AsianScientist (Apr. 2, 2015) – Researchers have uncovered a specific group of nerve cells that may be a valuable target in the treatment of diseases associated with our daily behavioral and biological rhythms. Their research has been published in Neuron.
Daily processes such as the sleep-wake cycle, hunger and hormonal secretions are controlled by the circadian cycle. The circadian cycle exists in almost every cell in our bodies and is regulated by a master pacemaker or clock, located within two tiny structures in the brain called the suprachiasmatic nuclei (SCN).
The SCN itself contains a network of about 20,000 neurons and is strategically positioned near the optic nerves. This location allows the SCN to receive signals relating to how much light is entering the eye, permitting the neurons to reset their clocks periodically.
Disruption of these circadian cycles has been associated with various disorders and diseases in humans, for example, the well-documented association between sleep disruption, obesity and diabetes. The roles of the specific cell types within the SCN responsible for generating circadian rhythms, in contrast, are poorly understood.
How does this huge network of neurons within the SCN work together to set the biological clock? Until now, it has been very difficult to answer this question. This has been due partly to the lack of genetic tools available to selectively study the specific cell types in the SCN responsible for this synchronization.
In the present study, researchers focused on the neuropeptide neuromedin S (NMS) in mice brains because it is produced exclusively in a particular subset of neurons in the SCN. This allowed them to create several different transgenic mice in which the expression of specific genes essential to circadian behavior could be selectively turned on or off in the NMS neurons simply by adding or removing a particular chemical to their drinking water.
The researchers showed that the NMS neurons can control the length of the circadian cycle and are essential for the generation of rhythmic behavior. Mice in which the essential pacemaking Clock gene had been overexpressed in NMS neurons had a circadian cycle significantly longer than that of control mice. When the Clock gene was turned off in these mice, they reverted to the normal rhythm. Turning off two other essential pacemaking genes, Bmal1 and Per2, abolished the normal circadian rhythms and behavior in the mice.
The researchers also found that NMS neurons make up about 40 percent of the SCN, suggesting that this subset of neurons is capable of reorganizing the entire SCN network.
To investigate how NMS neurons communicated with other neurons in the SCN, mice were generated in which the release of neurotransmitters from the synaptic vesicles of NMS neurons was blocked. These mice exhibited a loss of circadian rhythmicity, while control mice displayed normal rhythms.
When the release of neurotransmitters was unblocked, the mice completely recovered their rhythmicity. This demonstrates that NMS neurons are capable of synchronizing the thousands of neurons in the SCN network to set the biological clock via synaptic transmission.
The researchers believe that similarities in the neuro- and chronobiology of mice and humans mean it is likely that there is a human equivalent of this specific set of pacemaking neurons. These neurons would be attractive targets for the development of new diagnostic methods and treatments for disorders related to biological clock dysfunction.
The article can be found at: Lee et al. (2015) Neuromedin S-Producing Neurons Act as Essential Pacemakers in the Suprachiasmatic Nucleus to Couple Clock Neurons and Dictate Circadian Rhythms.
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Source: University of Tsukuba.
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