Schizophrenia! A Sleep Disorder?

As noted in my last entry, I am on this quest to find different biological markers that are made salient before full-fledge schizophrenia occurs. I am currently doing a project in Professor Tilden’s lab and by default, I believe that melatonin can do extraordinary things (It might be better than sliced bread)! I originally wanted to see if scientists have used melatonin to treat some of the symptoms of schizophrenia. Of course I found a minimal amount of information on the relationship between melatonin and schizophrenia, but an article entitled “Schizophrenia as a possible dysfunction of the suprachiasmatic nucleus (SCN)” caught my attention. We all know that our bodies are coordinated to the outside world when information is sent via the retinohypothalmaic tract to the SCN. Molecularly speaking, there are several genes that are responsible for the SCN output (for the sake of simplicity, I am going to describe the negative feedback loop). During this 24 hour loop, CLOCK and BMAL1 dimerize and form a complex that enters the cytosol of a cell. The complex binds to the E-box region on DNA and promotes the transcription of Per1/Per2 mRNA. The Per1/Per2 mRNA is translated into Per1/Per2 protein, exits the cytosol and forms a dimer with Cry1/Cry2. The presence of this complex negatively inhibits the dimerizatin of Bmal1 and Clock. When CK1 degrades the Cry/Per complex, Bmal1 and Clock will dimerize, re-enter the cytosol and bind to the E-box to facilitate Per1/Per2 gene transcription.

This paper specifically summarizes some important findings that should be of interest. First, they explain that people with schizophrenia and sleep apena utilize a CPAP machine more sporadically than people with sleep apena who have no psychiatric disorder. This essentially means that schizophrenics use the CPAP machine in an arrhythmic manner while non-schizophrenic patients have a distinct rhythm 12:12 rhythm. They incorporate this empirical finding into their hypothesis by explaining that people with schizophrenia clearly have reversed sleep/awake cycles and fragmented sleep, which suggest SCN dysfunction might be the problem. The authors go on to say that SCN dysfunction may be contribute to “dream rebound” during the day.  Dream rebound is the idea that we all have to enter REM sleep during the sleep cycle. Schizophrenics, however, have fragmented sleep and never get the opportunity to enter REM sleep. As a result, the REM portion of their sleep is manifested during the day (without atonia, of course!) You are probably like me at this point—You want hardcore EVIDENCE. Okay, let me go a little deeper. The authors suggest that “dream rebound” symptoms are seen in various studies on schizophrenics. For example, patients with schizophrenia have eye track dysfunction (refer to journal entry number 5). This eye track dysfunction is more prevalent during the day. Additionally, the authors say explicitly that positive symptoms are associated with short REM latency and increased REM density, which might mean that REM sleep builds up during the day.

Then there is a finale (there is always a finale). It might be my favorite part of their hypothesis in the entire paper. We know that the SCN is the master biological clock. Basically, scientists believe that it has the ability to entrain/control all of the biological clocks in different organs (e.g. Kidneys, Liver, Adrenal Glands, Stomach, etc). Also, the authors cite evidence from the New England Journal of Medicine which states that people born between January and May are at a higher risk of developing schizophrenia compared to people born between August and December. Oddly enough, the months between January and May is when people are more exposed to the influenza virus and have limited amounts of light. So… the authors argue that influenza virus has the ability to reset the SCN and exposure to the flu resets the SCN abnormally and causes SCN dysfunction. What? Let me make sure we are on the same page! Exposure to the flu in utero may cause the SCN to set abnormally. This abnormality may cause SCN dysfunction. SCN dysfunction might precipitate hallucinations in schizophrenics by forcing them to experience remnants of REM sleep during the day. SCN dysfunction may also change the output to other areas of the brain and abnormally synchronize other biological clocks. Do you see where this is going?

So, we must ask ourselves if all of this starts with the immune system? Could the SCN be responsible for all these misconnections, since the neurons innervate multiple areas of the brain? When we talk about schizophrenia spectrum disorders, are we really talking about different degrees of SCN dysfunction? The authors of this article also argue that the thalamus is one of the main circuits that sends/receives information from the SCN. We know that all sensory information passes through the thalamus (Olfaction is the exception) and is sent to other processing areas of the brain. Thus, this hypothesis fits nicely into the idea that misconnections in the brain may cause schizophrenia.

I personally believe more research needs to be done on positive/negative feedback in the molecular clock. A lot of research has been conducted on the molecular clock in rodents and Drosophila. It is possible to monitor the rhythmicity of these genes in order to understand SCN dysfunction in schizophrenics? Is it also possible that antipsychotics work by correct SCN dysfunction?

Think about it!

Peace,

*Sharonda

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5 thoughts on “Schizophrenia! A Sleep Disorder?

  1. Woah… The domino effect of a viral infection causing abnormalities in the SCN which influences biological rhythms and sleep cycles then leads to symptoms of schizophrenia. GAH it’s crazy (like us)!
    I also think its funny that you had to bring it all back to the immune system. Man, you love this system!

    While I think that this hypothesis sounds plausible, I am concerned with some of the logic. Where, then, do the negative and positive symptoms come into play? Does the SCN only cause these positive symptoms, which are also altered with antipsychotics? Furthermore, how would cultural and gender differences be explained? As usual, more questions than answers. But great post, Sharonda!

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  2. Wow, it is crazy to think about how something as distant as the time of year you were born can affect your body intensely enough to increase your chances of Schizophrenia! This can’t be the only factor but sure is an interesting one. This article would be good for our Advanced Neuro assignment…

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  3. Sharonda! I’m so glad you wrote this! I was JUST doing reading for Bio Basis about sleep cycles, and specifically Hobson’s theory on dream explanations. He proposed that the brain activation that occurs during REM sleep leads to a sort of hallucination that we attempt to make sense of in a somewhat plausible story. Underneath, I wrote, “like schizophrenia!”- the theory you mentioned about REM rebound fits in so well with this- schizophrenic brains may be experiencing the equivalent brain activation of REM sleep, and attempt to make sense of it as we do our dreams. As in dreaming, the actual stimuli of our dreams are not usually present (though in both dreams and schizophrenic hallucinations background noises are sometimes incorporated). In class we sort of struggled with the idea that a person’s brain can be receiving signals when there is no apparent stimulus initiating the signals… so similar to dreaming. I’m curious now about how those signals begin!

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  4. I’ve read a lot of paper and had a lot of discussions with other researchers who have used this viral hypothesis (or immune hypothesis i suppose) of schizophrenia. I think that it is incredibly interesting, and has a lot of implications in the field. However, I tend to draw parallels between this viral exposure to prenatal stress, because I feel like this could be very similar. Do you guys think that these could be comparable? Which do you find more compelling in terms of animal models?

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