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Probing Deeper: Shining Light on the Mysteries of the Brain With Optogenetics

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Elena Watts
Jack Wolfe

Floating in cerebral fluid inside 22 bones that form the face and skull, each of the seven billion brains belonging to Earth’s human inhabitants govern intelligence, creativity, memory, emotion, speech, movement, sensory systems and other organs.

Yet, for millennia, the 3-pound mass of delicate tissue, which is the essence of humanity and inhumanity experienced internally and externally by every living creature, has remained as mysterious as it is extraordinary. The human brain, which intimately controls every aspect of human life with complex communication between billions of neurons through trillions of connections, strangely enough, renders its possessor incapable of understanding its processes.

Advancements in computing technologies that enable big data analysis and discoveries of new engineering techniques have created watershed moments in the study of neuroscience. In 2013, the European Commission provided the Human Brain Project with $1.3 billion to build a computer model of the brain. Months later, the United States government invested $4.5 billion in the 12-year Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative to map the brain’s neural connections, the connectome, through an assortment of scientific methods.

In accordance with the international focus on human brain research, professors at the UH Cullen College of Engineering are converging on the globulous human command center from different perspectives with various research projects. By exploring the organ inside out and outside in, from both microscopic core and broad perimeter perspectives, with invasive and noninvasive methods, they hope to meet on common ground with research that contributes to a comprehensive understanding of its function.

Probing Deeper: Shining Light on the Mysteries of the Human Brain with Optogenetics

A scientific breakthrough that combines optics and genetics provides researchers with unprecedented insight into one of life’s most challenging puzzles – the human brain. Coherent processes in the brain that prompt unconscious movements such as walking with seamless fluidity are complex enough that they have remained somewhat mysterious.

Despite existence of technology and tools to explore brain activity, methods for tracking singular conversations among the hundreds of thousands of neurons necessary to perform even the simplest body movement remained elusive until 2005, the year Nature Neuroscience journal published the first paper on optogenetics. The ability to manipulate targeted neurons within specific neural circuits in the human brain – important in understanding the organ’s overall function – has spawned studies around the world. One such groundbreaking research project is in full swing at the University of Houston’s Cullen College of Engineering.

Jack Wolfe, professor of electrical and computer engineering at the UH Cullen College of Engineering, is leading an effort to develop a new tool for optogenetics. Wolfe’s collaborators are Wei-Chuan Shih and Ji Chen, also UH electrical and computer engineering professors, as well as Valentin Dragoi, professor of neurobiology and anatomy at UT Medical School-Houston, and a cadre of talented graduate students. Fabrizio Gabbiani at Baylor College of Medicine, John A. Dani at the University of Pennsylvania, and particularly, Gopathy Purushothaman, formerly with Vanderbilt University, provided Wolfe with neuroscience mentorship in the early stages of the project.

“I am indebted to my neuroscience mentors for providing the essential advice and guidance that I needed to tailor our technology toward important applications in neuroscience,” Wolfe said.

The implantable neural probe delivers light to photosensitive neurons in deep regions of the brain and simultaneously records and maps their optically-stimulated electrical signaling. The tool can provide a more detailed understanding of the neuronal networks near the probe to help researchers answer basic questions about microscopic structures in the brain. The project, which is supported by a $425,000 grant from the National Institutes of Health and additional funding from the Cullen Foundation and the Texas Center for Superconductivity, relies heavily on the unique toolset developed in the UH Nanosystem Manufacturing Center, directed by Wolfe.

“It’s a fascinating project because my background is in integrated circuit fabrication, and this project involves going beyond current fabrication techniques to define patterns on cylindrical optical fibers,” Wolfe said. “Until I started working on this, I had no contact with neuroscience, so it’s a window on a new field for me.”

Primitive meets modern to shine light on age-old brain

Remarkably, primitive microorganisms that form slimy green coatings on pools of still water make a modern scientific method possible. Optogenetics uses tools of molecular biology to insert a gene from green algae, a unicellular photosynthetic plant, into the neurons of living, freely behaving animals. Whether in a plant or a neuron, the gene enables the cell to produce a protein that detects light and generates electrical impulses by opening ion channels in the cell wall. In algae, these impulses move the cell toward regions of higher light intensity to increase photosynthesis. In neurons, the impulses are transmitted to each of the neurons that normally receive inputs from the photo-activated cell.

“The journey of optogenetics shows that hidden within the ground we have already traveled over or passed by, there may reside the essential tools, shouldered aside by modernity, that will allow us to map our way forward,” wrote Karl Deisseroth, a leading developer of optogenetics, in a 2010 Scientific American article. “Sometimes these neglected or archaic tools are those that are most needed – the old, the rare, the small and the weak.”

For 60 years, scientists have known that inducing electrical currents to flow in a region of the brain known as the lateral hypothalamus, LH, can trigger overeating in well-fed mice. It was concluded that the LH drives the primal functions, which include sexual activity and aggression in addition to eating. Exactly how the current-induced overeating was not clear since electrical stimulation activates many different types of neurons both inside and outside the LH.

A 2013 Science magazine article describes the use of optogenetics to pinpoint the neurons that provide the triggering input to the LH that causes overeating. Their hypothesis was that neurons in a region bridging the amygdala, responsible for emotion, and the LH could provide the spark. They tested their hypothesis by sensitizing just those neurons to light. As anticipated, shining a light on the cells induced overeating in well-fed mice. A surprising video that accompanies the paper shows the mouse’s overeating switched on and off by the light.

Electrical stimulation experiments helped determine the region of the brain that drives eating, but optogenetics was the key to identifying the specific neurons that trigger it. The study shows that a biological mechanism, not a lack of discipline, is responsible for binge eating and that potential exists for the development of drugs to target the pinpointed nerve cells to control binge eating and other disorders.

Among numerous accolades, the prestigious journal Nature named optogenetics the 2010 Method of the Year and Denmark’s Lundbeck Foundation split the $1 million Brain Prize between six of the method’s developers in 2013, which could serve as indicators of events to come. Murmurs circulating in scientific circles suggest that lead developers of the new technique might one day meet the King of Sweden and walk away with three-inch solid gold medals. Many expect the scientific breakthrough to win a Nobel Prize.

“We find meaning for the modern world – not just for science, but also for medicine and psychiatry – that makes a strong and clear statement for environmental protection, for preservation of biodiversity and for the pure quest for understanding,” Deisseroth wrote in the same magazine article about his discovery.

Wolfe joins hunt for better tools to explore the brain

The brain integrates the information generated by the sensory organs to build an internal model of the external environment. This is carried out by neurons, cells that process the inputs they receive from local and long-range connections and send outputs to other neurons. In the visual system, which is the focus of this study, retinal cells encode the visual image as electrical impulses that travel from neuron-to-neuron to a switching center in the middle of the brain. From there, information flows through a complex network to the visual cortex where a mental image is formed. Thus, understanding the visual system requires the ability to probe electrical activity in deep as well as shallow brain structures.

Mapping these circuits is typically done by stimulating a population of neurons chemically, electrically, or optically, and recording the resulting spike activity with an array of electrodes on an implanted probe. Probes may be planar blades or cylindrical needles. Planar probes can accommodate large, 24-to-48 electrode arrays at very low costs by leveraging semiconductor manufacturing technology. However, this approach is suitable only for flat substrates, not the curved surfaces of cylindrical probes. Because of this limitation, most cylindrical probes today have only four electrodes.

Wolfe has developed a powerful technique to fabricate dense electrode arrays on fine cylindrical substrates, thereby providing the design flexibility of planar probes in the cylindrical format required for deep brain applications. His approach is like printing letters on a pipe using a stencil and a can of spray paint – except the stencil is a thin membrane with etched open windows and the spray paint is a beam of energetic ions.

“These are not run-of-the-mill flat substrates we’re printing on, which would make tools used to manufacture them ubiquitous,” said Apeksha Awale, electrical and computer engineering graduate student and research assistant to Wolfe for five years. “It is difficult to print electrodes 2 microns wide on a cylinder.”

An optical fiber as thin as a single strand of human hair, about 60 microns, serves as the base material for Wolfe’s neural probe. The fiber is pointy enough at one end to penetrate brain tissue, long enough to reach the core of the brain and flexible enough to sway with the organ to activities as subtle as breathing. With modified integrated circuit design technology, Wolfe prints approximately 70 electrodes, each 5 microns wide, in dense tiers at varying depths around the diameter of the fiber.

“We are developing a very dense electrode pattern that no one has ever produced because it can provide a very detailed map of the active neurons in the neighborhood of the tip of the probe,” Wolfe said. “The real sweet spot for this technology is the thalamus – trying to understand parts of the circuitry that are very deep inside the brain.”

The UH team produced a prototype of the probe that Purushothaman tested in nonhuman primates to study the brain’s vision system. This led to their most recent design, which has the high electrode count necessary to pinpoint the photoactivated neurons.

“Activating a region anywhere in the visual system circuitry enables us to observe the signals that propagate downstream,” Awale said. “We can follow the impulses generated by the neurons as they travel through the neural circuitry.”

Neural probes are not built in a day

Before the manufacturing began, Awale, graduate student Pratik Motwani, and Mufaddal Gheewala, their predecessor in Wolfe’s lab who has since graduated and gone to work at Intel, helped to build the hardware and tools that make printing dense patterns of electrodes on cylindrical surfaces possible.

“The research assistants are learning techniques beyond integrated circuit manufacturing, though they’re all derived from the same principles,” Wolfe said. “I would hope to stimulate some of them to enter the neuroengineering field and solve some of the big problems that are still open.”

Manufacturing the probes raises challenges – mainly cost and time associated with production – that are entirely different from those encountered in research. The graduate students are currently refining processes to maintain optimal efficiency and reliability of the probes during mass production.

“We won’t produce anything we can’t mass manufacture, because what’s the point if you can only make one a year,” Awale said. “And we must be able to manufacture enough of them to bring the cost down and build a market for them.”

Wolfe and his assistants have developed tools and methods to manufacture 50 neural probes at once, and they have filed patents for their most important technological advancements. They expect to demonstrate the probe’s manufacturability next year.

“We ought to be able to make all the probes as good as the best probe,” Wolfe said.

Collaborators join Wolfe’s research pack

Initially, Wolfe intended to print high-density patterns of electrodes on wire for recording neuronal activity rather than optical fiber for activating and recording. He replaced the base material for his neural probe in 2009 when Shih, an optics engineer, arrived at the University with ideas about optogenetics. Because optics technology was already mature, Shih suggested Wolfe use optical fiber as the substrate to instantly achieve half of the probe’s function, delivering light stimulation to sensitized neurons.

“We had lots of interesting meetings where we collaborated on how to make these things, and some of the early work that is still very important was developed jointly during these discussions,” Wolfe said. “You have to know where the light is going, and its intensity at different distances from the tip, so Shih would be the one to design that type of probe.”

A novel probe design evolved out of these meetings for an optrode that encapsulated a twistedwire tetrode, a traditional four-channel probe, in a capillary tube. Easy to make, the invention made it possible for anyone making electrical recordings with tetrodes to produce a tool for optogenetics. The idea was published in Optics Letters in 2012.

While Wolfe began applying his prior research to the new substrate, a possibility because both were cylindrical, Shih and his graduate student, Arnob Masud, began building a 3-D model to analyze the power and intensity of the light in the brain tissue ahead of the fiber tip.

“Mapping light-brain interaction – writing code to understand how light is scattered and distributed from the excitation point and how it interacts with brain tissue – is very challenging for us,” Masud said.

Chen, their Cullen College colleague with expertise in modeling electromagnetic waves, especially in the biological sphere, joined the project to make sense of the immense amounts of data the Houston probe can generate. He and his graduate student are developing an algorithm to precisely map the patterns of electrical impulses emitted by the sensitized neurons.

Next year, neurobiologist Valentin Dragoi plans to begin testing the latest version of the neural probe on nonhuman primates, the modeling system genetically closest to humans. In his UT Medical School lab, his intention is to excite and record large-scale neuronal activity while primates perform behavioral tasks.

“Substantial progress has been made in rodents in the experimental world,” Dragoi said. “In primates, less is known about the ability of neurons to respond to optical stimulation and the control of behavior using optogenetic stimulation.”

Wolfe’s probe offers flexibility and large-scale recording of neural populations not available with existing state-of-the art technology, such as chronic implants. Dragoi can position the Houston Probe, or many of them, in different regions of the brain daily to record fresh, active neuronal activity with minimal damage to brain tissue. Implantable probes are printed with about 100 electrodes for large-scale neuronal recording, but remain fixed in one location, cause micro-bleeding at the penetration site and destroy neurons within months, resulting in a steady decline of signal recording.

“Essentially, Wolfe wants to develop his probe with our feedback, and we’ll test them, so it’s a handshake project that will provide a useful push for neuroscience and technology,” Dragoi said.

Better treatments for brain diseases

By mapping the ways billions of neurons interact through trillions of connections in the human brain, researchers hope to find better treatments for incurable brain disorders, such as Alzheimer’s disease, Parkinson’s disease, epilepsy and depression.

“Ultimately, the goal is to map brain circuits to understand how they work with the idea that if we have all that information, and we have something not working right, we can develop a therapy to address it,” Wolfe said.

In the meantime, while the field of neuroscience is still in its infancy, the National Institutes of Health, one of the federal BRAIN Initiative’s lead institutions, has urged scientists to shift their research approaches from practical to theoretical, like physicists who study the pure science behind particle collisions rather than practical applications for them, Dragoi said.

“We may not understand precisely how the brain works in our lifetime, but we can uncover fundamental principles applicable to sensory, memory, language and other systems,” Dragoi said. “The benefits will come, but they will take time.”

Despite lengthy lab-to-clinic approval processes for new medical technology, optogenetics could eventually benefit patients with drug-resistant brain disorders whose only approved treatment options are currently electrical and chemical stimulation.

With optogenetics, physicians could excite targeted neurons without disrupting others, alleviating negative side effects experienced by patients who undergo less accurate treatments. Furthermore, the new method does not seem to harm the neurons like the existing methods.

“While the benefits of electrical and chemical stimulation outweigh the drawbacks for some patients with drug-resistant brain diseases, injecting electrical currents into the brain is still detrimental,” Awale said. “Optogenetics is potentially a more benign way to stimulate activity in the brain for treatments of these disorders.”

Wolfe’s neural probe also shows promise for examining microcolumns, vertical arrangements of about 100 interconnected neurons that form 30-micron diameter structures prevalent in the outer layer of the brain called the cerebral cortex. Researchers have noticed potential links between abnormalities in microcolumn structures and patients with aging and diseased brains, but questions have remained unanswered because probes capable of exploring such small structures have not existed – until now.

“Our probe is very small in diameter, so we hope to observe communication that controls activity in these structures,” Awale said. “It’s terrible to have a disease of the brain and not understand what causes it or how to treat it, and this gives us a better chance for therapies – that’s the motivation for the whole project.”

 

 

 

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