National Academy of Sciences

Picture yourself driving home. Half way there, you find a huge tree in the middle of the road, blocking your normal route. Rather than abandoning hope, you turn around and go home by another way.

When our brain regains function after one region is damaged, this effectively is what it is doing. Though this plasticity of the brain has been observed for many years, how this happens is just starting to be understood.

In a new study life scientists from University of California, Los Angeles, and the Garvan Institute of Medical Research in Australia report one mechanism of brain compensation–recruitment of alternate circuits. These pathways, somewhat surprisingly, do not need to be near the damaged site.

“Most views of compensation following tissue loss (stroke for example) think of compensation occurring in adjacent tissue,” write the authors. “A unique finding here is that compensation can occur in regions that are not directly proximal to the site of injury.”

The hippocampus, a small seahorse-shaped structure deep in the brain, is the brain’s bedrock of learning and memory formation. It can be damaged by a lack of oxygen or a stroke, and its dysfunction is key in Alzheimer’s disease

To test the brain’s rewiring capacity, Moriel Zelikowsky and her colleagues taught lab rats to fear a tone, through conditioning with electrical shocks. Damage to the hippocampus removed this fear and slowed their ability to form memories post-injury. The animals were still able to learn, however, by bringing a section of the brain known for storing long-term memories, into action.

To find this, Zelikowsky traced early gene expression in the brain following injury to the hippocampus. She found dramatic rearrangement of cells in the frontal cortex, specifically in the infralimbic and prelimbic regions of the medial prefrontal cortex (mPFC).

The researchers believe the mPFC is playing a more general role in memory and context-sensitive learning, rather than the specific role it has been assigned in the past, of exciting and inhibiting fear.

Researchers hope this understanding will eventually direct them toward treatments for patients suffering degeneration or memory loss after a brain injury. Many have tried to simulate repair within the hippocampus, for instance, but these findings open new possible targets.

“Interestingly, previous studies had shown that these prefrontal cortex regions also light up in the brains of Alzheimer’s patients, suggesting that similar compensatory circuits develop in people,” co-author Bryce Vissel told UCLA.

“While it’s probable that the brains of Alzheimer’s sufferers are already compensating for damage, this discovery has significant potential for extending that compensation and improving the lives of many.”

At the moment a former smoker catches a whiff of tobacco, glimpses the corner store where they used to buy cigarettes, or sees a stranger pull a pack of smokes out of their pocket, something happens in their brain that causes an intense craving, even years after they’ve quit. In a PNAS Early Edition paper published this week, scientists have now described the molecular events that happen in the brain at this precise moment that a former nicotine addict is faced with a cue to smoke.

“The big question is what’s the neurobiology of why people are vulnerable to relapse,” says Peter Kalivas of the Medical University of South Carolina. And in his latest work, Kavilas narrowed in on an area of the brain that he suspected might be involved in relapse based on previous knowledge on habits.

“We all go through life with a series of habits,” Kalivas explains. These habitual tasks are mediated by habit circuitry in the brain, which lets your brain go into a kind of auto-pilot to complete them. When a habit is disrupted, however–whether that means the road you normally drive home is closed or the coffee shop rearranges its milk and sugar–a part of the brain called the frontal cortex becomes involved, more actively planning out your actions. But if the frontal cortex repeatedly mediates this new behavior, it becomes a new habit, replacing the old one in the brain’s habit cortex and no longer requiring that active control.

For cigarette smokers, as well as cocaine and heroin addicts, the habit cortex doesn’t become reprogrammed when they quit, Kalivas says. “Unlike normal habits, where if you get enough new signals, it changes the behavior, they don’t seem to be able to change their smoking habit very effectively.”

The frontal cortexes of former smokers are fully functional, so Kalivas and his colleagues suspected that the signalling between the frontal cortex and the habit circuitry might be to blame for the stubborn cravings. To test their hypothesis, the scientists trained nicotine-addicted rats to associate a particular light and sound with receiving a dose of nicotine. Then, the animals were forced to quit nicotine, given no doses for two weeks–long enough that the drug would have fully left their body and a normal habit would have been reprogrammed in the brain.

Next, the scientists flashed the same light and sound that the rats had previously learned to associate with nicotine. The animals’ brains showed huge increases in activity, unlike any normal response to trained stimuli (they tested rats that had been trained to associate the same stimuli with sugar, and didn’t see the same massive response in the brain).

The researchers saw a rush of signalling molecules–one called glutamate, specifically–in an area of the brain called the nucleus accumbens, a key connection between the frontal cortex and the habit circuitry.

“Not only do you get this huge outpouring of signalling,” Kalivas says, “but the connection actually keeps getting stronger.” This overstimulation is likely what causes an intense craving when faced with a cue to smoke, he says.

The team went on to show that when they blocked the molecules in this part of the brain that respond to glutamate, the rats no longer wanted a dose of nicotine when faced with the sound and light (they chose not to press a lever in their cage that would give them the drug).

“Just these kinds of drug-associated stimuli alone are capable of producing very rapid changes in the brain that stimulate drug-seeking behavior,” says Kalivas. “By discovering what some of those changes are, I think we can find some very strong potential targets for treatments.”

The scientists are now moving toward an initial human clinical trial of a drug that can block the response to glutamate, hoping to see the same diminished nicotine craving observed in the mice.