“Obesity is linked to the neural circuitry of the other behaviors but it may be the most pressing problem because it is the most prevalent and it is increasing,” Tye says. “Our currently available treatments for obesity are ineffective and completely insufficient for the problem that faces our society.”
So Tye proposed a strategy to discover the neural circuits underlying obesity and then reprogram them to eliminate obsessive craving and consumption. The proposal was bold, creative and risky — but it was just the kind of high-stakes project the National Institutes of Health (NIH) seeks to support with its Director’s New Innovator Award.
Now, Tye has been named a recipient of the NIH Director’s New Innovator Award for 2013 and will receive $1.5 million over the course of five years to work on her novel approach to obesity research.
The award is designed specifically to support creative new investigators with innovative research ideas at an early stage of their careers, when they may lack the preliminary data required to earn traditional funding.
“It’s a huge honor to be recognized as a new innovator by this amazing NIH program and to be associated with all the other people who have won the award this year and in the past. Now I have a chance to make my vision a reality and to make a dramatic difference in obesity research,” Tye says.
Tye joined the Picower Institute for Learning and Memory in January 2012; by August of this year, she published a paper in Neuron reporting the discovery of minute sub-circuits among the two well-studied brain regions involved in anxiety: the basolateral amygdala and the ventral hippocampus.
Her obesity project will build on the methods she used in that research to study the circuitry in unprecedented detail, and on her graduate school training that focused on animal models of addiction — which she conducted at the University of California at San Francisco.
Addiction is thought to “hijack” the brain’s natural reward system that motivates us to seek food and other necessities for survival. Because sugar is an inherently powerful natural reward — in nature, it was scarce and signaled a desirable, high-energy food — many addiction protocols use a sucrose solution to study an animal’s reward-seeking behavior. But, research recently suggests, sugar itself can also hijack the brain’s reward system and rewire the brain so that cues — such as a cookie displayed at the cash register — can fire a craving that drives behavior.
“We plan to use the brain’s natural plasticity, the ability to rewire itself, to reprogram the reward system so that sugar cues no longer trigger the transition from craving to compulsive consumption,” Tye explains.
However, the reprogramming must be precise and specific to excessive sugar consumption so that it does not reduce overall appetite for healthy food or for seeking other natural rewards.
To avoid this pitfall, Tye will adapt the optogenetic technology she has been refining since her postdoctoral training in Karl Deisseroth’s lab at Stanford University. In optogenetics, researchers modify neurons to express a light-activated protein and then use brief pulses of light to instantly activate or inhibit the specific type of neuron carrying the protein in a living animal.
The researcher can then control a small subset of neurons that are intermingled among other neural types in a discrete brain region such as the amygdala, which is implicated in anxiety. But within that subset, smaller subsets can connect to different brain regions, producing different functions when activated.
Tye’s innovation was to activate the neurons’ axon terminals in the different regions to which they project. Using that method in her recent paper, she says, “We found a novel circuit underlying anxiety, a distinct projection that has completely different effects on anxious behavior than you see when you nonspecifically activate the entire amygdala and get an average of all responses.”
Now Tye will apply this technique to the natural reward circuit involved in sugar-craving and obesity in animal models. Among the technologies she foresees her lab applying to this problem is a wireless, implanted device that can simultaneously record from the sub-circuits involved in the craving-compulsion-consumption process, while also optogenetically stimulating or inhibiting them to define their discrete functions.
Simultaneously, machine-learning algorithms under development in her lab will decode the neural signature that predicts craving, compulsion and consumption. When the algorithms identify a “craving” signal in real-time, the device will instantly, but briefly, inhibit the precise neural activity underlying this craving. If successful, this will prevent the over-consumption of sugar. Her lab will also explore non-invasive means of controlling the craving, such as ultrasound or transcranial magnetic stimulation.
How, then, will this achievement be translated to humans to help stop the obesity epidemic? Perhaps, Tye says, instead of going in for gastric bypass surgery or liposuction, a person will go to a type of biofeedback lab to restore the brain’s normal wiring in the reward circuit. Ultimately, she notes, those are engineering problems and MIT is the right place to solve them: “You have to take a big risk to make a big change.”