A treatment for Parkinson's disease reveals a brain switch for sadness: Researchers exploring why depression may be hard-wired now have a surprising theory .

At MIT, where he directs the Center for Neural Circuit Genetics, Tonegawa was ready.

Because he had trained as a molecular biologist, he already had a leg up on traditional neuroscientists. Because he was used to crossing disciplines — in 1987 he won the Nobel Prize in Physiology or Medicine for lifting the veil on antibody diversity — he already had the creativity necessary for discoveries. And because he continues to battle his own depression since the suicide of his teenage son more than four years ago, he understands better than most the importance of his potential breakthrough.

“My interests are very narrow now,” he admits. “I can’t enjoy many things.”

It was perhaps inevitable that Tonegawa’s research in memory would lead him to this current work. Over the past four years, he and his lab have shown that the physical traces of memories are not stored in the synapses, or connections, between cells, as previously thought, but in discrete circuits of cells, called memory engrams. Tonegawa then upended the common belief that the loss of long-term memory, which can result from a brain injury or disease such as Alzheimer’s, is not necessarily the result of damaged memory cells but of a damaged memory-retrieval system.

The first step was to identify and label happy-memory cells with the light-sensitive gene, then to stress those male mice with close confinement until they exhibited symptoms of depression — which meant, for instance, a lack of interest in sugar water. When reactivation of the positive memory neurons lessened the depression, Tonegawa wondered whether simply re-exposing those males to females to create new happy experiences would lift their depression. It did not, which didn’t surprise him at all.

“Depressed patients, they don’t seek pleasure. That’s a hallmark of depression. Enjoyable experiences don’t register anymore,” he said.

Tonegawa even found the curative sweet spot with his depressed mice: two light treatments a day on five consecutive days. While the same procedure cannot be performed on humans because of the invasiveness of fiber optics, Tonegawa says it is merely an “engineering problem.” In the not-too-distant future, he foresees a fast-acting treatment, with fewer of the side effects of current medications.

“People are working on this,” he said. “Others are using nanotechnology to try and activate the cells from outside the brain. It’s difficult, but I think this will be overcome.”

On the other side of the Charles River from Tonegawa, a 44-year-old physician-scientist named Paolo Cassano is also working on depression on the cellular level. His work, the first clinical trial of its kind, could similarly revolutionize patient treatment — not in a few years, but right now.

Like Tonegawa, Cassano came to psychiatric research in a roundabout fashion, through an infectious disease fellowship early in the AIDS epidemic. He became especially interested in patients’ emotional suffering, a major reason why he turned to neuropsychopharmacology, ultimately focusing on treatment-resistant depression.