When Yingxi Lin, a professor in MIT’s McGovern Institute for Brain Research, looks at the brain, she sees circuits. These are the signal-transmitting networks — formed by an estimated trillion neurons and their quadrillions of connections, or synapses — that carry out our brain function.
The vast majority of these circuits are excitatory. In other words, they transmit sensory input — the smell of coffee, brake lights flashing on a highway, a ringing phone — in the form of electrical signals that speed to and from the processing centers of the brain. Lin likens excitatory circuitry to an information superhighway.
“For a long time people have really been focusing on how excitatory synapses adapt to changes in environment. What has been sort of overlooked is how inhibitory synapses govern excitatory transmission in response to activity,” says Lin, who is pioneering research on inhibitory circuitry. Comprising a mere 10 to 20 percent of the brain’s neurons and synapses, inhibitory circuits put the brakes on the speeding traffic of their counterparts, thus keeping neural signaling from going awry. Impaired inhibitory circuits have been implicated in autism and other brain disorders.
Lin’s work builds on a breakthrough she made while a postdoctoral fellow at Harvard Medical School. She discovered the first-known “master switch,” a gene called Npas4, which governs the formation and maintenance of inhibitory synapses between neurons.
“It senses how much activity each neuron gets, and then decides how much inhibition the neuron needs,” says Lin. To verify this, she and her colleagues measured electrical activity in neurons with too little or too much Npas4 and found that the cells were correspondingly overexcited or overinhibited.
Npas4 regulates many genes in response to electrical activity. Two of those genes have been identified as risk factors for autism and schizophrenia, respectively. At the same time, impaired inhibitory circuitry has been implicated in these and other disorders. One striking example is epilepsy, which results from overexcited neural circuits. When Lin and her colleagues eliminated Npas4 in a mouse, the mouse developed chronic seizures. Seizures affect roughly one-third of people with autism. Meanwhile, Rett syndrome, a disorder with autistic features, has been linked to an excess, rather than an impairment, of inhibition.
Lin and others are studying the estimated 300 genes regulated by Npas4, some of which may provide additional clues to how brain disorders develop. Lin aims to understand more generally how inhibitory pathways affect brain function; she has recently begun investigating their role in drug addiction as well as in learning and memory.
Viewing the brain as a complex mass of circuits comes naturally to Lin, who studied engineering physics at Tsinghua University in China and admits that she “hated biology in high school.” After studying medical imaging, however, she began to warm to the life sciences. By the time she began her doctoral studies, she had become captivated by molecular neuroscience.
“I was fascinated by how neurons can adapt to their environment. They are just so plastic. I thought, ‘Wow, I didn’t know biology could be so interesting.’”