New Internal Clock Identified

New Internal Clock Identified
Pam Harrison
February 27, 2015
Researchers have identified a second internal clock in the brain that can desynchronize when dopamine tone is elevated, leading to aberrant patterns of arousal that are strikingly similar to perturbed sleep-wake cycles in certain psychopathologies, including bipolar disorder.
Published online February 12 in the journal eLife, the investigators, led by Ian Blum, a PhD candidate at McGill University, Montreal, Canada, note that the findings provide strong evidence that a dopaminergic ultradian oscillator (DUO) drives rhythms of behavioral arousal that can be dysregulated in the context of high dopaminergic tone.
"Under normal conditions, this DUO cycles in harmony with the circadian...pacemaker and the rhythmic information of both [internal clocks] are integrated...to create the daily pattern in locomotor activity," the investigators write.
However, in a series of experiments using genetically modified mice, the team was able to show that increasing extracellular dopamine levels by disrupting the dopamine transporter gene significantly lengthened periods of ultradian locomotor rhythms from the normal span of about 4 hours' activity to up to and beyond 48 hours.
Similarly, by exposing experimental animals to the psychostimulant methamphetamine, the team observed a gradual lengthening of locomotor oscillations from their standard 4-hour periods of activity to periods of activity lasting up to 100 hours or longer.
In contrast, haloperidol, which selectively blocks certain dopamine receptors in the brain and lowers dopaminergic tone, significantly shortened DUO activity cycles.
"Dopamine plays an integral role in the oscillator process, and it can be 'tuned' by changing dopamine tone," Kai-Florian Storch, PhD, McGill University, told Medscape Medical News.
"And by increasing brain dopamine levels, the oscillator and thus arousal systems can be pushed to periods of 24 to 48 hours and even much longer," he said.
This is very reminiscent of an individual's suffering from ultrarapid cycling bipolar disorder, in which patients show manic episodes every second day.
"We believe that it is very likely that these manic episodes are a product of the DUO running at 48 hours," he said.
Dr Storch also believes the findings are at least suggestive that dopamine dysregulation is possibly causal in bipolar disorder and that once dysregulated, the dopamine system causes the oscillator to run at what appears to be 48-hour cycles, "thereby creating the particular pattern of depression and mania that we often see in bipolar patients," he said.
The authors also speculate that oscillator imbalance may be associated with schizophrenic episodes in patients with schizophrenia who often exhibit rest-activity cycle aberrations that are also strikingly similar to those observed in their mouse models of oscillator dysregulation.
And although still speculative, Dr Storch believes that eventually being able to monitor cycles of activity in patients suspected of being bipolar or who might have schizophrenia could provide an objective measurement for diagnosis as well as treatment effectiveness.
Resource: Medscape
Date: 27/2/15

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