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The line of "depressed Rouen mice"
developed by researchers at the Unité de Neuropsychopharmacologie
Expérimentale (Experimental Neuropsychoparmacology Unit, CNRS -
Université de Rouen), is the first genetic model of depression
in mice. It opens the door to particularly interesting prospects for studying
the genes that influence susceptibility to depression and should make
it possible to take a closer look at the neurophysiological and neurochemical
mechanisms of antidepressants as well as at a selection of new antidepressants.
Depression represents a wide range of pathologies
caused by many different factors, including chronic stress. It is acknowledged
that genetic factors also play a role in the origin of depression: major
depression in one or both parents leads to a high risk of depression in
their offspring.
In order to understand the physiopathology of depressive disorders, it
is necessary to develop experimental models that potentially reproduce
the illness. Researchers at the Experimental Neuropsychopharmacology Unit
have implemented selective breeding in mice resulting in strikingly different
responses in a performance test. This test, known as the tail suspension
test, is currently used in mice and is aimed at screening potential antidepressants.
A second test, the Porsolt forced-swim test, is also used for this purpose.
Two types of mice can be distinguished on the basis of these tests: "helpless"
mice that are essentially immobile, and "nonhelpless" mice that
remain active and rise to a challenge.
Each of these types of mice were bred among themselves. For each generation,
scientists chose helpless/depressed mice to be interbred. By about the
twelfth generation, it was considered that 100% of the individuals had
a helpless/depressed phenotype.
Helpless mice, referred to as the "depressed Rouen mice", exhibit
behavior comparable to that of depressed human patients. When compared
to nonhelpless mice, helpless mice consume smaller quantities of a palatable
sucrose solution. This behavior, which is indicative of a loss of sensitivity
to pleasure, is similar to anhedonia, defined as the loss of the capacity
to feel pleasure, one of the major symptoms of depressive states. Compared
to nonhelpless mice, helpless mice also display higher basal seric corticosterone
levels (the equivalent of cortisol in humans). This is similar to the
hypercortisolism frequently found in depressed subjects that is a symptomatic
of the malfunction of the adrenal cortex in depression. Moreover, helpless
mice exhibit sleep-wakefulness alterations resembling those classically
observed in depressed patients.
A joint project with researchers from the INSERM U288 Unit, led by Dr.
Michel Hamon, made it possible to establish that the "depressed Rouen
mice" also suffered from lighter and more fragmented sleep, with
a decrease in REM latency (dream-related sleep).
Among the classic neurotransmitters that seem to play a role in the physiopathology
of depressive human patients, serotonin is the most important. Researchers
have shown that its metabolism is decreased in a region of the brain that
most certainly plays a major role in depression - the hippocampus. Stimulation
of specific serotonin receptors (serotonin1A autoreceptors) regulates
the electrical activity of serotoninergic neurons by inhibiting it and
also induces hypothermia. After stimulation of these serotonin1A autoreceptors,
a larger hypothermia and a stronger inhibition of serotoninergic neuronal
firing in the nucleus raphe dorsalis were observed in helpless mice as
opposed to nonhelpless mice. Therefore, helpless mice displayed a decrease
in the serotoninergic tone similar to the one associated with human depression.
Different expressions were more significant in females that in males,
given the pre-eminence of depressive disorders among females.
Finally, both behavior impairments and serotoninergic dysfunction can
be improved by regular treatment with proven antidepressants such as fluoxetine
(Prozac®).
The line of "depressed Rouen mice" is therefore an original
model for studying depression in humans and particularly the genes that
are at the root of these pathologies. Neurophysiological and neurochemical
mechanisms of antidepressants can be studied in these mice and we can
also foresee the selection of new antidepressants. This research offers
hope for the future, given that depression affects approximately 15% of
the population.
Reference:
Proceedings of the National Academy of Sciences U.S.A., 2003 May
13; 100(10): 6227-6232 Behavioral, Neurochemical, and Electrophysiological
Characterization of a Genetic Mouse Model of Depression. El Yacoubi M.,
Bouali S., Popa D., Naudon L., Leroux-Nicollet I., Hamon M., Costentin
J., Adrien J., Vaugeois J-M.
Researcher contacts:
Jean Costentin
Jean-Marie Vaugeois
Unité de Neuropsychopharmacologie Expérimentale (Experimental
Neuropsychopharmacology Unit)
Tel: +33 2 35 14 85 93, +33 2 35 14 86 02
E-mail: jean.costentin@univ-rouen.fr
jean-marie.vaugeois@univ-rouen.fr
Press Contact CNRS:
Muriel Ilous
Tel: +33 1 44 96 43 09
E-mail: muriel.ilous@cnrs-dir.fr
Life Sciences Department contact:
Françoise Tristani
Tel: +33 1 44 96 40 26
E-mail: francoise.tristani@cnrs-dir.fr
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