Biological Clock Neural Map Established

 Neuroscience  

In a recent issue of Neuron, researchers report the discovery of a crucial part of the biological clock: the wiring that sets its accuracy to within a few minutes out of the 1440 minutes per day. This wiring uses the neurotransmitter, GABA, to connect the individual cells of the biological clock in a fast network that changes strength with time of day.

The World Health Organization lists shift work as a potential carcinogen, says Erik Herzog, PhD, Professor of Biology in Arts & Sciences at Washington University in St. Louis. And that’s just one example among many of the troubles we cause ourselves when we override the biological clocks in our brains and pay attention instead to the mechanical clocks on our wrists.

In a recent issue of Neuron, Herzog and his colleagues report the discovery of a crucial part of the biological clock: the wiring that sets its accuracy to within a few minutes out of the 1440 minutes per day. This wiring uses the neurotransmitter, GABA, to connect the individual cells of the biological clock in a fast network that changes strength with time of day.

Daily rhythms of sleep and metabolism are driven by a biological clock in the suprachiasmatic nucleus (SCN), a structure in the brain made up of 20,000 neurons, all of which can keep daily (circadian) time individually.

If the SCN is to be a robust, but sensitive, timing system, the neurons must synchronize precisely with one another and adjust their rhythms to those of the environment.

Herzog’s lab has discovered a push-pull system in the SCN that does both. In 2005 they reported that the neurons in the clock network communicate by means of a neuropeptide (VIP) that pushes them to synchronize with one another.

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As the researchers now report, these neurons also communicate with GABA that pulls on them weakly, so they are not too tightly coupled.

Together these two networks (VIP and GABA) ensure the clock runs as coordinated, precise timepiece but one that can still adjust its timing to synchronize with the environment.
“We think the neurotransmitter network is there to introduce enough jitter into the system to allow the neurons to resynchronize when environmental cues change, as they do with the seasons,” Herzog says.

But, he says, since this biological ‘reset button’ evolved long before mechanical clocks, artificial lights, and high-speed travel, it doesn’t introduce enough jitter to allow us to adjust quickly to the extreme time shifts of modern life, such as flying “backward” (east) through several time zones.

Understanding the push-pull system in the SCN has enormous implications for public health, bearing, as it does, on daylight saving times, shift work, school starting times, medical intern schedules, truck driver hours, and many other issues where the clock in the brain is pitted against the clock in the hand.

The problem is knowing if that increase was a coincidence or a consequence. The technique, called BSAC (Between Sample Analysis of Connectivity) reliably reveals functional connections by first describing the statistics of impossible connections. If the two neurons are in different dishes, they cannot communicate so the increased firing of neuron 2 must have been a coincidence.

By recording from lots of neurons in independent networks, BSAC defines the weakest possible connections that can be detected within a neural network. This could be useful in mapping connections between pairs of neurons or between brain regions.

The goal of the recent work in the Herzog lab has been to figure out how the clock cells are connected to each other. “It wasn’t clear, for example, if each neuron communicated with just a few of its neighbors or with all of them,” Herzog says.

In this network the connections are made by the neurotransmitter GABA (γ-amino-butyric acid). “We proved we had found a GABAergic network by applying drugs that block GABA receptors on the cells,” Herzog says. “All of the connections we had mapped between neurons dropped out.”

Remarkably, when the network drops out, the clock becomes more precise. So the GABAergic network destabilizes the clock; it jiggles it a little.

Herzog points out that the GABAergic network, is sparse, weak and fast (much faster than the VIP network, which relies on the slower action of a neuropeptide), as you might expect a jitter-generator to be.

“We think the GABAergic network is there to let our clocks adjust to environmental cues, such as gradual, seasonal changes in sunrise and sunset,” says Herzog.

It’s a bit like whacking an old television set that has lost vertical synch to get it to resynch with the broadcast signal.

But there isn’t enough jitter in the clock to allow it to make abrupt adjustments, such as the one-hour forward jump when Daylight Savings Time starts. That “spring forward” has been statistically shown to increase the likelihood of heart attacks and car accidents, Herzog says.

In any case, it is clear that if people repeatedly force the clock to reset, they throw off more than sleep. The biological clock regulates metabolism and cell division as well as sleep/wake cycles. So shift work, for example, is associated both with metabolic disorders, such as diabetes, and with the unregulated cell division that characterizes cancer.

Herzog points out that the neurons in the SCN are coupled oscillators, like these metronomes on a table that has enough give that each metronome’s motion affects the others’. Like the metronomes, the neurons keep time individually and because they are coupled by the VIP network, they synchronize their beats. Video by the Ikeguchi Laboratory, in the graduate school of science and engineering at Saitama University in Japan.

SOURCE  Washington University in St. Louis

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