University of Virginia scientists have demonstrated that neurons in the brain that have been supplemented with a synthetic gene can be remotely manipulated by a magnetic field. The finding has implications for possible future treatment of a range of neurological diseases, such as schizophrenia and Parkinson’s disease.

“We may have discovered a major step toward developing a ‘dream tool’ for remotely controlling neural circuits, by manipulating specific cells using engineered that respond to magnets,” said Ali Deniz Güler, a UVA biology professor who led the study in his neuroscience lab.

Güler and UVA neuroscience Ph.D. candidate Michael Wheeler engineered a gene that can make a cell sense the presence of a . They coupled a gene that senses cellular stretch with another gene that functions as a nanomagnet. This synthetic combination turns on only when in the presence of a magnetic field, allowing them to control neuronal activity in the brain.

“We wanted to activate with magnetism a specific set of neurons in the brain responsible for pleasure,” Güler said.

Using to insert the gene, they expressed the in adult mice or in zebrafish embryos, and witnessed remote activation of neurons in the presence of a magnetic field through the altered behavior of the animals.

“We have validated that we can turn on cells in the brain with simple magnets, something that has not been achieved before,” Güler said. “We are actually magnetically evoking behavioral responses in animals by creating a cell that can sense magnetic fields. This could pave the way toward eventually treating through magnetism. It is precise and noninvasive.”

Güler and Wheeler call their synthetic gene “Magneto,” after a Marvel Comics cartoon character who can alter magnetic fields.

In a series of tests on mice that had the Magneto gene used to express comfort or pleasure, the mice voluntarily went to a chamber of their cage where the magnetic field was present, similar to going there as if food was present. Likewise, when the magnetic field was turned off, the mice did not display any particular preference for that area of the cage. But when the magnetic field was turned back on, they again moved to that area of the cage.

Mice without the Magneto gene did not display any behavioral changes in the presence of magnets.

“The mice were hanging out in the magnetic chamber because they were experiencing some pleasure there, since we were remotely turning on the neurons that signal reward,” Wheeler said.

In the team’s studies on zebrafish embryos, the embryos responded to a magnetic field by twirling, which they generally do in response to pressures in the water. When the magnetic field was removed, the embryos greatly reduced their twirling behavior.

“These response behaviors, in two separate species of animals, validate that the cells containing the synthetic gene turn on in a magnetic field,” Wheeler noted. “This field can penetrate the brain regardless of tissue density – like MRI – and can turn on specific circuits at a specific time, whenever the test subject is within the magnetic field.”

Güler added, “If we can use gene therapy to exert control over neurons, the potential exists to modify or eliminate the effects of certain neurological diseases by controlling ill-firing neural networks. Our method may be one possible approach.”

He emphasized, however, that at present the method is being used to better understand brain development, function and pathology.

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Optogenetic and chemogenetic actuators are critical for  deconstructing the neural correlates of behavior. However,  these tools have several limitations, including invasive modes  of stimulation or slow on/off kinetics. We have overcome these  disadvantages by synthesizing a single-component, magnetically  sensitive actuator, “Magneto,comprising the cation channel  TRPV4 fused to the paramagnetic protein ferritin. We validated  noninvasive magnetic control over neuronal activity by demonstrating remote stimulation of cells using in vitro calcium  imaging assays, electrophysiological recordings in brain slices,  in vivo electrophysiological recordings in the brains of freely  moving mice, and behavioral outputs in zebrafish and mice.

As proof of concept, we used Magneto to delineate a causal  role of striatal dopamine receptor 1 neurons in mediating  reward behavior in mice. Together our results present Magneto  as an actuator capable of remotely controlling circuits  associated with complex animal behaviors.

Opto and chemogenetic actuators have revealed critical properties  of neural networks in normal and pathological states. While botopto- and chemogenetics remotely control neuronal stimulation, optical strategies are limited spatially by poor light penetration into dense  tissues and chemogenetic strategies suffer from slow pharmacokinetics that prevent cellular activation on a physiologically relevant time– scale. Therefore, there remains a need for next-generation actuators  that are noninvasive and can respond rapidly and reversibly.

Several  recent studies have reported transient receptor potential vanilloid 1  (TRPV1) ion channels can be engineered to become sensitive to a  combination of radio waves and magnetothermal heating through  coupling to the iron storage protein ferritin or to inorganic paramagnetic nanoparticles.

While these reagents represent an important  advance, they are multicomponent systems (requiring, for example,  delivery of nanoparticles and a genetically encoded channel) witpossible offtarget heating effects. One study employed nonthermamagnetogenetic control of somatic tissues to regulate blood glucosebut a genetically encoded, single-component magnetogenetic system  has yet to be applied to the nervous system.

Here we have expandeon these strategies by engineering magnetogenetic actuatothrough fusion of the nonselective cation channel TRPV4 to the paramagnetic protein ferritin. We have successfully applied this actuator to the nervous system and validated it using in vitro calcium imaging, brain slice electrophysiology, in vivo electrophysiology and acute modulation of behavior in freely moving zebrafish and mice.

More information:
Genetically targeted magnetic control of the nervous system,
Nature Neuroscience, DOI: 10.1038/nn.4265
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