A new probe to study appetite and sleep-wake cycle
The correct functioning of the nervous system relies on a complex and delicate balance between billions of elements, the neural cells. Neurons communicate to each other tirelessly to make sure we can accomplish all our tasks, from breathing to doing maths. This finely regulated communication is in the hands of a series of molecular messengers, known as neurotransmitters and neuromodulators. Although they are produced and released by small pools of neurons in limited brain regions, neuromodulators are characterized by their long-range action, and are therefore capable of regulating a multitude of mechanisms throughout the nervous system. Orexins are one example of neuromodulators: they are synthesized by only 50,000 neurons (among over 80 billions) but, through a tangle of long-range connections, they control extremely complex functions such as our sense of hunger and sleep-wake cycle.
Type 1 narcolepsy is a chronic and disabling sleep disorder, characterized by daytime drowsiness and loss of muscle tone (cataplexy). It affects 4 out of every 10,000 people, and it is linked to the partial or total disruption of the orexinergic system. So, in order to identify the cellular basis of this impairment, scientists must first examine the orexins’ action at high spatial and temporal precision in healthy brains. These vital but challenging “high-resolution” studies have recently become a reality thanks to the collaboration between such seemingly distant disciplines as molecular engineering, optical microscopy, and neurophysiology: modern molecular design strategies allow artificial fluorescent molecules to act as ‘light tags’, binding to small proteins that are naturally present in our brain (e.g. the orexins), and allowing them to be investigated under the microscope lens. The research group led by Prof Tommaso Patriarchi, at the University of Zurich, leveraged this possibility to design OxLight1, the first molecular probe able to report, with unprecedented temporal fidelity, orexin’s concentration in the living brain. Thanks to DEEPER, a collaborative project funded by the European Commission under the Horizon2020 framework, it has been possible to test OxLight1 in multiple brain states, including during different phases of sleep, or during moderate physical exercise.
As reported in the journal Nature Methods, following the orexins’ action at high spatial and temporal resolution enables testing of the hypothesis that neuromodulators can regulate disparate complex functions thanks to their targeted action on specific brain regions, rather than through a mechanism of large-scale bulk signaling. The research group led by Dr Tommaso Fellin at the Italian Institute of Technology (IIT), in Genova, designs and applies novel optical approaches to study brain function. They have used a modern microscopy technique, known as two-photon imaging, to monitor OxLight1 signals in the brain. This research revealed that orexin levels increase in specific brain regions upon awakening from anaesthesia.
The multidisciplinary approach taken in this project paves the way for designing further high-fidelity molecular probes for the study of neuronal communication, as well as the discovery of novel therapeutic molecules capable to interfere with the neuromodulatory systems when their function is disrupted.