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Researchers identify elusive cell type in the brain that control circadian rhythms.

A team of researchers form the UT Southwestern Medical Center and University of Tsukuba have identified key cells within the brain that are critical for determining circadian rhythms, the 24-hour processes that control sleep and wake cycles, as well as other important body functions such as hormone production, metabolism, and blood pressure.  Circadian rhythms are generated by the suprachiasmatic nucleus (SCN) located within the hypothalamus of the brain, but researchers had previously been unable to pinpoint which of the many thousands of neurons in the region were involved in controlling the body’s time-keeping mechanisms.

Now, the team has found that a group of SCN neurons that express a neuropeptide called neuromedin S (NMS) is both necessary and sufficient for the control of circadian rhythms.  The findings may offer important targets for future treatments of diseases and problems related to circadian dysfunction, which range from jet lag and sleep disorders to neurological problems such as Alzheimer’s disease, as well as metabolism issues and psychiatric disorders such as depression.  The opensource study is published in the journal Neuron.

Key studies in the 1970s revealed that the SCN communicates and coordinates cells throughout the body to control circadian rhythms, but the SCN contains many neurons with different expression patterns of neuropeptides and neurotransmitters.  Which of these neurons responsible for producing circadian rhythms was a major unanswered question in neurobiology. The team state that the current study marks a significant advancement in the understanding of the body clock.

NMS is a neuropeptide, a protein made of amino acids that neurons, which are cells in the brain, use to communicate. Researchers created unique mouse models to determine that NMS-expressing neurons act as cellular pacemakers to regulate circadian rhythms. Specifically, the research team found that modulating the internal clock in just the NMS neurons altered the circadian period throughout the whole animal. In addition, the study provided new insights into the mechanisms by which light synchronizes body clock rhythms.

Previously the team identified and cloned the first mammalian gene, called Clock, related to circadian rhythms. Since then, the lab has determined that disruptions in the Clock and Bmal1 genes in mice can alter the release of insulin by the pancreas, resulting in diabetes, and they determined the 3-D structure of the CLOCK-BMAL1 protein complex, which are considered to be the batteries of the biological clock.

The team were also the first to identify the important role that endothelin plays on the cardiovascular system, and later, with their discovery of orexin, showed that sleep/wakefulness is controlled by a single neuropeptide.  The team have since identified numerous receptors involved in the regulation of appetite and blood pressure, as well as other neuropeptides that play an important role in the regulation of energy metabolism, stress responses, emotions, and other functions.

Source:  UT Southwestern Medical Center

 

Schematic Summary of Findings.  (A) NMS-expressing neurons are localized in the core, central, and shell regions of the SCN and encompass the majority of VIP- and AVP-expressing neurons, but do not overlap with GRP-producing neurons. A small number of VIP- or AVP-expressing neurons (~5% each) that do not express NMS are not depicted here.  (B) Green cells represent Nms neurons. Lengthening the intracellular circadian period of Nms neurons lengthens behavioral circadian period. Abolishing molecular rhythmicity of Nms neurons or blocking synaptic transmission from Nms neurons leads to the loss of coherent circadian rhythms.  Neuromedin S-Producing Neurons Act as Essential Pacemakers in the Suprachiasmatic Nucleus to Couple Clock Neurons and Dictate Circadian Rhythms.  Yanagisawa et al 2015.
Schematic Summary of Findings. (A) NMS-expressing neurons are localized in the core, central, and shell regions of the SCN and encompass the majority of VIP- and AVP-expressing neurons, but do not overlap with GRP-producing neurons. A small number of VIP- or AVP-expressing neurons (~5% each) that do not express NMS are not depicted here. (B) Green cells represent Nms neurons. Lengthening the intracellular circadian period of Nms neurons lengthens behavioral circadian period. Abolishing molecular rhythmicity of Nms neurons or blocking synaptic transmission from Nms neurons leads to the loss of coherent circadian rhythms. Neuromedin S-Producing Neurons Act as Essential Pacemakers in the Suprachiasmatic Nucleus to Couple Clock Neurons and Dictate Circadian Rhythms. Yanagisawa et al 2015.

 

 

 

 

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