Sleep research with a conditional transgenic mouse mutant: the effects of CNS-specifically overexpressed CRH on sleep and an involvement of the HPA axis in sleep-wake regulation

 

Mayumi Kimura

Max Planck Institute of Psychiatry, Munich, Germany

 

     In recent years, genetic approaches have become popular among many fields of science. Especially, to find causative genes specific to severe illness is the hottest target in biomedical sciences, and such an effort has been made also in the filed of sleep research. Meanwhile, it is getting relatively convenient to have access to genetically manipulated models, thus, several researchers have conducted sleep studies using transgenic or knock-out (KO) mice, in which a gene encoding their favorite ‘a sleep-promoting factor’ is over-expressed or depleted. Initially, the purpose of these gene manipulations was to create or seek an animal (or a mouse) that sleeps a lot or does not at all. However, the results were complicated more than we suspected. Since sleep is such a fundamental animal behavior, other endogenous factors or transmissions could have compensated the effects of a missing/overflowing gene-product on sleep to survive. Therefore, determining a sleep-related gene or an insomnia-triggering gene seems not to be as easy as we would imagine.

     However, aren’t there any benefits of using genetic techniques and apply them to our sleep studies? There surely have been interesting reports showing a gene that influences a particular frequency of sleep EEG or diminishes some effects of psychostimulants on vigilance. Upon this lecture, I would like to introduce my recent study with a conditional transgenic mouse mutant in which a gene of corticotropin-releasing hormone (CRH) is overexpressed restrictedly in the CNS. CRH is known as an initial mediator that controls all descending chemical reactions in responses to stress-related stimuli. Stress activates the hypothalamic-pituitary-adrenal (HPA) axis as well as the autonomic nervous system, resulting in increased levels of arousal. Indeed, exogenously administered CRH is capable of promoting wakefulness, although its effects on sleep are not really distinguished from the effects of other stress-related hormones. Using the regional-specific CRH-overexpressing mice makes it possible to investigate a solo effect of CRH on sleep. In this model, significant changes in sleep patterns were found, especially in REM sleep. Further, an appearance of rebound sleep was similar to that seen in other animal models for depression. According to the results obtained from the CRH-overexpressing mice, a role of CRH and the HPA system in sleep-wake regulation will be discussed.