Adapted from a news story that originally appeared on the Schizophrenia Research Forum

9 April 2007. Doctors and caregivers have known for years that people with Alzheimer disease have an altered sense of time. Demented patients lose their normal diurnal rhythm, for example, and are often found wandering around in the middle of the night—a particularly troubling prospect for caregivers. Reports of “sundowning,” or late-afternoon bouts of agitation, confusion, and disorientation are also suggestive of altered biological rhythms (see recent review by Bachman and Rabins, 2006). But are these behaviors due to malfunctions in the circadian clock itself, or are they due to a failure of the brain to read a properly running clock? Time may soon tell. Over the last few decades, scientists have made strides in understanding the molecular machinery that drives the endogenous mammalian clock, and some surprising associations have emerged.

Recently, for example, researchers reported that the protein SCOP, or SCN oscillatory protein, plays a crucial role in learning and memory (see ARF related news story), even though SCOP levels do not oscillate outside the SCN. (The SCN, or suprachiasmatic nucleus, is a tiny area that sits above the optic chiasm and houses the circadian clock). Of more immediate relevance, Dick Swaab and colleagues at the Netherlands Institute for Neuroscience, Amsterdam, reported that as AD progresses, circadian oscillation of key clock components—Bmal 1, cryptochrome 1, and period 1—begins to break down in the pineal gland (see Wu et al., 2006), which is believed to modulate circadian output from the SCN. But perhaps most intriguingly, in the March 26 PNAS online, Colleen McClung and colleagues at University of Texas Southwestern Medical Center in Dallas reported that mutation of the protein CLOCK, a key cog of the mammalian circadian oscillator, causes manic symptoms in mice akin to those found in people with bipolar disorder. This may not be immediately relevant to AD, but it raises the possibility that perturbances in circadian clock proteins may be sufficient to profoundly alter behavior.

Manic Mice
In the human SCN, a molecular feedback loop involving CLOCK and many other proteins operates on a precise, almost 24-hour cycle. This endogenous clock acts as the body’s central pacemaker, setting the rhythm for a wide range of biological processes, including sleep/wake cycles, body temperature, and hormone levels. Though it has been 30 years since scientists reported that the cyclical episodes of mania and depression that characterize bipolar disorder oscillate in phase with the circadian cycle (see Sitaram et al., 1978), it is only recently that scientists have been able to investigate that relationship at the molecular level.

“We wanted to look at some of the specific genes involved in circadian rhythm to see if they would have any effect on mood and reward or other measures that might be associated with psychiatric disorders,” McClung said in an interview with the Schizophrenia Research Forum. First author Kole Roybal and colleagues chose to examine mice originally described by coauthor Joe Takahashi and colleagues at Northwestern University, Illinois (see King et al., 1997). In these animals, a point mutation causes exon skipping and a loss of 51 amino acids in the CLOCK protein. The mutation renders CLOCK inactive and perturbs the transcriptional feedback loop that serves as the central circadian oscillator.

“In every way that we could test them they looked like bipolar patients in the manic state,” said McClung. Roybal and colleagues found that the CLOCK mutants have heightened preference for rewarding stimuli, such as self-administered stimulation of the medial forebrain bundle in the brain, which leads to a type of hedonic state, preference for sucrose, and the effects of cocaine. “This is similar to behavior seen in the manic state when patients with bipolar disease often succumb to shopping or gambling sprees,” suggested McClung.

The CLOCK mutant mice were also less likely to become depressed, for example when put through stressful tests such as a forced swim. In these tasks, normal mice gave up much earlier than CLOCK mutant mice. The latter were also more likely to remain exposed in an open field test, suggesting that they are generally less anxious than their wild-type counterparts. In addition, the researchers found that lithium, which has been used for years as a mood-stabilizing drug, calms the animals and restores behavior to near wild-type levels.

CLOCK Around the Brain
It is unclear whether these behavioral changes are related to perturbation in the circadian oscillator itself or some other area of the brain. CLOCK, for example, is highly expressed in the hippocampus, as is SCOP. “It could be that CLOCK has an independent function that is unrelated to its role in the SCN, but it could also be that CLOCK is having an effect in dopamine cells,” said McClung. “One thing that we and others have found is that basically all the components of the dopamine system are circadian. Dopamine levels, receptors, the enzymes involved in dopamine synthesis all have a circadian rhythm, so maybe its normal function is to control the rhythm in dopamine firing and dopamine transmission.”

The researchers tested this idea by introducing functional CLOCK into the ventral tegmental area (VTA) of the brain, a region that plays a key role in the brain’s reward pathways and is laden with dopaminergic cells. McClung and colleagues used viral vectors to transfect the VTA of CLOCK mutant mice with functional CLOCK genes, a technique that coauthor William Carlezon at McLean Hospital, Belmont, Massachusetts, has successfully employed to transfect cells in specific areas of the brain. Thirty-five percent of VTA cells were infected with the viral vectors, normalizing behavior. “This gives us a focal point to target for future studies,” said McClung.

More generally, these CLOCK mice may represent a useful model of manic symptoms. “These mice are a complete and well-characterized model of human mania and that is something that has been lacking in the field. We haven’t really had a good mouse model to test why mania develops and also to test how mood stabilizers function. It is still somewhat of a mystery as to how they have their effects in the brain. So this mouse gives us an opportunity to study both the development of bipolar disorder and the treatment of bipolar disorder,” said McClung.

In an accompanying PNAS commentary, Joseph Coyle, also from McLean Hospital, noted that “an important limitation of the mutant CLOCK model is that it recreates only the behavioral homologues of mania but not the mood oscillations characteristic of bipolar disorder.” McClung said that she is uncertain why the mice do not have the full-blown spectrum. “They seem to only show manic phase. As far as we looked they don’t seem to go into depression spontaneously, but we are planning to test them in some different paradigms to see if activity or stress may make them go into depression, but we haven’t tested that yet,” she said. She added that bipolar disorder is a complicated disease and people can go through long periods where they seem perfectly normal.

It will be interesting to see if rescue of CLOCK mutants by VTA-transfection of normal CLOCK is related to circadian oscillation in dopamine cells, and if mutation of CLOCK in the SCN alone leads to any effect on behavior. A direct role of the circadian clock would support proposals to use melatonin, which is normally secreted by the pineal gland at night, bright lights, or perhaps pharmacological means to reset and maintain robust circadian rhythms.—Tom Fagan.

Reference:
Roybal K, Theobold D, Graham A, DiNeri JA, Russo SJ, Krishnan V, Chakravarty S, Peevey J, Oehrlein N, Birnbaum S, Vitaterna MH, Orsulak P, Takahashi JS, Nestler EJ, Carlezon Jr. WA, McClung CA. Mania-like behavior induced by disruption of CLOCK. PNAS. 2007, March 26, early edition. Abstract

Coyle JT. What can a clock mutation in mice tell us about bipolar disorder? PNAS. 2007, March 26 early edition. Abstract

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  1. It is my belief that the role of melatonin merits further analysis in dementia research.

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References

News Citations

  1. Signal Transduction and Memory—SCOP Scuppers MAPK Pathway

Paper Citations

  1. . "Sundowning" and other temporally associated agitation states in dementia patients. Annu Rev Med. 2006;57:499-511. PubMed.
  2. . Pineal clock gene oscillation is disturbed in Alzheimer's disease, due to functional disconnection from the "master clock". FASEB J. 2006 Sep;20(11):1874-6. PubMed.
  3. . Circadian variation in the time of "switch" of a patient with 48-hour manic-depressive cycles. Biol Psychiatry. 1978 Oct;13(5):567-74. PubMed.
  4. . Positional cloning of the mouse circadian clock gene. Cell. 1997 May 16;89(4):641-53. PubMed.
  5. . Mania-like behavior induced by disruption of CLOCK. Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6406-11. PubMed.
  6. . What can a clock mutation in mice tell us about bipolar disorder?. Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6097-8. PubMed.

External Citations

  1. Schizophrenia Research Forum

Further Reading

Papers

  1. . Mania-like behavior induced by disruption of CLOCK. Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6406-11. PubMed.
  2. . What can a clock mutation in mice tell us about bipolar disorder?. Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6097-8. PubMed.

News

  1. Signal Transduction and Memory—SCOP Scuppers MAPK Pathway

Primary Papers

  1. . Mania-like behavior induced by disruption of CLOCK. Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6406-11. PubMed.
  2. . What can a clock mutation in mice tell us about bipolar disorder?. Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6097-8. PubMed.