Flying a lot? Jet lag may cause anxiety and inhibit neurogenesis

Reference: Horsey, E. A., Maletta, T., Turner, H., Cole, C., Lehmann, H., & Fournier, N. M. (2020). Chronic jet lag simulation decreases hippocampal neurogenesis and enhances depressive behaviors and cognitive deficits in adult male rats. Frontiers in Behavioral Neuroscience.

Imagine flying from New York to Paris. You board your flight at 6pm and settle in for eight hours of cramped slumber. But you are a night owl with a typical bedtime in the small hours of the morning, so right after you finally doze off, the plane lands. Sleep-deprived, you find yourself in the streets of Paris, smelling fresh baguettes – it is eight in the morning here! You have trouble even remembering what you had planned for the day, so instead of visiting the Louvre, you drag yourself to the hotel and pass out. By the time you wake up, the famous Paris bistros are serving dinner.  You are jet lagged.

(1) Hopping over time zones disrupts circadian rhythms and causes jet lag. Photo by Eva Darron on Unsplash

Rapid switches between multiple time zones, such as those that occur when flying across long distances, can upset our internal clocks, called circadian rhythms. This causes a temporary sleep disorder known as jet lag. Occasional jet lag is rarely worse than confusion and a scrambled sleep schedule, but its chronic occurrence can cause learning and memory difficulties and even reduce the volume of the brain. A new study suggests that jet lag-induced disruptions of mood and memory may be rooted in diminished neurogenesis, or birth of new nerve cells in the brain.

A team of researchers at Trent University, Canada, used rats to investigate the brain mechanisms behind jet lag symptoms. Instead of flying their long-tailed research subjects across time zones, the science team adjusted the rats’ sleeping schedules by simply changing when the lights turned on and off. 

The rats routinely got twelve hours of light and twelve hours of darkness, but once a week, the lights went out six hours too early. This prolonged “nighttime” simulated travel from New York to Paris. On the next day, the room went dark at the usual time once again, until early nightfall was repeated the following week. This artificial weekly jet lag continued for two months, while a control group of rats enjoyed an uninterrupted normal sleep schedule. Then, the scientists studied how chronic schedule shifts affected the rats’ behavior and brains.

Jetlag causes anxiety
(2) Elevated plus maze assesses anxiety in laboratory rodents. This cross-shaped construction stands about one-and-a-half feet off the ground; two of its arms are enclosed by walls and the other two are open to the world. Confident rats (left) explore its open arms, and the anxious rats (right) hide in the enclosed ones.

The researchers were interested in whether disruptions of circadian rhythms made the rats more anxious, depressed, or forgetful. To measure the rats’ anxiety, the researchers used the elevated plus maze, which has two open arms and two enclosed arms (2). Rodents prefer lurking in corners to roaming in the open, but they also like to explore new spaces. The rats on the normal dark-light schedule spent much more time exploring the open arms than the jet- lagged rats, who hid in the enclosed arms. The researchers interpreted this result as high anxiety levels among the jet lagged rats. 

(3) Novel object recognition test reveals how well animals form memories. A rat briefly explores two novel objects, a ball and a tiny basket, spending about equal time on each (left). After a break, the rat recognizes the ball and spends more time sniffing around the unfamiliar cube (right).

The exploratory nature of rodents also allowed the researchers to measure memory in the jet-lagged rats. In the novel object recognition test (3), the rats explored two objects for five minutes, sniffing them and touching them with their paws. After one hour, one of the objects was swapped out for a new one. The rats once again spent five minutes exploring the two objects: one old, one new. At this point, the rats on the normal schedule were not very interested in the old object and spent their time sniffing around the new one. However, the jet-lagged rats were equally interested in both objects, acting as if they couldn’t remember that they had already seen one of them.

(4) Forced swim test measures signs of depression in rodents. Depressed rats are more likely to stop swimming around in search of an exit, so researchers rescue them from the water.  After fifteen minutes of swimming, all rats get pulled out of the tank to prevent exhaustion.

Finally, the researchers studied whether disrupted circadian rhythms caused depression in the rats. They measured how quickly the rats “gave up” in a forced swim test (4). Each rat swam around in a cylinder full of water for a few minutes, trying to find the exit or somewhere to stand. Rats who stopped searching and just floated were considered to give up on the task, and were promptly rescued and dried off. The jet-lagged rats gave up much sooner than the normal light-dark scheduled rats, suggesting depression in the jet-lagged rats. 

Lacking new brain cells

Mimicking chronic jet lag made the rats anxious, forgetful, and prone to depressive symptoms. But behavior is only half of the story: what are the brain mechanisms behind these symptoms? The researchers investigated the possibility that these symptoms stemmed from disrupted neurogenesis.

Neurogenesis occurs in the brains of many adult mammals, including humans, and is thought to participate in memory formation and emotional response. Sleep deprivation halts formation of new neurons, and disrupted neurogenesis is linked to anxiety and depression. Since sleep deprivation is a key component of jet lag, could repressed replenishment of brain cells be the reason behind its ill effects?

The hippocampus (“seahorse” in Latin) was named after its long and curved shape, reminiscent of a seahorse. Photo by Paul Hewart on Unsplash

The researchers collected the rat brains and used a technique called immunohistochemistry to search for a protein called doublecortin in the rat neurons. This protein is found in newborn neurons, and its presence in the brain indicates neurogenesis. The research team focused on the hippocampus – a brain region that creates new memories and constantly makes new neurons.

In the brains of jet-lagged rats, cells with doublecortin were few and far between. To make matters worse, most of the new cells were stuck in the early stages of maturation, suggesting that they were reluctant to grow up and be useful. By contrast, new neurons appeared and developed normally in the brains of rats who were not jet lagged.

Direction of jet lag matters

Chronic jet lag appeared to quench neurogenesis in rats and make them anxious, forgetful, and prone to giving up – but not all jet lag is created equal. The researchers also examined a group of rats whose lights went out six hours too late once a week for two months, mimicking travel from New York to Hawaii. Interestingly, performance on the behavioral measures and neurogenesis was similar for these rats compared to rats with normal sleep schedules. 

This discrepancy in findings between the two groups of jet-lagged rats suggests that it matters which way we travel around the world – an eastward expedition may wreak more havoc upon our circadian rhythms than a voyage to the west. More research is needed to discover why this is the case. 

Although globetrotting is off the table amid the COVID-19 pandemic, maintaining a healthy sleep schedule is as important as ever: inconsistent bedtimes can also disrupt circadian rhythms. This study focused on rats, but confusing our internal clocks can be dangerous for mental health in humans, too. Circadian rhythms control neurogenesis and brain function, and a good night’s sleep goes a long way in keeping the brain healthy.