Microexons tied to zebrafish sleep and arousal in study
UPF and CRG researchers report that altered neuronal microexons made zebrafish larvae overactive and sleep less, pointing to a conserved arousal pathway.
By Tom Brennan · Health & Medicine Correspondent
3 min read
Tiny gene segments called microexons may help set the brain’s level of alertness, according to a zebrafish study led by Pompeu Fabra University and the Center for Genomic Regulation. The finding matters because disrupted arousal, poor sleep and sensory hypersensitivity are also seen in some neurodevelopmental conditions.
The international team reported in Science Advances that abnormal inclusion of neuronal microexons pushed zebrafish larvae into a hyperaroused state. The researchers linked that state to stronger neural activity, changed swimming behavior and reduced sleep.
Microexons are very small sections of genes that can be included or skipped when cells make RNA. According to the UPF and CRG team, that process, known as alternative splicing, helps organisms produce related proteins with different functions.
The researchers said proper control of arousal depends in part on that protein variety during development and adulthood. Arousal regulation is conserved across animals, they said, helping balance low responsiveness with excessive alertness.
Sleep and movement changed in larvae
In the zebrafish experiments, larvae with abnormal neuronal microexon patterns swam differently from normal fish and slept less. Tahnee Mackensen, the study’s first author, said the affected larvae had fewer sleep bouts, shorter sleep periods and a longer delay before sleep.
The team used calcium imaging to assess neural activity in the transparent larvae. According to the researchers, the abnormal fish showed increased activity in the forebrain, consistent with an overexcited state.
The study also focused on cyclic AMP, or cAMP, a signaling molecule inside cells that helps regulate neuronal excitability. The researchers found that microexon mis-splicing changed cAMP levels, making neurons more or less excitable.
Drug experiments supported that link, according to the paper. Lowering cAMP with a chemical inhibitor brought activity in the abnormal fish down toward normal, while keeping cAMP elevated in normal fish by boosting its production or limiting its breakdown produced highly aroused behavior.
The researchers said those results point to the cAMP-PKA-CREB pathway as a driver of the arousal changes observed in zebrafish. Mackensen described cAMP as acting like a control system for neuronal activity.
Possible links beyond fish
Manuel Irimia, who led the research, said the same group had previously seen a similar set of behavioral and neuronal changes in flies. He said the mechanism is likely conserved in mammals, including humans, though it may not work in the exact same way.
The researchers connected the work to autism and schizophrenia because sleep disruption and sensory hypersensitivity are common in those disorders, and both have been associated with altered microexon regulation. Irimia said the protein-production changes are not described as the cause of disease, but may contribute to symptoms.
The team said the fish results raise the question of whether correcting arousal in this model could ease related symptoms in other species. Mackensen also noted that the same cAMP-regulated arousal pathway has been implicated in anxiety and depression, giving researchers another reason to study it further.
The study was titled “Neuronal microexons modulate arousal via the cAMP-PKA-CREB pathway in zebrafish.” It was published in Science Advances with Tahnee Mackensen and colleagues as authors.
This story draws on original reporting from Medical Xpress.