Tahnee Mackensen watches zebrafish larvae dart across her screen, their movements tracked by software that reveals more than just swimming patterns—it captures the rhythm of their rest. In a dim lab at Pompeu Fabra University, these nearly transparent creatures are helping unravel a mystery deep in the brain: how tiny genetic switches called microexons regulate when we sleep, when we’re alert, and what happens when that balance breaks. The answer, her team has found, lies in fragments of genes so small they were once overlooked, now revealed as critical conductors of arousal.
Arousal—the brain’s readiness to respond to the world—is essential for survival. Too little, and we’re drowsy and unresponsive; too much, and we spiral into insomnia and sensory overload. This balance, conserved across species from fish to humans, depends on precise protein production in neurons, guided by alternative splicing. When microexons—gene segments as short as 3 to 27 nucleotides—are incorrectly spliced, the consequences are profound. In zebrafish, it triggers hyperarousal: larvae swim erratically, fall asleep later, sleep less, and show heightened neural activity, especially in the forebrain.
The team, led by Mackensen and senior researcher Manuel Irimia at UPF and the Center for Genomic Regulation (CRG), discovered that mis-spliced microexons disrupt cAMP signaling, a key cellular messenger. "Abnormal fish are permanently overexcited," Mackensen says. Their neurons fire more, driven by elevated cAMP levels. But when researchers used a chemical inhibitor to reduce cAMP, the hyperactive fish calmed down, their behavior returning to normal. Conversely, boosting cAMP in healthy fish made them act like the mutants—proof that cAMP acts as a neural thermostat.
This mechanism isn’t unique to fish. The same microexon disruptions caused sleep deficits in flies in earlier work by the same team, suggesting an evolutionary thread stretching to humans. In people, altered microexon splicing is linked to autism and schizophrenia—conditions often marked by sleep disturbances and sensory hypersensitivity. While these genetic changes aren’t the root cause of such disorders, they likely shape symptom severity. "We know that changes in protein production can contribute to symptoms of the disorder," Irimia explains.
The discovery opens a path not to cures, but to understanding—offering a new lens on how subtle genetic shifts can ripple through neural circuits. By tuning the thermostat of arousal, science may one day help quiet overactive minds, not by rewriting genes, but by restoring the balance they once kept.