【Science sub-journal】Break the traditional concept! Luo Donggen's team at Peking University discovered a new mechanism for maintaining circadian rhythms

This article is the original of the translational medicine network, please indicate the source when reprinting

Author: Sophia

Circadian rhythms are coordinated by the brain's main clock and operate
freely even under constant conditions.

At its core is the molecular rhythm with a 24-hour cycle of negative feedback between the clock gene and its protein (won the 2017 Nobel Prize in Physiology or Medicine
).

For a long time, it was widely believed that the main biological clock alone was sufficient to maintain circadian rhythms
.

Luo Donggen's team's new discovery breaks through this traditional theory
.

On September 2, Luo Donggen's team of researchers from the School of Life Sciences of Peking University published a research paper titled "An extra-clock ultradian brain oscillator sustains circadian timekeeping" in the journal Science Advances, reporting on a new type of electrical signal and its neural mechanism
that maintains circadian rhythms.

It turns out that the master clock is not self-sufficient and cannot maintain a free-running rhythm of behavior, but requires additional endogenous input
from the extra-clock superpotential brain oscillator.

_msthash="251139" _msttexthash="381004">Research background

 01 

The main biological clock in the brain consists of interconnected neuronal circuits, each containing its own molecular clock
.

The molecular clock generates an active cycle
of approximately 24 h through the cell-independent transcriptional translation feedback loop (TFL).

Because these molecular clocks cycle synchronously with each other, neurons within the central master clock can maintain a uniform timing to continuously coordinate circadian rhythms
, even under constant darkness (DD).

However, it remains unknown
whether the master clock is only able to maintain a free-running timing by relying on communication between its cell-autonomous molecular clock and neurons within the central biological clock.

To solve this problem, the research team performed multielectrode patch-clamp recordings of Drosophila clock neurons to characterize the pattern and origin of basal electrical activity, which is organized for circadian timing without external time input
.

Research process

 02 

This is the first time to develop a method that can record the fine electrical activity of all Drosophila clock neurons, and during the course of the study, the team further developed the four-electrode patch-clamp recording technology of Drosophila brain clock neurons, and then observed that clock neurons produce synchronized rhythmic action potential emission throughout the brain, and found that this synchronous emission is completely dependent on synaptic input
outside the main biological clock.

Through a large-scale screening of tens of thousands of Drosophila strains, it was found that this rhythmic electrical activity came from a small group of spontaneously oscillating neurons, named xCEO (extra-Clock Electrical Oscillator
).

After the nerve activity of the x CEO is silenced by genetic methods, the circadian electrical activity output of the clock neuron completely disappears, and the behavior rhythm of the fruit fly also disappears; When xCEO's neural activity is restored, the rhythm of behavior is restored
.

Thus, the work revealed that the brain's main clock itself is not enough to maintain circadian rhythms, but to determine the circadian electrical activity output
by integrating the endogenous brain oscillation input of xCEOs and the membrane potential changes regulated by its own molecular clock.

Studies suggest that endogenous brain oscillation signals that maintain circadian rhythms may be the core mechanism
of the biological clock that is conservative in both insects and mammals.

xCEOs maintain circadian rhythms

The study found

 03 

The study found that most clock neuron subtypes exhibit a pattern of synchronous superelectric subburst discharges, which is driven by synaptic inputs from outside the
master clock.

In addition, the researchers found a set of true ultramicrobrain oscillators that mediate bursts of input from outside the clock into clock neurons
.

In addition, additional clock oscillators and clock neurons form a hub circuit
through parallel single synaptic connections at the adnexal medulla oblongata (aMe).

The genetic silencing of these ultraclock ultraelectric oscillators suggests that it is critical that they maintain the free operation of the motor rhythm by working with molecular clocks to set the circadian rhythm (the key timing output of the
central circadian rhythm output).

The study identified the first group of oscillator neurons within the Drosophila brain and revealed their neural mechanisms
in maintaining circadian rhythms.

The study breaks through the traditional theoretical framework, updates the understanding of biorhythms in the field, and also provides a new way
to study the generation of oscillating nerve signals in the brain and its function.

Resources:

https://news.

This article is intended to introduce medical research advances and cannot be used as a reference for
treatment options.

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