All mice groom themselves to keep their fur clean, but some in a lab in Columbia University, New York, have started grooming to an unusual and excessive degree. This isn’t vanity. Instead, it’s the rodent equivalent of the repetitive rituals that many people with obsessive-compulsive disorder (OCD) go through, like an irresistible urge to wash their hands or clean themselves.
The mice didn’t start off with their compulsions. Over five days, psychiatrist Susanne Ahmari used flashes of light to activate neurons that run between two regions at the front of their brains—the orbitofrontal cortex (OFC) and the striatum. She didn’t do it for long—just five minutes a day—but slowly, the mice groomed themselves more and more.
Meanwhile, a few states away, another group of scientists did the opposite. Eric Burguière at MIT in Boston worked with mice that were born without a gene called Sapap3without a gene called Sapap3—a loss that leads to anxiety, repetitive grooming, and other symptoms that are similar to those of OCD.
Burguière used the same strategy as Ahmari: He activated specific neurons in the rodents’ brains using flashes of light. But he aimed his pulses at a different set of neurons in the striatum and his mice stopped their unnecessary grooming. Ahmari had created a compulsion, while Burguière had erased one.
These studies, conducted independently, tell us more about the brain circuits that produce compulsive behaviours and those that suppress them. “In order to treat people with severe and disabling compulsions, it is important to understand precisely how their brain is functioning and how it may be different,” says Dawn Eagle, a neuroscientist at the University of Cambridge. “This will potentially allow us to tailor different treatments to different types of compulsive problem.”
And as Ahmari says, “I find that the more understanding we have about the biological basis of a psychiatric illness, the less stigma is associated with it and the less shame patients feel regarding their symptoms.”
When scientists have scanned the brains of people with OCD, they’ve seen more neural activity in areas like the OFC and the striatum. But why? Is this activity the cause of obsessions and compulsions, or does it actually reflect an attempt to hold those symptoms at bay?
To answer this question, Ahmari turned to a technique called optogenetics, which involves implanting neurons with light-sensitive proteins. Scientists can then turn those specific neurons on or off by flashing them with different colours of light, delivered by an optic fibre. Invented in 2005, optogenetics has revolutionised the study of the brain by allowing neuroscientists to control specific sets of neurons in specific parts of the brain.
Ahmari used the technique on her mice to specifically stimulate the neurons that connect the OFC and striatum. At first, nothing happened. But as Ahmari repeatedly activated the circuits, for five minutes a day every day, the mice spent more time grooming. Even when the flashes stopped, the mice still continued their excessive grooming for weeks.
That’s a pretty clear result. Small bursts of abnormal activity in the OFC-striatum circuits can produce compulsive behaviours, but only if repeated over time. “The implication is that it’s lasting [changes] in the circuit, not the acute activation, that makes a difference,” says Chris Pittenger, a psychiatrist from Yale University. “That is a key insight.”
If the results hold in humans, what causes the abnormal bursts of activity in the first place? “The short answer is we donʼt know,” says Ahmari. Genetic differences might mean that the neural circuits aren’t set up correctly, making them unusually responsive to incoming signals. Alternatively, stress, trauma or even infections could make these circuits more active. Most likely, it’s all of the above.
“If we can figure out triggers, we may be able to prevent the condition before it starts,” says Ahmari. Alternatively, there may be ways of stopping the neurons from becoming fixed in their abnormally active ways, either with new drugs or through strategies learned during therapy. (For example, when she gave her rodents Prozac—one of the few drugs that can treat OCD—their grooming habits returned to normal in a few weeks.)
Burguière’s study suggested a different way of treating compulsions. He works in the lab of neuroscientist Ann Graybiel, who has spent decades studying how habits are formed and broken. Last year, she used optogenetics to show that even longstanding habits can be broken by silencing neurons in one part of the brain. And she wondered: Could compulsions be busted in the same way?
To find out, Burguière worked with mutant mice that naturally groom themselves in a compulsive way. Just dabbing a drop of water onto their heads will set them off. The team showed that this behaviour was due to a hyperactive striatum—the same area that Ahmari had focused on. The striatum is mostly made of ‘medium spiny neurons’ (MSNs), a type that carries signals to other parts of the brain. But it also contains a smaller set of ‘fast-spiking interneurons’ (FSIs) that act like supervisors, keeping the classroom of rowdy MSNs in check. If the MSNs are acting up, maybe it’s because the FSIs aren’t doing their jobs.
To test this idea, Burguière once again turned to optogenetics. When he stimulated neurons connecting the OFC and striatum, they spurred the FSIs into silencing their hyperactive MSNs. The flashes of light, just three-seconds long, jolted the supervisors into controlling the charges, and completely stopped the mice from grooming abnormally.
This might explain why deep-brain stimulation, in which implanted electrodes deliver electricity to specific neurons, has shown promise in reducing the symptoms of OCD in early trials. DBS is a bit of a blunt instrument but Burguière thinks that this study might sharpen it, by showing doctors which areas to stimulate to get the best effects.
Now, a careful reader might be slightly confused. How did Burguière erase compulsions by activating OFC-striatum circuits, when that’s what Ahmari did to create compulsions? The answer is that they weren’t activating the same circuits.
Ahmari focused on neurons that connects the middle of the OFC with the bottom of the striatum, and is involved in reward and emotion. Stimulate these, and you can create compulsive behaviour. Burguière targeted a neurons connecting the sides of the OFC with the centre/top of the striatum, which are more involved in learning and carrying out actions. Stimulate these, and you can treat OCD-esque symptoms. “The two manipulations are similar but when you look at the anatomical details, they are actually targeting different sub-circuits,” says Pittenger.
Last year, I wrote about two studies on depression, which used optogenetics to trigger neurons in the same part of the brain and got completely different effects. This is yet another reminder of how fiendishly complicated the brain can be, even when we’re using tools as powerful as optogenetics.
There are, of course, some caveats. Eagle notes that while a rodent’s striatum is reasonably analogous to a human’s, there’s a lot more debate about how similar the OFC is in both species. And “neither study produces compulsive behaviour in the true sense of the word—behaviour that continues to excess despite adverse consequences,” she says.
Many researchers treat excessive grooming as a decent rodent proxy for excessive hand-washing in people with OCD, since both behaviours can be triggered by similar genetic mutations and suppressed by the same drugs. “But mice and people are clearly different,” cautions Ahmari. “Mice can’t tell us when they are obsessing, and they can’t describe why they are engaging in abnormal repetitive behaviours.” Still, “the rodents are proving to be excellent translatable models of components of compulsive behaviours, and are invaluable for studying the expression of symptoms of compulsion,” says Eagle.
There is still a lot of work to do. Burguière is designing tasks that might allow his team to study the rodent versions of other OCD-like behaviours, from intrusive thoughts to other ritualised actions.
And Ahmari wants to know exactly which types of cells or brain chemicals in the striatum are responsible for producing compulsions. “This may help us identify new treatment targets based on altering activity in specific cell types,” she says. “I want to make it very clear that this study is only the first step towards finding new and more effective treatments for OCD.”
More on optogenetics:
Ahmari, Spellman, Douglass, Kheirbek, Simpson, Deisseroth, Gordon & Hen. 2013. Repeated Cortico-Striatal Stimulation Generates Persistent OCD-Like Behavior. Science http://dx.doi.org/10.1126/science.1234733
Burguière, Monteiro, Feng & Graybiel. 2013. Optogenetic Stimulation of Lateral Orbitofronto-Striatal Pathway Suppresses Compulsive Behaviors. Science. http://dx.doi.org/10.1126/science.1232380