Behavioral, neurochemical, and electrophysiological characterization of a genetic mouse model of depression

Abstract

Depression is a multifactorial illness and genetic factors play a role in its etiology. The understanding of its physiopathology relies on the availability of experimental models potentially mimicking the disease. Here we describe a model built up by selective breeding of mice with strikingly different responses in the tail suspension test, a stress paradigm aimed at screening potential antidepressants. Indeed, ''helpless'' mice are essentially immobile in the tail suspension test, as well as the Porsolt forced-swim test, and they show reduced consumption of a palatable 2% sucrose solution. In addition, helpless mice exhibit sleep-wakefulness alterations resembling those classically observed in depressed patients, notably a lighter and more fragmented sleep, with an increased pressure of rapid eye movement sleep. Compared with ''nonhelpless'' mice, they display higher basal seric corticosterone levels and lower serotonin metabolism index in the hippocampus. Remarkably, serotonin 1A autoreceptor stimulation induces larger hypothermia and inhibition of serotoninergic neuronal firing in the nucleus raphe dorsalis in helpless than in nonhelpless mice. Thus, helpless mice exhibit a decrease in serotoninergic tone, which evokes that associated with endogenous depression in humans. Finally, both the behavioral impairments and the serotoninergic dysfunction can be improved by chronic treatment with the antidepressant fluoxetine. The helpless line of mice may provide an opportunity to approach genes influencing susceptibility to depression and to investigate neurophysiological and neurochemical substrates underlying antidepressant effects.T he prevalence of depression worldwide is such that this disorder represents a major health problem. It is estimated, for example, that Ϸ10% of men and 20% of women in Western Europe will suffer from a major depressive episode at some time in their life. The monoamine hypothesis of depression suggests that one of the biological bases of affective disorders is a deficiency in the neurotransmitter serotonin (5-HT). During the past 40 yr, this hypothesis has been refined, as more experimental and clinical evidence has emerged. The selective 5-HT reuptake inhibitors, in particular, allowed important progress in our understanding of the role of 5-HT in depression. To some extent, the mechanism of action of 5-HT reuptake inhibitors, which are the most widely prescribed antidepressant drugs today, can be anticipated from our knowledge of the anatomy and chemistry of the central serotoninergic system. However, it must be accepted that extensive investigations have so far failed to find convincing evidence of a primary dysfunction of the serotoninergic system in patients with depression. Disturbances of sleep are typical for most depressed patients and belong to the core symptoms of the disorder. Polysomnographic sleep research has demonstrated that, besides disturbances of sleep continuity, depression is associated with a reduction of slow-wave sleep and a shortening of rapid eye movement (REM...

Homeostatic Regulation of Sleep in a Genetic Model of Depression in the Mouse: Effects of Muscarinic and 5-HT1A Receptor Activation

“…For all other experiments, data were collected from females only. Indeed, previous studies showed that differences between H and NH mice (regarding notably adaptive behavioural and neurobiological responses to chronic treatment with antidepressants) were larger in females than in males (El Yacoubi et al, 2003).…”

“…All mice used for these studies were of the H and NH lines (CD1 strain), selected across 12-14 generations for high or low spontaneous 'helplessness' in the tail suspension test, as described previously (El Yacoubi et al, 2003). For the study of spontaneous sleep-wakefulness patterns, both males and females were used.…”

“…With respect to both spontaneous sleep-wakefulness characteristics and responses in depression-related behavioural tests (El Yacoubi et al, 2003), females of the H line were generally more affected than males. Accordingly, the following studies were performed only with females.…”

“…To date, these aspects have only been studied in a few of these models, and mostly in rats (Adrien et al, 1991;Dugovic et al, 2000;Overstreet, 1993;Willner, 1990). We recently developed a line of mice selected from its long duration immobility in the tail suspension test ('Helpless' -H), compared to 'non-Helpless' (NH) mice which exhibited short duration immobility in the test (El Yacoubi et al, 2003). H mice exhibited several neurochemical and behavioral impairments, that mimic those found in depression, with notably an increased pressure of REM sleep and a lighter slow wave sleep (SWS) (El Yacoubi et al, 2003).…”

“…We recently developed a line of mice selected from its long duration immobility in the tail suspension test ('Helpless' -H), compared to 'non-Helpless' (NH) mice which exhibited short duration immobility in the test (El Yacoubi et al, 2003). H mice exhibited several neurochemical and behavioral impairments, that mimic those found in depression, with notably an increased pressure of REM sleep and a lighter slow wave sleep (SWS) (El Yacoubi et al, 2003). Here, to further assess the relevance of H mice as a model of depression, we detail these sleep impairments and we examine the cycle of locomotor activity and body temperature over the dark-light cycle.…”