complex spikes, characterized by a profound decrease in action potential amplitude. Apostolides et al. investigate how action potentials of varying amplitudes are transformed into all-or-none signals in the axon. © 2016 Elsevier Inc.


Dolan M.-J.,University of Cambridge | Dolan M.-J.,HHMI Janelia Research Campus | Huoviala P.,University of Cambridge | Jefferis G.,University of Cambridge
Current Biology | Year: 2015

The same sensory signal can be interpreted differently according to context. A new study in Drosophila uses cell-type-specific tools to identify neural circuits that integrate context during olfactory processing and surprisingly implicates memory-recall neurons. © 2015 Elsevier Ltd.


Chhetri R.K.,HHMI Janelia Research Campus | Keller P.J.,HHMI Janelia Research Campus
eLife | Year: 2016

A custom-built objective lens called the Mesolens allows relatively large biological specimens to be imaged with cellular resolution. © Chhetri and Keller.

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