The Stanley team will focus on the development of tools to instantly and precisely target cell activity deep in the brain using radio waves, nanoparticles and genetically modified viruses.
A fundamental goal of neuroscience is to understand the function(s) of defined neural populations in a complex organism. We propose to develop and validate a technology for non- invasive modulation of neural activity in vivo. There has been huge progress in developing tools for temporal regulation of neural activity. These techniques, from light activated channels to designer receptors, enable modulation of defined neural populations in vivo to examine their roles in many physiological functions. But current technologies have their limitations. Optical methods require permanent implants and activate only local neural populations while designer receptors and their specific ligands have a significantly slower time course. Ideally, tools would be capable of remote modulation of neural activity in local or dispersed neural populations at multiple stages of development with rapid temporal resolution. We address this challenge by using a distinctive combination of non-invasive radiowave and magnetic field signals, biological ferritin nanoparticles and bioengineered ion channels for non- invasive modulation of neural activity in freely moving animals. Radiofrequency or magnetic fields remotely modulate neurons that express nanoparticles formed in a modified ferritin shell. These are tethered to a modified ion channel, transient receptor potential vanilloid 1, TRPV1. Radiowaves or magnetic fields penetrate tissue to heat or move the nanoparticle respectively and activate TRPV1. Modifications of TRPV1 allow either neural activation or silencing. We will develop and validate tools for non-invasive activation and silencing of neural populations using viral vectors applicable to several species and demonstrate their utility in regulating complex behaviors. Specifically, we will 1) characterize the electrophysiological responses to RF and magnetic manipulation of neural populations in vitro, 2) examine the responses to RF or magnetic field modulation of hypothalamic neurons in vivo and compare them to optogenetic modulation and 3) determine the effects of modulating a neural population that is dispersed through a cortical lamina, the cerebellar Purkinje cells, in vivo in comparison to designer receptors exclusively activated by designer drugs (DREADD) modulation. Using bioengineered nanoparticles to transduce electromagnetic signals, we will develop a unique technology for targeted, non-invasive manipulation of neural activity that is applicable to local or dispersed cells through development. Our technology will be a valuable addition to the available tools to investigate the physiological roles of neural populations.
Public Health Relevance Statement
This application aims to validate and characterize a novel technology, radiogenetics, for external, non-invasive activation of defined cell populations in living animals. We will use radiowaves or magnetic fields and biological nanoparticles to activate ion channels to switch on and switch off neural activity. We will develop viruses for remote modulation of local and dispersed neural populations in vivo and validate their efficacy. The studies proposed in this application will provide a new technology that is broadly applicable to neuroscience with the potential for translation to clinical applications.
NIH Spending Category
Bioengineering; Eye Disease and Disorders of Vision; Nanotechnology; Neurosciences
Address; Animals; Area; Behavior; Biological; Biomedical Engineering; Brain; Calcium; Cations; cell growth regulation; Cells; Characteristics; Chloride Ion; Clinical; clinical application; Communities; Complex; Designer Drugs; Development; Drug Modulation; efficacy testing; Electromagnetics; Endocrine; Exposure to; Ferritin; Goals; Heating; Hypothalamic structure; Implant; In Vitro; in vivo; Individual; Ion Channel; Ions; iron oxide; Kinetics; Life; Ligands; Light; magnetic field; Magnetism; Mechanics; Mediating; Methods; Modification; Motor; Movement; Mus; nanoparticle; Neurobiology; Neuroglia; Neurons; neuroregulation; Neurosciences; new technology; Optical Methods; optogenetics; Organism; patch clamp; Penetration; Peripheral; Physiological; Point Mutation; Population; public health relevance; Publishing; Purkinje Cells; radiofrequency; receptor; relating to nervous system; Resolution; response; Role; Signal Transduction; Slice; Staging; System; Techniques; Technology; Temperature; Time; Tissues; tool; Translations; TRPV1 gene; Vanilloid; Viral; Viral Vector; Virus; Work
BRAIN Initiative Press Release
Rockfeller Newswire 10/7/14
A proposal to develop a new way to remotely control brain cells from Sarah Stanley, a Research Associate in Rockefeller University’s Laboratory of Molecular Genetics, headed by Jeffrey M. Friedman, is among the first to receive funding from U.S. President Barack Obama’s BRAIN initiative. The project will make use of a technique called radiogenetics that combines the use of radio waves or magnetic fields with nanoparticles to turn neurons on or off.
The NIH is one of four federal agencies involved in the BRAIN (Brain Research through Advancing Innovative Neurotechnologies) initiative. Following in the ambitious footsteps of the Human Genome Project, the BRAIN initiative seeks to create a dynamic map of the brain in action, a goal that requires the development of new technologies. The BRAIN initiative working group, which outlined the broad scope of the ambitious project, was co-chaired by Rockefeller’s Cori Bargmann, head of the Laboratory of Neural Circuits and Behavior.
Stanley’s grant, for $1.26 million over three years, is one of 58 projects to get BRAIN grants, the NIH announced. The NIH’s plan for its part of this national project, which has been pitched as “America’s next moonshot,” calls for $4.5 billion in federal funds over 12 years.
The technology Stanley is developing would enable researchers to manipulate the activity of neurons, as well as other cell types, in freely moving animals in order to better understand what these cells do. Other techniques for controlling selected groups of neurons exist, but her new nanoparticle-based technique has a unique combination of features that may enable new types of experimentation. For instance, it would allow researchers to rapidly activate or silence neurons within a small area of the brain or dispersed across a larger region, including those in difficult-to-access locations. Stanley also plans to explore the potential this method has for use treating patients.
“Francis Collins, director of the NIH, has discussed the need for studying the circuitry of the brain, which is formed by interconnected neurons. Our remote-control technology may provide a tool with which researchers can ask new questions about the roles of complex circuits in regulating behavior,” Stanley says.