Enigma is an acronym for Enhancing Neuro Imaging Genetics through Meta Analysis. ENIGMA has found 8 common gene mutations leading to brain age in over 30,000 brain scans that may some day unlock mysteries of Alzheimer’s, autism and other neurological disorders.
OnAir Post: ENIGMA mapping brain’s genetic code
The site will help to accelerate the advance of neuroscience research by providing a centralized resource for collecting and comparing data on neuronal function.
OnAir Post: NeuroElectro.org – Wikipedia for Neurons
Principal Investigator: Lawrence Wald Neuroscience@Harvard Title: “Magnetic Particle Imaging (MPI) for Functional Brain Imaging in Humans” BRAIN Category: Next Generation Human Imaging (RFA MH-14-217)
The Wald team plans to use an iron-oxide contrast agent to track blood volume, which will permit dramatically more sensitive imaging of human brain activity than existing methods.
Schematic set up and operating principle of the Magnetic Particle Imaging technology. Phillips MPI.
In this planning grant we propose several engineering developments to advance Magnetic Particle Imaging (MPI) to replace MRI as the next-generation functional brain imaging tool for human neuroscience. We assemble a group of technology experts to solve a myriad of identified and unidentified barriers, we employ simulation and bench-top experiments to characterize and test solutions for these technical obstacles and validate solutions by bench testing specific sub-sections of the imager. Finally we simulate the overall performance of the planned device and assess its benefit for human functional brain imaging. MPI is a young but extremely promising technology that uses the nonlinear magnetic response of iron- oxide nanoparticles to localize their presence in the body. MPI directly detects the nanoparticle’s magnetization rather than using secondary effects on the Magnetic Resonance relaxation times. ...
OnAir Post: Magnetic Particle Imaging (MPI)
Principal Investigator: Michael Garwood Institute for Translational Neuroscience, University of Minnesta Title: “Imaging Brain Function in Real World Environments & Populations with Portable MRI” BRAIN Category: Next Generation Human Imaging (RFA MH-14-217)
By employing smaller, less cumbersome magnets than used in existing MRI, Dr. Garwood and colleagues will create a downsized, portable, less expensive brain scanner.
Functional magnetic resonance imaging (fMRI) continues to play a critical role in understanding the human brain. Yet current fMRI technology is far less than ideal for studying brain function due to the unnatural environment and restricting space of the magnet bore. Furthermore, fMRI cannot be performed on subjects who have metallic implants in their body (e.g., the elderly, soldiers and veterans), or who are impaired by certain physical disabilities as occurs in a variety of neurological and vestibular disorders. Finally, due to its expense and infrastructure requirements, MRI’s predominant accessibility to wealthier institutions has resulted in a highly biased subject sampling and a shortage of studies in non-western environments and cultures. The general methodology used to obtain MR images today is essentially the same as that used approximately 4 decades ago. One major drawback of such methodology is that the tolerated magnetic field variation over the brain is ...
OnAir Post: Imaging Brain Function with Portable MRI
PI: Robert Desimone Massachusetts Institute of Technology Title: “Vascular Interfaces for Brain Imaging and Stimulation” BRAIN category: Next Generation Human Imaging (RFA MH-14-217)
Dr. Desimone’s project will access the brain through its network of blood vessels to less invasively image, stimulate and monitor electrical and molecular activity than existing methods.
Sketch showing constitution of blood vessels inside the brain. Credit: Armin Kübelbeck
Functional MRI (fMRI), EEG, and other completely noninvasive modalities for large-scale imaging of human brain activity have pioneeringly revealed many human brain functions, but cannot reach the single-neuron, single-spike level of neural code analysis possible in animals obtained using electrodes. This is partly due to the indirect methods of observation employed (e.g., blood flow for fMRI) and due to blurring of signals over distance by the skull (e.g., for EEG). In contrast, invasive approaches such as trans-cranially implanted multi- electrode arrays can achieve single-cell, single-spike resolution, but they necessitate opening of the skull – and, for implanted arrays, damage of the brain tissue – limiting utility to a small fraction of the population, those undergoing neurosurgery for some intractable brain disorder that justifies the risk. Trans-cranially implanted arrays also degrade i performance over time ...
OnAir Post: Vascular Interfaces for Brain Imaging
Principal Investigator: Julie Brefczynski-Lewis WVU Center for Neuroscience Title: Imaging the Brain in Motion: The Ambulatory Micro-Dose, Wearable PET Brain Imager BRAIN Category: Next Generation Human Imaging (RFA MH-14-217)
Dr. Brefczynski-Lewis and co-workers will engineer a wearable PET scanner that images activity of the human brain in motion – for example, while taking a walk in the park.
Brefczynski-Lewis, assisted by graduate student Chris Bauer, dons her PET-helmet prototype to demonstrate the device’s portability. (Lois Raimondo/For The Washington Post)
Our vision is to design the first truly mobile molecular brain imager that can be used on healthy subjects to study the functioning of the human brain during motion. The ultimate goal is to be able to image subjects during a proverbial “walk in the park” and other natural activities. We selected PET technology as the most likely to succeed in the next decade to provide the desired functionality of such a brain imager. While MRI is an exceptionally powerful and versatile imaging modality, and there are even upright MRIs for structural brain scans, for functional fMRI scans the subjects must stay still and in horizontal position inside a narrow bore of a strong-field MRI magnet. What we ...
OnAir Post: Micro-Dose, Wearable PET Brain Imager
Principal Investigator: Ian Wickersham MIT Neuroscience Title: “Novel technologies for nontoxic transsynaptic tracing” BRAIN Category: Tools for Cells and Circuits (RFA MH-14-216)
Dr. Wickersham and colleagues will develop nontoxic viral tracers to assist in the study of neural circuitry underlying complex behaviors.
(a–c) Injection site in mouse somatosensory thalamus of an equal mixture of two deletion-mutant rabies viral vectors: VSVG-enveloped vector encoding mOrange2 (yellow), and an RVG-enveloped vector encoding mCherry (red). The VSVG-enveloped vector prolifically infects thalamic neurons at the injection site, whereas the RVG-enveloped one infects far fewer cells locally. (d–f) In the somatosensory cortex of the same mouse, mOrange2-filled thalamocortical axons ascend to layer 4 and densely ramify among the apical dendrites of mCherry-filled layer 6 corticothalamic cells retrogradely infected by the co-injected retrograde virus. Scale bar, 200 μm, applies to all panels.
Genetic tools have dramatically increased the power and resolution of neuroscientific experiments, allowing monitoring and perturbation of specific neuronal populations within the brain, often in the context of complex cognitive and behavioral paradigms. However, the usefulness of these tools is limited by the available means of delivering them in circuit-specific ways, a major drawback in view of the critical importance of specific connectivity ...
OnAir Post: Nontoxic transsynaptic tracing
Principal Investigator: Michael Dickinson Caltech Neuroscience Title: “Integrative Functional Mapping of Sensory-Motor Pathways” BRAIN Category: Understanding Neural Circuits (RFA NS-14-009)
Dr. Dickinson will lead an interdisciplinary team to study how the brain uses sensory information to guide movements, by recording the activity of individual neurons from across the brain in fruit flies, as they walk on a treadmill and see and smell a variety of sights and odors.
Flying Patch Clamp. Meausuring interneurons while flying.
The goal of the project team is to develop a robust, multi-lab research framework, enabled by large scale imaging, which will lead to principled integrative models of ethologically-relevant behaviors that incorporate a detailed knowledge of individual cell classes. The specific neurobiological question that the team will address is how the brain integrates sensory information in order to guide locomotion in a particular direction. Our strategy is to systematically map and functionally characterize the neural circuits that underlie goal-directed locomotion, using the fruit fly, Drosophila, in order to exploit the convergence of powerful genetic, optical, behavioral, and analytical tools that are available in this species. The proposal focuses primarily on refining functional imaging approaches to map the activity of small ...
OnAir Post: Mapping Sensory-Motor Pathways
PI: Sebastian Seung, Princeton University Title: “Vertically integrated approach to visual neuroscience: microcircuits to behavior” BRAIN category: Understanding Neural Circuits (RFA NS-14-009)
Dr. Seung and colleagues Thomas Euler (U Tübingen), Andrew Huberman (UC San Diego), Markus Meister (Caltech), and Rachel Wong (UW Seattle) will use state-of-the-art genetic, electrophysiological, and imaging tools to map the connectivity of the retina, the light-sensing tissue in the eye. The goal is to delineate all the retina’s neural circuits and define their specific roles in visual perception and behavior.
Visual neuroscience is finally beginning to achieve a “vertically integrated” understanding of the retina, bridging all levels from molecules to microcircuits to behavior. Success could be achieved for all retinal microcircuits in just a decade, if progress were sped up drastically. Such acceleration will be attained by generating the following foundational data and disseminating it to the community. (1) We will use genetic control of ganglion cell types to pinpoint their specific roles in a suite of ethologically relevan, visually guided behaviors. Our functional explorations will be guided by the tracing of downstream pathways into subcortical and cortical regions using genetic techniques. (2) We will apply two-photon calcium imaging and serial electron microscopy to a single patch of ...
OnAir Post: Integrated approach to visual neuroscience
PI: Alan Jasanoff Massachusetts Institute of Technology Title: “Calcium sensors for molecular fMRI” BRAIN category: Large-Scale Recording-Modulation – New Technologies (RFA NS-14-007)
Dr. Jasanoff’s team will synthesize calcium-sensing contrast agents that will allow functional magnetic resonance imaging (fMRI) scans to reveal activity of individual brain cells.
The development of minimally invasive direct readouts of neural activity is one of the greatest challenges facing neuroscience today. Our recent work has shown that it is possible to perform high resolution functional magnetic resonance imaging (fMRI) of molecular-level phenomena using MRI contrast agents sensitive to hallmarks of neurotransmitter release. An even more valuable contribution would be the creation of calcium sensors suitable for molecular fMRI of intracellular neural signaling processes. Functional imaging performed with these sensors would combine the noninvasiveness and whole-brain coverage of MRI with the molecular specificity and broad applicability of established optical calcium neuroimaging techniques. Calcium-dependent fMRI will be a breakthrough technique for analysis of neural circuits in animals, with potential longer term applications in humans. The technique could achieve cellular resolution in conjunction with ultrahigh field MRI scanners and cell labeling techniques. A major hurdle in realizing this advance is the creation of effective calcium-dependent MRI contrast agents, however. This proposal describes ...
OnAir Post: Calcium sensors for molecular fMRI
Principal Investigator: Elly Nedivi Massachusetts Institute of Technology Title: “Next generation high-throughput random access imaging, in vivo” BRAIN category: Large-Scale Recording-Modulation – Optimization (RFA NS-14-008)
Dr. Nedivi’s team proposes a new imaging technology to simultaneously record activity at each of the thousands of synapses, or communication points, on a single neuron.
https://www.youtube.com/watch?v=lHLSFhp5HawVideo can’t be loaded because JavaScript is disabled: Neurotech 1: Multi-Photon Microscopy (https://www.youtube.com/watch?v=lHLSFhp5Haw)The goal of this proposal is to develop new methods for high speed monitoring of sensory-driven synaptic activity across all inputs to single living neurons in the context of the intact cerebral cortex. Although our focus is on understanding how synaptic inputs are integrated across a single neuron embedded in an intact circuit, the next generation random access imaging technology we propose is more broadly applicable for monitoring multi-cellular activity representing large intra-and inter areal neuronal networks. The approach improves on the speed and sensitivity of current random-access technology by nearly 2 orders of magnitude, enabling high- throughput interrogation of up to 104 independent locations within a fraction of a millisecond and compatible with imaging using next generation voltage sensitive indicators. ...
OnAir Post: Next generation imaging in vivo
Researchers at the Howard Hughes Medical Institute Janelia Research campus are using a new type of computer software to track and image how a nervous system develops in unprecedented detail. The new system is able to track individual cells during embryonic development, giving scientists a powerful to tool to create a blueprint of how brains form. Ben Gruber reports, Reuters.
Published Aug. 6, 2014 by Reuters
OnAir Post: Unraveling embryonic development cell by cell
https://www.youtube.com/watch?v=2R2ll9SRCeoVideo can’t be loaded because JavaScript is disabled: Eric Betzig: Imaging Life at High Spatiotemporal Resolution (https://www.youtube.com/watch?v=2R2ll9SRCeo)
In this lecture, held on 3/9/15 at UC Berkeley, Nobel Laureate Eric Betzig, describes three areas focused on addressing the challenges of high resolution imaging: super-resolution microscopy; plane illumination microscopy using non-diffracting beams; and adaptive optics to recover optimal images from within optically heterogeneous specimens.
Published on March 15, 2015 by UC Berkeley Events
OnAir Post: Imaging Life at High Spatiotemporal Resolution
https://www.youtube.com/watch?v=GcQ24khZzvUVideo can’t be loaded because JavaScript is disabled: Eric Betzig and Harald Hess (Janelia Farm/HHMI): Developing PALM Microscopy (https://www.youtube.com/watch?v=GcQ24khZzvU)
During their 20-year friendship, Eric Betzig and Harald Hess, now at Janelia Farm/HHMI, worked together and separately, in academia and industry, before eventually joining forces to develop the first super-high-resolution PALM microscope.
They tell us the story of this journey and emphasize how their unusual and varied backgrounds provided the skills to complete the project.
Uploaded on Jan. 8, 2011 by iBioMagazine
OnAir Post: Betzig and Hess: Developing PALM Microscopy
https://www.youtube.com/watch?v=esC6cr6qfs8Video can’t be loaded because JavaScript is disabled: Resolving Everything (https://www.youtube.com/watch?v=esC6cr6qfs8)
Harald Hess of the Janelia Research Campus of the Howard Hughes Medical Institute describes his path in basic physics, industry and biology and how the challenge of resolution in microscopy has guided and inspired his research.
Published April 1, 2015 by the National High Magnetic Field Laboratory
OnAir Post: Resolving Everything: Harald Hess
“A platform for large-scale neuroscience” Jeremy Freeman (HHMI Janelia Farm Research Campus)
Filmed and recorded live at Spark Summit 2014 in San Francisco at the Westin St. Francis.
Published on July 17, 2014 by Apache Spark
OnAir Post: Platform for large-scale neuroscience
“Tools for studying neurons, the only important cells in the brain” from the Glia in Health & Disease 7/19/2014
Presented by Dr. Loren Looger, HHMI Janelia Farm Part of Cold Springs Harbor Laboratory Keynote lecture series
Pulbished on July 21, 2014 by CSHL Leading Strand
OnAir Post: Tools for studying neurons: Loren Looger
Using a new high-speed, high-resolution imaging method, researchers at Washington University were able to see blood flow, blood oxygenation, oxygen metabolism, and other functions inside a living mouse brain at faster rates than ever before.
The new method is called “photoacoustic microscopy” (PAM), a single-wavelength, pulse-width-based technique developed by Lihong Wang, PhD, the Gene K. Beare Professor of Biomedical Engineering in the School of Engineering & Applied Science, and his team.
Schematic of fast functional photoacoustic microscopy (PAM) of the mouse brain. OAC, optical-acoustic combiner; PBS, polarizing beam splitter; UT, ultrasonic transducer. (credit: Junjie Yao et al./Nature).
Washington University in St. Louis 3/30/15 by Beth Miller
These images show fast functional photoacoustic microscopy of the mouse brain. Figure (d) shows a representative x-y projected brain vasculature image through an intact skull. Figure (e) shows a representative enhanced x-z projected brain vasculature image. Figure (f) shows photoacoustic microscopy of oxygen saturation of hemoglobin in the mouse brain, acquired by using the single-wavelength pulse-width-based method with two lasers.Researchers studying cancer and other invasive diseases rely on high-resolution imaging to see tumors and ...
OnAir Post: Rapid imaging of a living brain
Assistant Professor, Department of Biochemistry and Molecular Medicine, UC Davis Director, Tian Lab
The goal of Tian’s research is to invent new molecular tools for analyzing and engineering functional neural circuits. We also leverage these tools, combined with optical imaging techniques, to study molecular mechanisms of neurological disorders at system level and to empower searching for novel therapeutic treatments.
Webpage: ucdmc.ucdavis.edu/biochem/faculty/tian/ UC Davis Neuroscience Brain Initiative Grant
Email: lintian@ucdavis.edu Phone: (916) 734-8070 Address: 2352 Oak Park Research Building Sacramento Campus
I was born and raised in China. After graduating from University of Science and Technology of China, I joined a interdisciplinary PhD program at Northwestern University, where I studied the mechanisms of protein processing via ubiquitin-proteasome pathway in Dr. Andreas Matouschek’s lab. I then moved to HHMI Janelia Farm as a postdoc. The highly collaborative environment at Janelia resulted in my multidisciplinary training under three principle investigators, Dr. Loren Looger, Dr. Karel Svoboda and Dr. Luke Lavis. There, my research focused on engineering optical probes for monitoring and controlling neural circuitry in living behaving animal. These new imaging techniques have greatly impacted the field of neuroscience, facilitating new types of biological experiments performed to address previously intractable questions. One indication of the impact of this ...
OnAir Post: Lin Tian, PhD – UC Davis
Professor of Physics, Applied Physics, and Bioengineering, CalTech Division of Engineering and Applied Sciences Director, Roukes Group
Roukes research activities are currently focused on developing advanced nanodevices, engineering them into complex systems, and using them to enable fundamental problems in neuroscience and proteomics. A continuing thread in theoretical and experimental investigations focuses on fundamental properties of nanomechanical systems.
Lab webpage: caltech.edu/people/3185/profile Division webpage: nano.caltech.edu/people/roukes Caltech Neuroscience Brain Initiative Grant
Email: roukescaltech.edu Phone: 626-395-2916 Address: MC 149-33Pasadena, CA 91125
B.A., University of California (Santa Cruz), 1978; Ph.D., Cornell University, 1985. Associate Professor, Caltech, 1992-96; Professor of Physics, 1996-2002; Professor of Physics, Applied Physics, and Bioengineering, 2002-11; Abbey Professor, 2011-; Director, Kavli Nanoscience Institute, 2004-06; Co-Director, 2008-2013.
Professor Roukes’s research focuses on nanobiotechnology, nanotechnology, nanoscale physics, nanoscale and molecular mechanics.
nanobiotechnology, nanotechnology, nanoscale physics, nanoscale and molecular mechanics
The Kavli Nanoscience Institute, Center for the Physics of Information
OnAir Post: Michael Roukes, PhD – CalTech
Principal Investigator: Florian Engert Program in Neuroscience @Harvard Title: “Neural circuits in zebrafish: form, function and plasticity” BRAIN Category: Understanding Neural Circuits (RFA NS-14-009)
Dr. Engert’s team will combine a wide array of cutting-edge neuroscience techniques to watch the entire brain activity of a see-through fish while it swims, and to make detailed maps of its brain circuitry.
n order to examine response properties of specific neuronal subpopulation in freely swimming larvae we have developed an imaging technique based on the bioluminescence of Aquorin-GFP that does not require excitation light and can therefore operate on a zero background signal 17. This optical signal can be collected with large angle optics and detected as a one-dimensional temporal signal by a photon multiplier tube. Figure 3 shows data from a first series of experiments in which Aquorin is expressed in the hypocretin system, a small nucleus consisting of less than 20 neurons that are known to regulate the sleep-wake cycle.The left side shows an in-vivo two-photon image of the transgenic fish and a diagram of the set-up. On the right side bioluminescence photon counts from the same fish are shown in green below traces describing the simultaneously monitored ...
OnAir Post: Neural circuits in zebrafish
Principal Investigator: Carlos D Brody Princeton Neuroscience Institute Title: “Mechanisms of neural circuit dynamics in working memory” BRAIN Category: Understanding Neural Circuits (RFA NS-14-009)
Dr. Brody and his colleagues will study the underlying neuronal circuitry that contributes to short-term “working” memory, using tools to record circuit activity across many brain areas simultaneously while rodents run on a track-ball through virtual mazes projected onto a screen.
Figure: A decision-making task requiring accumulation of evidence over time. The capacity to gradually and steadily accumulate evidence favoring one choice or another is thought to be a core component of many different types of decision-making. In order to establish a rodent model of this cognitive process, we developed a task in which subjects hear simultaneously presented trains of randomly timed clicks, one train coming from a speaker to their left, the other from a speaker to their right. At the end of the trains, the subjects have to decide which side played the greater total number of clicks. We were able to train rats to perform this task, and to show that well-trained animals use a strategy of accumulating clicks over time. Having established a behavior that depends on gradual ...
OnAir Post: Neural circuit dynamics in working memory
Principal Investigator: John Maunsell Neuroscience at University of Chicago Title: “The role of patterned activity in neuronal codes for behavior” BRAIN Category: Understanding Neural Circuits (RFA NS-14-009)
Dr. Maunsell’s team will explore how large populations of neurons process visual information, using a newly developed light stimulation technique to induce brain cell activity in the visual cortex of mice.
A key aspect of brain function is how the activity of neuronal populations encodes information that is used to guide behavior. A longstanding model system to understand population coding is the visual cerebral cortex, because its structure and anatomy are well understood, and because visual stimuli can be presented to subjects with high levels of temporal and spatial control. Thousands or more neurons fire action potentials in response to a single visual stimulus, and an important open question is how this population response carries information – how the detailed timing and pattern of these spikes across neurons is decoded to guide behavior. Because it is known that genetics controls the identity and morphology of neurons, and influences which other neurons they form synaptic partners with, it appears likely that the precise details of which neurons in a population fire spikes is vitally important for behavior. But ...
OnAir Post: Patterned activity and codes for behavior
Principal Investigator: Patrick Kanold UMD Neuroscience and Cognitive Science Title: “Crowd coding in the brain: 3D imaging and control of collective neuronal dynamics” BRAIN Category: Understanding Neural Circuits (RFA NS-14-009)
Dr. Kanold and his team propose cutting edge methods to stimulate neurons at different depths in the auditory cortex, and will use new computational methods to understand complex interactions between neurons in mice while testing their ability to hear different sounds.
To overcome this we extensively use in vivo 2-photon imaging which can detects the activity of many single neurons in the brain of a living animal. the image below on the left shows many neurons in the brain loaded with a Ca-indicator dye which reports neuronal activity.
The cortex is a laminated structure that is thought to underlie sequential information processing. Sensory input enters layer 4 (L4) from which activity quickly spreads to superficial layers 2/3 (L2/3) and deep layers 5/6 (L5/6) and other cortical areas eventually leading to appropriate motor responses. Sensory responses themselves depend on ongoing, i.e. spontaneous cortical activity, usually in the form of reverberating activit from within or distant cortical regions, as well as the state and behavioral context of the animal. Receptive ...
OnAir Post: Crowd coding in the brain
Principal Investigator: Chris Xu Cornell University Title: “Optimization of 3-photon microscopy for Large Scale Recording in Mouse Brain” BRAIN Category: Large-Scale Recording-Modulation – Optimization (RFA NS-14-008)
Dr. Xu and his collaborators will build new lasers and lenses to use three-photon microscopy to watch neuronal activity far deeper inside the brain than currently possible.
The goal of this research program is to optimize three-photon fluorescence microscopy (3PM) for large scale, noninvasive, volumetric imaging of neuronal activity. To leverage the superb performance of green-fluorescent protein based genetically engineered Ca-probes (e.g., GCaMPs), 3PM at the 1300-nm spectral window will be developed, which not only preserves the tissue penetration capability of 3PM at the longer excitation wavelength but also enables a wide variety of blue and green fluorophores, including a number of fluorescent proteins and Ca-indicators, to be excitable via three-photon excitation. To improve the signal-to-noise ratio (SNR) so that a practical frame rate can be achieved for imaging dynamic brain activity even at a penetration depth of 1.1 mm or beyond, new objective lenses will be designed and fabricated that will collect the signal efficiently at depth. In additin, the lens design will also support convenient integration with adaptive optics (AO), with the goal of making ...
OnAir Post: Optimization of 3-photon microscopy
Principal Investigator: Vincent Allen Pieribone Yale Neuroscience Title: “Development of Protein-based Voltage Probes” BRAIN Category: Large-Scale Recording-Modulation – Optimization (RFA NS-14-008)
Dr. Pieribone and his team will optimize fluorescent voltage probe technology, to allow scientists to measure the activity of thousands of neurons using only a camera and a microscope.
Fluorogenetic Voltage Sensors. From website.
The use of genetically encoded fluorescent activity probes represent the most advanced method to monitor the electrical activity of networks of neurons without using electrodes. While genetically encoded calcium indicators have been evolved to produce robust signals in a variety of different neuronal preparations, fluorescent probes of membrane potential have not been well evolved. Current voltage probes, while finally in expanded use, will need considerable improvement if the goal of recording the activity of a large number of neurons simultaneously in vivo is to be achieved. The goal of this project is to discover protein-based fluorescent voltage probes with signal to noise characteristics that allow routine optical recording of action potentials from single cortical neurons in vivo. We are seeking probes with significantly improved signal to noise characteristics, red-shifted fluorescence spectra, faster on and off rates and better plasma membrane expression. This ...
OnAir Post: Protein-based Voltage Probes
Principal Investigator: Mark J Schnitzer Stanford Neuroscience Title: “Protein voltage sensors: kilohertz imaging of neural dynamics in behaving animals” BRAIN Category: Large-Scale Recording-Modulation – Optimization (RFA NS-14-008)
Dr. Schnitzer and his team have created a new system for developing optical voltage sensors, which will allow scientists to simultaneously record firing of large groups of neurons or electrical activity in precise locations inside of neurons, such as synapses.
The diagrams show a hypothetical protein (orange oval) and the formation of an active site, which is due to a voltage-induced conformational change that is mediated by the defined regions of the protein (green and yellow cylinders). a | Charged amino acids may move within membranes in response to changes in voltage. The side groups of Asp and Arg are shown. b | Reorientation of an intrinsic residue dipole, such as Tyr, through changes in the field. c | An alpha-helix that is the length of the membrane (red to blue gradient) has a dipole moment that is equivalent to the length of the helix that separates plusminus0.5 electronic charges (e0); therefore, it can also reorientate when the field is changed. The oval that is attached to the alpha-helix ...
OnAir Post: Protein voltage sensor imaging in vivo
Principal Investigator: Fritjof Helmchen Zurich Brain Research Institute Title: “Multi-area two-photon microscopy for revealing long-distance communication between multiple local brain circuits” BRAIN Category: Large-Scale Recording-Modulation – Optimization (RFA NS-14-008)
Dr. Helmchen and his colleagues propose a system to simultaneously record neuronal activity in four different areas of the neocortex and discover how brain cells in different regions interact during specific behaviors.
Two-photon laser-scanning microscopy has become the method of choice for imaging nerual dynamics on the cellular level in the intact brain. The particular advantage of 2-photon microscopy is its reduced sensitivity to light scattering so that individual cells with their dendrites can be resolved several hundreds of micrometers deep in neural tissue in living animals.
Two-photon microscopy is a widely used, key method for functional imaging of cellular activity in living animals. Most recently, in vivo calciu imaging experiments have started to reveal the spatiotemporal activity patterns that occur in various areas of the neocortex during head-fixed mouse behavior. Typically, however, the field-of- view for imaging cellular activity is fairly small, on the order of a few hundred micrometers. This restriction limits the size of neuronal networks that can be studied and thus leaves open ...
OnAir Post: Multi-area two-photon microscopy
Principal Investigator: Baldwin Goodell Graymatter Research Title: “Large-Scale Electrophysiological Recording and Optogenetic Control System” BRAIN Category: Large-Scale Recording-Modulation – Optimization (RFA NS-14-008)
Dr. Goodell and his colleagues aim to develop optrodes, which are implantable columns of lights and wires for simultaneous electrical recording of neurons and delivery of light flashes to multiple brain areas.
Example data collected from 4 electrodes during a single recording session. A: short epoch of raw data sampled from 4 electrodes in area 7a of the posterior parietal cortex of an alert monkey. The signals are broadband (1 Hz to 10 kHz). Extracellular action potentials are visible as negative going spikes in the signals. B: plot of 1,000 superimposed waveforms extracted from the high-pass filtered signal on channel 3. The high-amplitude waveforms reveal a single unit that is well separated from the lower amplitude multiunit activity.
In order to gain a greater understanding of the neural mechanisms that mediate human cognitive function new approaches and technologies are needed to dramatically expand the ability to record and manipulate the activity of large numbers of neurons throughout widespread areas of the primate brain. Over the past 5-10 years, our groups have made two major ...
OnAir Post: Electrophysiological Recording and Control
PI: Tim Gardner, Laboratory of neural circuit formation Institution: Boston University (Charles River Campus) Title: “High-Density Recording and Stimulating Microelectrodes” BRAIN Category: Large-Scale Recording-Modulation – New Technologies (RFA NS-14-007)
Dr. Gardner and his colleagues will develop ultrathin electrodes that minimize tissue damage and are designed for long-term recording of neural electrical activity.
Time-frequency microstructure is unstable for regions of the time-frequency plane with spectrally dense content. For those regions, small changes in analysis parameters or added background noise in the signal can lead to changes in the details of a sonogram or contour shapes. Structurally unstable portions of the representation can be eliminated by showing only contour fragments that are in agreement across different angles and time-scales of analysis.The image below illustrates that process. On top, all long contours are shown, weighted by sonogram power.On bottom, only the structurally stable “consensus” elements are shown, also weighted by sonogram power.
This project seeks to develop a high density, minimally invasive electrode array for long-term recording and control of brain activity. Multielectrode arrays are an essential tool in experimental and clinical neuroscience, yet current arrays are severely limited by a mismatch between large or stiff electrodes and the fragile environment ...
OnAir Post: High-Density Recording Microelectrodes
Principal Investigator: Kendall H Lee Mayo Clinic Rochester Title: “Neurotransmitter Absolute Concentration Determination with Diamond Electrode” BRAIN Category: Large-Scale Recording-Modulation – New Technologies (RFA NS-14-007)
Dr. Kendall and his colleagues will develop diamond-coated electrodes to measure concentrations of the brain chemical dopamine more accurately and over long periods of time in the brain.
An implantable diamond-coated flexible electrode. Image from Qmed.
Determining the levels of neurotransmitters present in the living brain in real time is a matter of current scientific interest for research and clinicl reasons. Among these reasons is the need for understanding and mapping brain function and for improvement in the clinical application of deep brain stimulation (DBS). One analytical technique that holds potential promise in this application is fast-scan cyclic voltammetry (FSCV), however technical limitations have hindered its adoption for chronic in vivo use. Of particular difficulty has been the construction of a chronically-implantable FSCV electrode that possesses both the proper chemical properties for the monitoring of neurotransmitter levels as well as sufficient durability for chronic implantation in humans or animals. Carbon fiber has been used successfully under some circumstances, particularly at low voltage potentials, but at the higher voltages required for detection ...
OnAir Post: Diamond Electrodes for Measurement
Principal Investigator: Lin Tian UC Davis Neuroscience Title: ” Genetically encoded sensors for the biogenic amines: watching neuromodulation in action” BRAIN Category: Large-Scale Recording-Modulation – New Technologies (RFA NS-14-007)
Dr. Tian and her colleagues will create sensors that will allow researchers to see how molecules like dopamine, norepinephrine and serotonin regulate activity of neural circuits and behavior in living animals.
Genetically encoded indicators of neural activity.Fluorescent protein based biosensors can transfer changes in neural state (e.g. membrane potential or essential ion flux or enzyme activity) to fluorescence observables. They are genetically encoded, and can thus be used to label large populations of defined cell types and/or sub-cellular compartments.
The goal of this proposal is to develop a toolbox of genetically encoded indicators for biogenic amines, the most important family of neuromodulators. All nervous systems are subject to neuromodulation, which reconfigure the dynamics of neural circuitry by transforming the intrinsic firing properties of targeted neurons and regulating their synaptic plasticity. The altered dynamics of the neuromodulators have been implicated in a number of human neurological and psychiatric diseases, including Parkinson’s, schizophrenia and addiction. Biogenic amines are a group of neuromodulators used by all animal brains to regulate the ...
OnAir Post: Genetic sensors for biogenic amines
Principal Investigator: Loren Frank UCSF Neuroscience Title: ” Modular systems for measuring and manipulating brain activity” BRAIN Category: Large-Scale Recording-Modulation – New Technologies (RFA NS-14-007)
Dr. Frank and his colleagues will engineer a next-generation, all-in-one neural recording and stimulating system, which can simultaneously monitor thousands of neurons in the brain for several months while also delivering drugs, light or electrical pulses.
NSpike Instructions – The diagram shows the overall organization of the data acquisition system as it is used in the Frank lab,
The brain is a massively interconnected network of specialized circuits. Even primary sensory areas, once thought to support relatively simple, feed-forward processing, are now known to be parts of complex feedback circuits. All brain functions depend on millisecond timescale interactions across these brain networks, but current approaches cannot measure or manipulate these interactions with sufficient resolution to resolve them. We need the capacity to measure and manipulate the activity large ensembles of neurons distributed across anatomically or functionally connected circuits. That technology does not yet exist, a lack that motivates our efforts to develop a new system for large scale, multisite recording and manipulation that takes integrates biocompatible polymer electrodes, new headstage ...
OnAir Post: Modular systems measuring brain activity
Principal Investigator: Lihong Wang Washington University Neuroscience Program Title: “Fast High-Resolution Deep Photoacoustic Tomography of Action Potentials in Brains” BRAIN Category: Large-Scale Recording-Modulation – New Technologies (RFA NS-14-007)
Dr. Wang and his collaborators will test a way to image the electrical activity of neurons deep inside the brain, using a variation on ultrasound imaging he invented called photoacoustic tomography.
https://www.youtube.com/watch?v=yNPqOuk_YdgVideo can’t be loaded because JavaScript is disabled: Lihong Wang Hot Topics presentation: Photon-Phonon Synergy: Photoacoustic Tomography and Beyond (https://www.youtube.com/watch?v=yNPqOuk_Ydg)Revealing how our brain works is a great challenge but yet worth our every effort: it will not only illuminate the profound mysteries in science but also provide the key to understanding and treating neurological diseases such as Alzheimer’s and Parkinson’s. The objective of the proposed three-year research is to develop a high- speed, high-spatial-resolution, deep-penetration photoacoustic computed tomography (PACT) system for real- time imaging of action potentials in mouse brains. The proposed hardware imaging system will be unprecedented in the field of PACT in ...
OnAir Post: Deep Photoacoustic Tomography
Principal Investigator: Kit S. Lam UC Davis Center for Neuroscience Title: “Genetically encoded reporters of integrated neural activity for functional mapping of neural circuitry” BRAIN Category: Large-Scale Recording-Modulation – New Technologies (RFA NS-14-007)
Dr. Lam’s team plans to develop fluorescent sensors that will mark ion channels, molecules that help control information flow in the brain, and enable scientists to observe the neurons that are activated during a specific behavior, such as running.
Graphic from Shultz Chemical Cell Biology Group at Heidelberg
One of the major challenges in neuroscience is to link the structure to the function of neural circuits. To achieve this goal, we need to understand the connectivity between defined neuronal populations and the contribution of these neurons to physiological processes, behavioral responses and disease states. Recent advances in imaging techniques allow us to visualize the brain structure with cellular resolution. Application of the current generation of genetically encoded optical tools, such as sensors and controllers, is facilitating measurement and manipulation of neuron activity from molecular-defined cell populations in awake, behaving animals. However, probing the dynamics of neural circuitry underlying behavior, specifically for dissecting functional-defined circuitry beyond molecular-defined circuitry, not only depends on the improvement ...
OnAir Post: Genetically encoded reporters
Neuronal depolarization and neurotransmitter release underlie some of the most fundamental components of normal physiology and the etiology of brain pathophysiology. There is a tremendous need for high temporal resolution measurements of neurotransmitter release and its modulation of brain neuronal networks. While there has been progress in measuring neuronal depolarization in vivo in small animals, the current overall methodology of deployment, excitation and measurement of signal from voltage sensitive dyes (VSDs) commonly entails craniotomy and other invasive measures, and thus is currently only practical in rodent studies. We aim to develop a transformative brain imaging technique which will allow minimally invasive/non-invasive imaging of neuronal depolarization and related neurotransmitter release ultimately in the living human brain. While challenging methodologically, we believe that our team of multidisciplinary experts consisting of neuroscientists, neuropharmacologists, electrical and bioengineers, and brain imaging physicists and chemists, will be able to plan over a period of three years a practical and clear path to the development of such a potentially paradigm-shifting imaging technique. To do so, we propose three Aims. Aim 1 is to develop voltage sensitive probes for sub-millisecond measurements of membrane potentials and action potentials of cortical neurons in humans and other primates in vivo. ...
OnAir Post: Imaging in vivo neurotransmitter modulation
Principal Investigator: David Alan Feinberg Helen Wills Neuroscience Institute Title: “MRI Corticography (MRCoG): Micro-scale Human Cortical Imaging” BRAIN Category: Next Generation Human Imaging (RFA MH-14-217)
To image the activity and connections of the brain’s cortex on a micro scale – with dramatically higher resolution than existing scanners – Dr. Feinberg’s group will employ high sensitivity MRI coils that focus exclusively on the brain’s surface.
MRI is the only technology that can image the connectivity of the human brain in vivo and non-invasively. However, neither BOLD fMRI nor diffusion-based fiber tracking has been able to break the barrier of 1-mm voxel spatial resolution. Yet, 1-mm voxel contains roughly 50,000 neuronal cells and the human cortex is less than 5 mm thick. The disparity between the spatial scales has thus created a large gap between MRI studies of the whole brain and optical imaging and cell recordings of groups of neurons. The overarching objective of this proposal is to bring noninvasive human brain imaging into the microscale resolution and begin to bridge studies of neuronal circuitry and network organization in the human brain. Our breakthrough technology, termed MR Corticography (MRCoG), will achieve dramatic gains in spatial and temporal resolutions by focusing exclusively to the cortex. Higher-sensitivity ...
OnAir Post: MRI Corticography (MRCoG)
Principal Investigator: X. William Yang UCLA Neuroscience Title: “Novel Genetic Strategy for Sparse Labeling and Manipulation of Mammalian Neurons” BRAIN Category: Tools for Cells and Circuits (RFA MH-14-216)
Dr. Yang’s team will develop a new way to genetically target specific neurons, incorporating streamlined imaging and mapping methods that will enable the detection of sparse populations of cells that often elude existing methods.
Cajal revolutionized the study of the brain through the use of the Golgi stain to label cells sparsely and stochastically in a fashion that revealed a neuron’s morphology in its entirety. Although genetic tools for sparse and stochastic labeling and manipulation of single neurons in Drosophila have been used extensively over the past 15 years, they have only recently become available for mammalian systems, but the latter tools are limited to only a few systems for which cell-type specific reagents (e.g. enhancers) are available or otherwise involve cumbersome manipulations. Thus, there is an important need in the field to develop robust reagents for analysis of neurons at the level of single cells. Indeed, analysis of neurons at the single identified cellular level provides critical information on the control of neuronal morphology, connectivity, physiology and plasticity. This application is in response to BRAIN ...
OnAir Post: Genetic Sparse Labeling Mammalian Neuron
Principal Investigator: Pavel Osten Cold Spring Harbor Laboratory Title: “Towards quantitative cell type-based mapping of the whole mouse brain” BRAIN Category: Census of Cell Types (RFA MH-14-215)
The Osten team will develop an automated system to image different types of brain cells and their connections in mice, to pinpoint differences between males and females, across the lifespan.
3-D rendering of coronal section of a mouse brain imaged with STP tomography at 20x at a resolution of half a micron. GFP-expressing pyramidal neurons in hippocampus and cortex are targeted.
The mouse brain comprises ~70 million neurons and ~30 million glia and other cells. Neurons have been traditionally classified based on their morphology, connectivity, stimulus-response, gene expression, and location in the brain. While we know reasonably well the main cell types that are present at different brain locations, we have little quantitative knowledge about brainwide cell type distribution. In addition, cell type-based brainwide connectivity, especially at the level of projection patterns of single neurons, also remains largely unmapped. This knowledge gap prevents us from incorporating the accumulated cell type-based cellular data into comprehensive circuit models of mammalian brain function. Here we propose to develop a largely automated methodology ...
OnAir Post: Quantitative cell type-based mapping
Research Scientist Head of MIT Genetic Neuroengineering Group
Research interests: viral vector engineering, synthetic biology. Engineering genetic tools for neuroscience.
LinkedIn Webpage: linkedin.com/in/ianwickersham MIT Neuroscience Brain Initiative Grant
Email: wickersham@mit.edu
Ian obtained a PhD from UCSD, where he developed new retrograde viral technologies for cell-targetable transsynaptic circuit tracing. After a postdoctoral fellowship in MIT Brain and Cognitive Science, he joined the Synthetic Neurobiology group as a research scientist to develop new integrative cell and circuit analysis methods. He then went on to launch the MIT Genetic Neuroengineering Group.
Ian is eveloping new integrative cell and circuit analysis methods
Namburi, P., A. Beyeler, S. Yorozu, G.G. Calhoon, S.A. Halbert, R. Wichmann, S.S. Holden, K.L. Mertens, M. Anahtar, A.C. Felix-Ortiz, I.R. Wickersham, J.M. Gray & K.M. Tye, Nature 520(7549):675-8 (2015).
Wickersham, I.R., H.A. Sullivan, G.M. Pao, H. Hamanaka, K.A. Goosens, I.M. Verma & H.S. Seung, Cold Spring Harbor Protocols 2015 Apr 1;2015(4):368-74.
Wickersham, I.R. & H.A. Sullivan, Cold Spring Harbor Protocols 2015 Apr 1;2015(4):375-85.
OnAir Post: Ian Wickersham, PhD – MIT
MIT engineers have developed a way to make a brain expand to about four and a half times its usual size, allowing nanoscale structures to appear sharp with an ordinary confocal microscope.
The new “expansion microscopy” technique uses an expandable polymer and water to enable researchers to achieve “super-resolution” without the slower performance of existing “super-resolution” microscopes.
NSF Press Release 1/15/15
While most efforts to understand the brain focus on new technologies to magnify small anatomical features, engineers at the MIT-based Center for Brains, Minds and Machines have found a way to make brains physically bigger.
The technique, which the researchers call expansion microscopy, uses an expandable polymer and water to swell brain tissue to about four and a half times its usual size, so that nanoscale structures once blurry appear sharp with an ordinary confocal microscope.
Expansion microscopy enables researchers to resolve details down to about 70 nanometers, while 300 nanometers was the previous limit with a conventional microscope.
Development of the novel process, which is detailed in the Jan. 15 issue of Science, was partially funded by the National Science Foundation (NSF), including support via an NSF early faculty career development award and ...
OnAir Post: Expansion microscopy and super-resolution
A University of Otago researcher is part of an international collaboration that has developed an exciting and expansive new set of tools to probe cell types in the brain.
This workpartly involves using techniques that manipulate the genes of a small subset of cells so that the cells glow under fluorescent microscopes. By manipulating unique gene markers for each cell type into fluorescent labels or probes, the structure and function of various types of neurons can be visualized and studied. Neuron 3/6/15
Illuminating the diversity of motor neuron types in the mouse brain with specific fluorescent markers. University of Otago
A University of Otago researcher is part of an international collaboration that has developed an exciting and expansive new set of tools to probe cell types in the brain.
The scientists’ work, reported this week in the leading journal Neuron, partly involves using techniques that manipulate the genes of a small subset of cells so that the cells glow under fluorescent microscopes. By manipulating unique gene markers for each cell type into fluorescent labels or probes, the structure and function of various types ...
OnAir Post: New tools to probe brain’s mysteries
Vanderbilt University researchers have achieved the first “image fusion” of mass spectrometry and microscopy that could, among other things, dramatically improve the diagnosis and treatment of cancer.
Combining the best features of both imaging modalities allows scientists to see the molecular make-up of tissues in high resolution.
Nature Methods 2/23/2015
Image of a section of the brain shows the fusion of microscopy (pink area) and mass spectrometry (pixelated colors at bottom) to produce a detailed “map” of the distribution of proteins, lipids and other molecules within sharply delineated brain structures (upper left). Image: Vanderbilt University press
Vanderbilt University researchers have achieved the first “image fusion” of mass spectrometry and microscopy — a technical tour de force that could, among other things, dramatically improve the diagnosis and treatment of cancer.
Microscopy can yield high-resolution images of tissues, but “it really doesn’t give you molecular information,” said Richard Caprioli, Ph.D., senior author of the paper published last week in the journal Nature Methods.
Mass spectrometry provides a very precise accounting of the proteins, lipids and other molecules in a given tissue, but in a spatially coarse or pixelated manner. ...
OnAir Post: Blending High-end Imaging Techniques
