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| Fig. 1: Mice Neural Optogenetic Stimulation Setup. (Source: Wikimedia Commons) Wikimedia Commons |
Optogenetics, a core technology pioneered by Karl Deisseroth, encompasses the development of optical tools that (1) respond to light and deliver effector function to cells and tissues of interest and (2) perform analysis through imaging or electrical recording. [1]
Specific techniques involve genetically modifying light-sensitive proteins to alter and control neural functions. Electrically polarized cells like neurons in the brain are integral to the pathophysiology of many biological processes. Because neurons are embedded in dense, heterogeneous tissue, they are difficult to selectively control with conventional electrical stimulation methods. However, by introducing a light-sensitive protein called channelrhodopsin into neurons, researchers are now able to instantly activate neurons with a pulse of a laser. This allows for a more detailed visualization of neural circuits. [2]
Early optogenetic techniques in the lab involved attaching fiber-optic cables to a mouse's head to deliver light directly to the neurons. Previous advances include both wireless and battery-powered devices that use LED to deliver light to the surface of the mouse brain. These earlier wireless adaptations have been limited by the mass and size of the devices, which weigh around 1-3 grams compared to the mass of a mouse head, which is around 2 grams. Often the devices protrude through the skin and cannot be left attached to the animal for prolonged periods of time. [3]
Conventional electrical microstimulation systems still require tethers and head-mounted devices, which can undermine experiments by disrupting animal behavior. [3] Tethered systems significantly constrain experimental design by requiring researchers to physically restrain animals and perform incisions to insert the optical fibers into the regions of interest before behavioral testing and limiting the range of environments in which optogenetic experiments can be performed. [4] Fortunately, Kate Montgomery and Alexander Yeh from Stanford University recently reported a new method for wirelessly powering implantable devices in mice. This new method works around the mobility constraint by allowing animals to behave naturally with optogenetic manipulation of both central and peripheral targets. [3]
The Stanford team designed a 16 cm-wide platform that relies on the resonant interaction between an radio-frequency cavity and intrinsic modes in the tissue of the mice to power the implant, shown in Fig. 1. [4] The wireless power enables self-tracking over a relatively expansive area and can be applied to a myriad of smaller optogenetic devices. The smallest working prototype made by the group is two orders of magnitude smaller than previously reported systems, which allows the entire device to be implanted under the skin. The implant is powered and controlled with a hexagonal surface-carved resonant cavity in order to associate EM energy with the tissue of the mouse. Because energy is concentrated in the mouse everywhere on the lattice, the power transfer is self-tracking and efficient enough to power the wireless implant within the mouse. [4]
Radio Frequency, defined as EM wave frequencies falling in the range extending from around 3 kHz to 300 GHz is tuned to a frequency that resonates within mouse bodies and that can also be trapped by a grid with smaller-than-wavelength holes inside the cavity. [5] When a mouse is on top of the grid, its body conducts and transmits energy to a coil inside the implanted device. The mouse body comes in contact with the energy wherever it moves, drawing it in and powering the device.
Wireless optogenetics provides precise experimental tools to elucidate function of specific circuits in the brain. This is important to achieving gain- and loss-of-function in an experimental setup and to identifying specific circuits that mediate behavior. Optogenetics has lead to many therapeutic applications such as relieving tremors in Parkinson's patients, however, addressing human neurological disorders requires an advancement in the technology's efficiency in sensitivity and reliability on par with that of its wireless tracking.
The minimization of tethered systems is an important step toward studying disease states of the brain in humans. Complex disorders such as depression, anxiety and PTSD are enmeshed with social components and do not solely operate on the cellular physics level. Human disorders are conjoined with emotional interaction and complex movements that cannot be effectively studied with restrictive headgear limited for use to small animals like mice.
The ability to directly manipulate neural circuits is key to understanding brain function. Neuroscience experiments can finally establish causal role of neural states in brain diseases by disturbing neural activity in a controlled setting. This new method is easily adaptable to human subjects, requires no special equipment aside from a resonance cavity filled with saline solution, and fundamentally expands leeway that experimenters have without sacrificing the precision of control. This has important implications for elusive multifactorial disorders such as Alzheimer's, Parkinson's, Autism, for which targeted therapy is nonexistent. For example, in a five month study at the University of Tokyo, researchers used more recent optogenetic techniques to stimulate transgenic mice brains. They reported doubled Aβ deposits in the hippocampus, evidencing a potential link between Aβ activity and amyloid and were able to visualize the most metabolically active areas in the brain secreting Aβ. They subsequently found that these regions are the first to be infiltrated by Alzheimer's pathology. [6]
The method outlined by Alexander and Yeh elaborates on the optical tools offered by optogenetics and allows researchers to gain a better understanding of how the brain controls behavior and to visualize how neural activity can be disrupted. The group's current prototype may be optimized in terms of the size, geometry and resonant frequencies of the implant and cavity for use in larger animals and humans.
© Jennifer Adams. The author grants permission to copy, distribute and display this work in unaltered form, with attribution to the author, for noncommercial purposes only. All other rights, including commercial rights, are reserved to the author.
[1] K. Deisseroth, "Optogenetics," Nat. Methods 8, 26 (2011).
[2] J. Dai, D. I. Brooks, and D. L. Sheinberg, "Optogenetic and Electrical Microstimulation Systematically Bias Visuospatial Choice in Primates," Curr. Biol. 4, 63 (2014).
[3] J. S. Ho et al., "Self-Tracking Energy Transfer For Neural Stimulation in Untethered Mice," Phys. Rev. Applied 4, 024001 (2015).
[5] S. I. Park et al., "Ultraminiaturized Photovoltaic and Radio Frequency Powered Pptoelectronic Systems For Wireless Optogenetics," J. Neural Eng. 12, 056002 (2015).
[6] K. Yamamoto et al., "Chronic Optogenetic Activation Augments Aβ Pathology in a Mouse Model of Alzheimer Disease," Cell Reports 11, 859 (2015).
