People who have pulled an all-nighter may be familiar with that “tired and wired” feeling. Although the body is physically exhausted, the brain feels slap-happy, and almost giddy. Northwestern University neurobiologists suggest they may be the first to uncover what produces this punch-drunk effect. For their study the researchers induced mild, acute sleep deprivation (SD) in mice and then examined their behaviors and brain activity. The team found that not only did dopamine (DA) release increase during the acute sleep loss period, synaptic plasticity also was enhanced—literally rewiring the brain to maintain the bubbly mood for the next few days.

These new findings could help researchers better understand how mood states transition naturally. It also could lead to a more complete understanding of how fast-acting antidepressants (like ketamine) work and help researchers identify previously unknown targets for new antidepressant medications.

“Chronic sleep loss is well studied, and it’s uniformly detrimental effects are widely documented,” said Yevgenia Kozorovitskiy, PhD, an expert in neuroplasticity, an associate professor of neurobiology, and the Irving M. Klotz professor at Northwestern’s Weinberg College of Arts and Sciences, who is corresponding author of the team’s published paper in Neuron. “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.”

Kozorivitskiy, together with first author, Northwestern postdoctoral fellow Mingzheng Wu, PhD, and colleagues described their findings in a paper titled, “Dopamine pathways mediating affective state transitions after sleep loss.” In summary, they wrote, “Using behavioral, genetically targeted, and projection-specific chemogenetic manipulations, we dissected the functions of distinct subgroups of dopamine (DA) neurons in state transitions characterized by elevated activity across several behavioral domains and diminished depressive-like behavior.”

Affective disorders, characterized by significant mood disturbances, are psychiatric disorders that can significantly diminish quality of life and increase mortality, the authors wrote. “Predominant affective disorder states are depression, featuring sadness and loss of interest in activities, and mania, characterized by elevated mood and overactivity that impair cognitive function.” Scientists have long known that acute perturbations in sleep are associated with altered mental states and behaviors. Alterations of sleep and circadian rhythms in patients can, for example, trigger mania, but they can also reverse depressive episodes. “Alterations in sleep and circadian rhythms are common features in affective disorders,” the team noted. “Sleep deprivation (SD) and chronobiological treatments can reverse depressive episodes, suggesting that sleep loss induces a global switch of affective states.”

Wu further explained, “Interestingly, changes in mood state after acute sleep loss feel so real, even in healthy subjects, as experienced by myself and many others. But the exact mechanisms in the brain that lead to these effects have remained poorly understood.”

To explore these mechanisms, Kozorovitskiy and team developed a new method for inducing acute sleep loss in mice that had no genetic or pharmacologic predisposition related 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. “Here, we create a hybrid method for automated SD to evaluate dopaminergic correlates of behavioral state transitions featuring changes across several behavioral domains,” they stated. “This relatively mild and acute sleep perturbation provides a tool to understand and control the affective state lability.”

The investigators found that after a sleepless night, the animals’ behavior shifted to becoming more aggressive, hyperactive, and hypersexual, compared with control animals that experienced a typical night’s sleep. The team also noted, “… acute SD evoked the transition to a hyperactive state but normalized a depressive-like state, raising the question of whether these two directions of state transitions depend on the same or different neural mechanisms.”

Changes in the dopaminergic system have been broadly implicated in affective disorders and sleep regulation. For their study, using optical and genetically encoded tools, the researchers measured the activity of dopamine neurons, which are responsible for the brain’s reward response. And they found activity was higher in animals during the brief sleep loss period. “We were curious which specific regions of the brain were responsible for the behavioral changes,” said Kozorovitskiy.  “We wanted to know if it was a large, broadcast signal that affected the entire brain or if it was something more specialized.”

To investigate this further, Kozorovitskiy and the team examined four regions of the brain responsible for dopamine release: the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), hypothalamic area (HA), and dorsal striatum (dStr). 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.

Looking to hone their results even further, the team then systematically silenced the dopamine reactions. “We used projection-specific chemogenetic inhibition of DA neurons to dissect the dopaminergic regulation of behavioral changes in affective state transitions induced by acute sleep loss.” They found that the antidepressant effect disappeared only when the dopamine response was silenced in the medial prefrontal cortex. By contrast, the nucleus accumbens and hypothalamus appeared to be most involved in the hyperactivity behaviors, but were less connected to the antidepressant effect. “Altogether, these findings suggest that multiple subgroups of distributed DA projections broadly control the transition to manic-like states, while mPFC-targeting DA neurons more specifically mediate the transition from a depressive-like state,” they commented.

Kozorovitskiy further explained, “The antidepressant effect persisted except when we silenced 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.”

While most of the behaviors (such as hyperactivity and increased sexuality) disappeared within a few hours following acute sleep loss, the antidepressant effect lingered for a few days. This suggested that synaptic plasticity in the prefrontal cortex might be enhanced.

When Kozorovitskiy and her team examined individual neurons, they discovered just that. The neurons in the prefrontal cortex formed tiny protrusions called dendritic spines, highly plastic features that change in response to brain activity. Our results showed that dendritic spine density on apical dendrites of deep-layer pyramidal neurons in the mPFC was significantly increased 24 h after SD.”

When the researchers used a genetically encoded tool to disassemble the synapses, it reversed the antidepressant effect. The findings, they said, “… show that acute SD enhances structural synaptic plasticity in the mPFC in a DA-dependent manner, similar to the plasticity driving effects recently described for several rapidly acting antidepressants,” they wrote.

While researchers do not fully understand why sleep loss causes this effect in the brain, Kozorovitskiy suspects evolution is at play. “It’s clear that acute sleep deprivation is somehow activating to an organism,” Kozorovitskiy said. “You can imagine certain situations where there is a predator or some sort of danger where you need a combination of relative 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 also cautions people not to start pulling all-nighters in order to brighten a blue mood. “The antidepressant effect is transient, and we know the importance of a good night’s sleep,” she said. “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.”

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