A clear connection between sleep and neuronal changes

Sleep is a rhythmic behaviour largely controlled by the circadian clock, a biochemical mechanism. This is driven by a group of nerve cells in the brain that entrains certain physical, mental and behavioural changes over a roughly 24-hour period.

Scientists have studied rhythmic synaptic plasticity (changes in the strengths of neural synaptic contacts) in the well-defined zebrafish model. With EU funding of the SLEEP PLASTICITY (The role of rhythmic synaptic plasticity in regulating sleep and behavioral performance) project, researchers characterised synaptic protein function in neuronal circuits that are involved in rhythmic and sleep-dependent synaptic plasticity.

They developed a hypocretin/orexin (HCRT) knockout narcolepsy model to study the function of HCRT neurons and identify new neurotensin (NTS) secreting neurons in the hypothalamus. The fish showed an increase in sleep and sleep/wake transitions, as well as an altered response to external light and sound stimuli. The scientists also ascertained the interaction between NTS secreting neurons and the HCRT system.

Using live imaging and a mutant monocarboxylate transporter 8 (mct8) knockout model, the research results pointed to a link between deficiency of the thyroid hormone transporter, reduced synaptic density in several neuronal circuits and increased sleep. Lack of mct8 in humans disturbs thyroid hormone levels and results in mental retardation.

Another mutant zebrafish, this time devoid of the protein neuronal pentraxin II (Nptx2a), displayed reduced locomotor response to light-to-dark transition states and to a sound stimulus as well as reduced synaptic density. These results indicate that Nptx2a affects locomotor response to external stimuli by mediating structural synaptic plasticity in excitatory neuronal circuits.

Understanding the mechanisms of sleep will facilitate development of therapies for the debilitating sleep disturbances that affect a large percentage of the human population. The novel zebrafish narcolepsy model and other disorders should be invaluable for large-scale pharmaceutical testing in vertebrates.

SLEEP PLASTICITY research has resulted in a string of publications in high-impact journals including Journal of Neuroscience, Frontiers in Neural Circuits, Journal of Comparative Neurology, Journal of Biological Chemistry and PLoS genetics.