Most people who have pulled an all-nighter are all too familiar with the “tired and wired” experience. Although the body is physically exhausted, the brain is slap-happy, loopy, and almost joyful.
Northwestern University neurobiologists have discovered what causes this punch-drunk effect. Researchers conducted a new study in which they produced mild, acute sleep deprivation in mice and then analyzed their behaviors and brain activity.
During the time of acute sleep loss, not only did dopamine release go up, but synaptic plasticity also went up. This literally rewired the brain to keep the happy mood for a few days.
These fresh findings may aid scientists in better understanding how mood states change naturally. It may also contribute to a better understanding of how fast-acting antidepressants (such as ketamine) function and assist researchers in identifying previously identified targets for future antidepressant drugs.
Potent Antidepressant Effect
Chronic sleep loss has been extensively researched, and its consistently negative effects are well documented.
“But brief sleep loss — like the equivalent of a student pulling an all-nighter before an exam — is less understood. We found that sleep loss induces a potent antidepressant effect and rewires the brain. This is an important reminder of how our casual activities, such as a sleepless night, can fundamentally alter the brain in as little as a few hours,”
said Professor Yevgenia Kozorovitskiy, the paper’s corresponding author. Kozorovitskiy is an expert in neuroplasticity and an associate professor of neuroscience at Northwestern’s Weinberg College of Arts and Sciences. Northwestern postdoctoral fellow Mingzheng Wu is the paper’s first author.
Investigating Sleep Loss Mechanisms
Scientists have long recognized that acute disruptions in sleep are linked to changed mental states and actions. Sleep and circadian rhythm changes in patients, for example, might precipitate mania or, in rare cases, reverse depressive episodes.
“Interestingly, changes in mood state after acute sleep loss feel so real, even in healthy subjects, as experienced by myself and many others,” Wu said. “But the exact mechanisms in the brain that lead to these effects have remained poorly understood.”
Kozorovitskiy and her colleagues devised a new experiment to induce acute sleep loss in mice with no genetic predispositions to human mood disorders. The experimental setup needed to be gentle enough to avoid causing substantial stress for the animals but just uncomfortable enough to prevent the animals from falling asleep.
When compared to controls who had a normal night’s sleep, the animals’ behavior changed to become more aggressive, hyperactive, and hypersexual after a sleepless night.
The researchers used optical and genetically encoded instruments to assess the activity of dopamine neurons, which are responsible for the brain’s reward response. They found that activity was higher in animals during the brief sleep deprivation phase.
“We were curious which specific regions of the brain were responsible for the behavioral changes. We wanted to know if it was a large, broadcast signal that affected the entire brain or if it was something more specialized,”
Kozorovitskiy said.
Medial Prefrontal Cortex Activity
Kozorovitskiy and her colleagues studied four brain regions involved in dopamine release: the prefrontal cortex, nucleus accumbens, hypothalamus, and dorsal striatum. After monitoring these areas for dopamine release following acute sleep loss, the researchers discovered that three of the four areas (the prefrontal cortex, nucleus accumbens and hypothalamus) were involved.
However, the team wanted to narrow the results even further, so they systematically silenced the dopamine reactions.
Only when researchers muted the dopamine response in the medial prefrontal cortex did the antidepressant effect vanish. The nucleus accumbens and hypothalamus, on the other hand, appeared to be most implicated with hyperactive behaviors but were less linked to the antidepressant effect.
The antidepressant effect persisted except when we silenced dopamine inputs in the prefrontal cortex. That means the prefrontal cortex is a clinically relevant area when searching for therapeutic targets. But it also reinforces the idea that has been building in the field recently: Dopamine neurons play very important but very different roles in the brain. They are not just this monolithic population that simply predicts rewards,”
Kozorovitskiy said.
Synaptic Plasticity
While the majority of the behaviors (such as hyperactivity and enhanced sexuality) vanished within a few hours of acute sleep deprivation, the antidepressant effect lasted for a few days. This suggested that synaptic plasticity in the prefrontal cortex was increased.
Kozorovitskiy and her colleagues noticed this when they analyzed individual neurons. Neurons in the prefrontal cortex generated tiny protrusions known as dendritic spines, which are extremely malleable and vary in response to brain activity.
When the researchers used a genetically encoded tool to disassemble the synapses, it reversed the antidepressant effect.
While researchers are unsure why sleep deprivation causes this effect in the brain, Kozorovitskiy believes evolution is at work.
“It’s clear that acute sleep deprivation is somehow activating to an organism. You can imagine certain situations where there is a predator or some sort of danger where you need a combination of relatively high function with an ability to delay sleep. I think this could be something that we’re seeing here. If you are losing sleep routinely, then different chronic effects set in that will be uniformly detrimental. But in a transient way, you can imagine situations where it’s beneficial to be intensely alert for a period of time,”
Kozorovitskiy said.
Kozorovitskiy also warns against pulling all-nighters to lift one’s spirits. The antidepressant effect is only temporary, and we all know how important a good night’s sleep is.
“I would say you are better off hitting the gym or going for a nice walk. This new knowledge is more important when it comes to matching a person with the right antidepressant,”
she said.
Reference:
- Mingzheng Wu et al. Dopamine pathways mediating affective state transitions after sleep loss. Neuron (2023). DOI: 10.1016/j.neuron.2023.10.002
Last Updated on November 11, 2023