Striking study links fight-or-flight brain pathway to appetite hormone

Striking study links fight-or-...
The zebrafish were more likely to win a fight for social dominance if they had been deprived of food for six days
The zebrafish were more likely to win a fight for social dominance if they had been deprived of food for six days
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The zebrafish were more likely to win a fight for social dominance if they had been deprived of food for six days
The zebrafish were more likely to win a fight for social dominance if they had been deprived of food for six days

For several years, researchers from the RIKEN Center for Brain Science have been running regular zebrafish “fight clubs” to study exactly what kind of neural mechanisms differentiate those that quickly concede from those that are victorious. A new study has now discovered a common appetite hormone, also present in humans, seems to activate a key neural pathway that determines how quickly the fish withdraw from fights.

Zebrafish have been found to be incredibly useful organisms for modeling social conflict. If two male fish are dropped into the same tank they will immediately battle for social dominance. They don’t fight to the death, but instead they face-off until one surrenders.

“Winners tend to show active behaviors, such as biting, chasing, striking, and freely swimming around the tank, whereas losers tend to show passive behaviors, such as fleeing, freezing, retreating, and staying at the bottom of the tank,” the researchers write in their new study, recently published in the journal Cell Reports.

Prior work homed in on activity in a tiny pea-sized region of the brain called the habenula as fundamental to whether a zebrafish wins or loses a fight. This revealed that two separate, competing neural pathways in the habenula could determine whether a fish concedes in a fight or vigorously battles on.

Genetically engineering the fish would quite literally create winners and losers. Silencing the “winning” pathway made the fish quicker to withdraw from a fight, while knocking out the "losing" circuit predisposed the fish to fight on longer.

So, once these two competing neural pathways were identified, the next step in the research was to work out what factors regulate their activity. This new research explored the effect of starvation on habenula activity, and the outcomes of zebrafish social conflicts.

The research found the zebrafish were much more likely to win in a fight after they had been starved for six days. In fact, the hungry zebrafish won around 75 percent of the fights.

“Hungry fish are more motivated to obtain food,” explains Haruna Nakajo, an author on the new study. “And since winners of fights secure more resources such as food, it makes sense that starved fish try harder to win fights.”

Even more interestingly, the research revealed starvation induced greater activity in the previously identified “winning” neural circuit prior to a fight even beginning, a finding that is novel to this new study. This suggests several days of starvation already primes the “winning” neural circuit.

It is still unclear how much food deprivation is necessary to effectively activate this "winning" neural circuit, but the researchers do suggest mere hunger from skipping one meal is not enough, but instead several days of starvation may be needed.

The research also discovered this entire mechanism seems to be mediated by a hormone called orexin. This particular hormone, only recently discovered in the late 1990s, is known to play a role in regulating appetite and wakefulness.

In the context of this research, orexin was found to directly activate the “winning” neural circuit in response to several days of starvation. This is the first study to provide clear evidence of orexin playing a role in social behaviors such as fighting, however, it is not an outlier. A recent study in mice suggested orexin may play a key role in the animal’s fight-or-flight mechanism – a hypothesis that is certainly backed up by the findings in this new zebrafish research.

Nakajo does note these particular animal studies are not entirely divorced from human outcomes. These newly discovered neural mechanisms should translate to humans.

“The habenula–interpeduncular pathway is evolutionary conserved from fish to humans,” says Nakajo. “So we think that similar functions are conserved even in humans.”

Oh, and in case you were wondering, the researchers did indeed pit two starved zebrafish against each other to see what would happen. A fight between two of the fish would generally last around 400 seconds, even if one of the fish had been starved. But, a fight between two starved fish lasted around 800 seconds on average. It seems when both participants were hungry, and showing active “winning” habenula activity, neither would easily give up and the fights would last for significantly longer.

The new research was published in the journal Cell Reports.

Source: RIKEN

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