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Zawartość zarchiwizowana w dniu 2024-05-29

Disorders of sleep regulation: basic mechanisms and thepapeutic perspectives

Final Report Summary - ENOUGH SLEEP (Disorders of sleep regulation: basic mechanisms and thepapeutic perspectives)

The general objectives of the project were the following:
1) To spearhead the first integrated effort at understanding the different mechanisms of sleep regulation using a combined genetic, molecular, electrophysiological and systems approach.
2) To develop novel diagnostic tools (genetic, molecular and electrophysiological) for identifying disorders of sleep regulation and for characterising their pathophysiology.
3) To apply such tools in the diagnosis and cure of disordered sleep, with special emphasis on insomnia and depression.

More specific the project included the following objectives:
1) Identify cortical mechanisms of sleep regulation.
2) Identify sub-cortical mechanisms of sleep regulation.
3) Identify humoral and genetic mechanisms of sleep regulation.
4) Explore the role of glia in sleep regulation.
5) Develop new diagnostic tools to specifically study sleep regulation in humans.
6) Understand the mechanisms responsible for the alterations of sleep regulation in insomniac / depressed patients in order to envision new treatments.

The relationships of cortical activity and excitability and sleep / sleep homeostasis were examined using High density electroencephalography (EEG) and Transcranial magnetic stimulation (TMS). The magnetic pulse used to stimulate the brain needed to be targeted with great accuracy.

An important advancement was to show that high sleep pressure is associated with an increased slope of slow waves, allowing the use of the slope as an indicator of sleep homeostasis. Interesting differences in the cortical excitability and Slow wave activity (SWA) were found between normal subjects and bipolar patients. The amount of SWA was decreased in the frontal areas but increased in the occipital areas.

New interesting results were found regarding memory and sleep. In mice, sleep deprivation immediately following acquisition induced a memory deficit, when the experiment was performed during daytime (the rest period of mice), but had no effect when performed during night-time (the waking-period of mice).

The roles of basal forebrain, Suprachiasmatic nucleus (SCN) and thalamus were addressed with a series of experiments. It was shown that the Basal forebrain cholinergic (BF) cells are essential for the production of recovery sleep (sleep that follows prolonged waking periods).

The relationships between immune system and sleep were addressed by measuring the expression of SOCS, regulators of cytokine activity, and iNOS induction as well as NO and microglia. It was found that short term sleep deprivation did not induce SOCS expression, although SOCS genes are induced by cytokines, and IK-1b and TNFa are induced by sleep deprivation. It was also demonstrated that the effects of NO on recovery sleep are only partially mediated through the cGMP pathway and that NO can either activate (low doses) or inhibit (high doses) BF neurons.