What do we know:
Our brain tries to maintain balance: the longer we stay awake, the more we need to sleep. However, we know very little about what signals in the brain help us maintain this balance. We know of one protein, called BDNF, that accumulates in the brain the longer you stay awake, which could be a signal that tells your brain that you have been awake for a long time and need to sleep. Consistent with this, putting BDNF into the brain promotes sleep. We also know that BDNF tends to function when it interacts with its receptor, called TrkB.
What don’t we know: It is unknown how BDNF and its receptor, TrkB, increase sleep.
What this study shows: The researchers found that getting rid of one type of the TrkB receptor causes mice to have increased sleep/wake fragmentation (i.e., frequent flip-flopping between sleep and wakefulness). They also found that these mice spend more time in REM sleep (the stage of sleep when you dream) and enter REM sleep more quickly. These effects on REM sleep are interesting because they are similar to sleep changes observed in depressed people.
What we can do in the future because of this study: Future studies could show if BDNF still causes sleepiness in mice lacking the TrkB receptor. Also, it is possible that changing TrkB activity might improve sleep quality, which may be relevant for the depressed population.
Why you should care: Although every animal sleeps, we know very little about why we sleep and what makes us sleepy. This study not only helps us better understand what in our brains makes us sleepy, but may help shed light on mental health disorders, such as depression.
Most animals, including humans, cycle between wakefulness and two different types of sleep—rapid eye movement (REM) sleep and non-REM sleep (NREM). However, little is known about how our brain regulates wake, REM, and NREM onset and offset, and how much REM and NREM sleep we need to feel well rested. Scientists are beginning to figure out which brain areas and which signaling molecules are important for sleep regulation. One signaling molecule, BDNF, is produced in the brain during wakefulness and high levels of BDNF can induce sleep. It is unknown, however, how BDNF causes sleepiness. There are different types of BDNF receptors (i.e., anything that binds to BDNF, thus propagating the signal), so this study explored the importance of one type of BDNF receptor—TrkB.T1—on sleep regulation. The researchers performed experiments with a mouse strain lacking only the TrkB.T1 receptor with other types of BDNF receptors unaffected. They were surprised to find that overall wake and NREM time were normal in mice without the TrkB.T1 receptor. However, the researchers found that these mutant mice had many abnormalities regarding REM sleep; specifically, TrkB.T1 knockout mice entered REM sleep sooner and spent more time in REM sleep compared to control mice. These effects on REM sleep are especially interesting because psychiatric illnesses, including depression, are associated with these same types of sleep changes. Moreover, some people who commit suicide have reduced levels of TrkB.T1 in certain areas of their brain, suggesting a potential link between sleep disturbances and major depressive disorder. Therefore, it is possible that this study discovered why some mentally ill people have abnormal sleep, which helps future studies design better, more targeted therapeutics.
Sleep timing is regulated by both circadian rhythms and poorly-understood homeostatic processes. The neurotrophin BDNF may be a key player in sleep homeostasis since interstitial BDNF levels rise after prolonged wakefulness and intracerebroventricular infusion of BDNF promotes sleep. However, it is unclear which signaling pathways are responsible for mediating the sleep-promoting effects of BDNF. The high-affinity receptor for BDNF—TrkB—has at least two major isoforms: a kinase-containing full-length isoform, TrkB.FL, and a truncated, kinase-lacking isoform, TrkB.T1. The function of TrkB.T1 is far less-well understood, but it has comparable brain expression to TrkB.FL and is enriched in brain areas critical for normal sleep/wake regulation. Therefore, the authors hypothesized that BDNF promotes sleep through the TrkB.T1 receptor. To test this hypothesis, they performed polysomnographic (EEG) sleep/wake recordings in TrkB.T1 constitutive knockout mice. Surprisingly, TrkB.T1 knockout (KO) mice exhibit normal amounts of wakefulness and NREM sleep, although wake and NREM sleep fragmentation is increased (i.e., shorter bouts and more transitions between sleep and wake). Further, TrkB.T1 KO mice spend more time in REM sleep, enter REM sleep sooner, and have longer REM bouts compared to wildtype controls. These results suggest that BDNF acting through the TrkB.T1 receptor suppress REM sleep. These results are relevant for the REM sleep abnormalities associated with several psychiatric disorders, as reduced BDNF levels correlate with depression and reduced TrkB.T1 receptor expression is associated with increased suicide mortality. Collectively, this study demonstrates one pathway by which BDNF influences sleep expression, which may also be relevant for understanding the role of neurotrophins in mental illnesses.