Yang Xiang, PhD, assistant professor of neurobiology, and Gang Han, PhD, assistant professor of biochemistry & molecular pharmacology, have received a three-year, $900,000 grant from the Human Frontiers Science Program to lead an international team of scientists in the development and implementation of a new optogenetic platform that can remotely activate neurons inside a free-moving organism.
Using a new class of nanoparticles developed by Dr. Han, Dr. Xiang and colleagues propose to selectively turn on non-image forming photoreceptors (NIFP) inside mice and Drosophila unencumbered by the fiber optic wires used in currently available optogenetic technologies. By wirelessly stimulating these photoreceptors, which are able to sense light even though they don’t generate vision, scientists can better understand their role in regulating physiological functions such as circadian rhythm, sleep and melatonin secretion. The hope is that this new technology can also be used to study the links between other types of neurons, physiology and behavior.
“Current optogenetic technologies are limited in their application because they require using ‘wired’ fiber optic implants to deliver blue light to activate neuron activities,” said Xiang. “This is a major technological problem that has become an obstacle to understanding the physiological role NIFP play in animal behavior. If we’re able to overcome this hurdle by using the nanoparticles developed by Dr. Han, it would open the door to more informed investigations of not only NIFP but a wide range of neurons and their effect on behavior.”
In use for only about a decade, optogenetic technology combines techniques from optics and genetics, allowing scientists to precisely control activities of individual neurons using light. By genetically inserting light-activated biological molecules such as channelrhodopsins, a family of proteins found in algae, into neurons, scientists can instantaneously turn them on using beams of blue light with millisecond precision.
A limiting factor to the wider application of this technology, however, is that blue wavelengths are unable to penetrate skin, bone and other tissues deep enough to activate the neurons inside free-moving animals. To overcome this obstacle, current techniques require the insertion of fiber optic wires close enough to the neurons so the light that activates them can be delivered. This technique restricts animal movement and makes it difficult to observe behavioral responses in natural conditions. This fiber optic approach further limits scientists’ ability to study behavior over longer periods of time as the effectiveness of light delivery is relatively short due to scarring.
Han has developed an “upconversion nanoparticle” (UCNP) that has the potential to solve the limitations of wired optogenetic techniques. These nanoparticles are capable of absorbing infrared light that can’t be seen and converting it into visible blue light. In contrast to blue light, infrared light is capable of penetrating skin and tissue to a depth of several centimeters. Xiang and Han believe these nanoparticles, tuned to emit blue light, can be inserted into the brain and used as a substitute for traditional fiber optics to wirelessly activate neurons in animals.
The hope is that the nanoparticles will absorb infrared light that passes through the tissue, and convert it to blue light inside the animal. This blue light would then activate the NFIPs. If successful, Xiang and colleagues will be able to observe any changes in animal behavior brought about by activating these non-image forming photoreceptors.
“The nanoparticles act as a kind of relay station,” said Han. “They convert the low-energy red light into a high-energy blue light that can activate the neurons. This technique completely alleviates the need to use intrusive fiber optic wires. It vastly simplifies the technology and expands the potential uses for optogenetics.”
Xiang said, “In many ways, this is the perfect bridge between a technological advancement and an important biological question. With these nanoparticles it’s possible for us to begin answering fundamental neurobiological questions about NIFPs.
“More broadly, it would open up the possibility of using other model organisms, such as Drosophila, that can’t be used with the current wired optogenetic technologies, to investigate and answer important questions about how neural activities regulate behavior.”
HFSP awards are given to highly innovative teams that demonstrate that they have developed and can test a paradigm-shifting idea that holds promise for the development of new approaches to problems in the life sciences with potential to advance the field of research significantly.