Taking cues from binge drinking mice

Researchers have found mice that binge drink when given free access to alcohol have a previously unidentified brain circuit that is out of whack.

The wiring error may mean the rodents don’t experience the negative outcomes of drinking, such as bad feelings and pain hypersensitivity, which pushes them to over imbibe.

The finding, published in the journal Science, could fuel new research to hunt down a similar circuit in people with alcohol use disorders.

The researchers, led by neurobiologist Kay Tye from the Salk Institute for Biological Studies, US, point to the puzzling statistic that while 80% of people will try alcohol, less than 30% go on to become compulsive drinkers.  

“So many people are exposed to alcohol at some point in their lives, but why is it that some people can drink casually, just for fun, and other people develop alcohol use disorders?” asks Tye.

Excess alcohol is a factor in more than 200 diseases, yet only half of heavy drinkers in the US can cut down or quit, despite the heavy toll. Tye’s group set up a meticulous experiment in mice to find out why.

First they gauged the natural propensity to binge drink. The mice were given access to plain alcohol laced with increasing amounts of quinine, a bark derivative that gives tonic water its bitter taste.

The quinine top-up called last drinks for some of the mice. But one group remained unfazed – they not only drank more straight booze, they simply carried on guzzling as the drink got tainted with tonic.

The binge-like behaviour roused the researchers’ suspicion that something might be amiss in a brain bit called the periaequeductal grey (PAG). It’s a ring of tissue in the midbrain that modifies behaviour by punishing it with, among others, negative feelings.

The team also knew changes in the medial prefrontal cortex (mPFC) – which deals with judgment, decision making and keeping a lid on impulses – are linked to compulsive drinking.

Could something be up with the crosstalk between those two zones, they wondered?

To find out they turned to calcium imaging. It’s a technique that uses fluorescence, and the intimate role of calcium in the release of the brain’s chemical messengers, to visualise which neurons are firing – in real time.

Armed with the tech the researchers zoomed in on 352 neurons that relay signals between the mPFC and the PAG.

The chatter, they found, was way off in the binge mice.

The pathways that turn down “punishment” from the PAG were overactive in the mice, which meant they weren’t getting the message “alcohol is bad”.

Crucially, the messaging error was there before the critters did any drinking – it was part of their make-up.

“I think that the things I’m most excited about with this study are simply that we’ve identified a biomarker that can predict the future development of compulsive drinking,” says Tye.

As a double check, the team deployed optogenetics, which uses light to turn on or off brain cells labelled with a light-sensitive protein, to alter the messaging between PAG and mPFC.

When they turned down input from the PAG punishment centre, binge drinking got worse. Turning up the PAG had the opposite effect, all consistent with its proposed role.

The main game, of course, is to find ways to help people. The team plans to genetically sequence these neurons in a bid to find drug targets for human alcohol use disorders.

Tye is upbeat on the prospects.

“[I]f we could leverage synaptic plasticity mechanisms to target this circuit, we might be able to prevent, inoculate, change someone’s proclivity to become a compulsive drinker,” she says.

“[T]his just is an amazing handle, an entry point to be able to study compulsive drinking which we haven’t had before.”

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