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Muriel KOEHL

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47 publication(s) since Juin 1997:

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07/11/2003 | Brain Res   IF 2.9
Prenatal stress in rats predicts immobility behavior in the forced swim test. Effects of a chronic treatment with tianeptine.
Morley-Fletcher S, Darnaudery M, Koehl M, Casolini P, Van Reeth O, Maccari S

Prenatally-stressed (PS) rats are characterized by a general impairment of the hypothalamo-pituitary-adrenal (HPA) axis and sleep disturbances indicating that this model has face validity with some clinical features observed in a subpopulation of depressed patients. The prolonged corticosterone secretion shown by PS rats in response to stress was positively correlated with an increased immobility behavior in the forced swim test. To investigate the predictive validity of this model, a separate group of animals was chronically treated with the antidepressant tianeptine (10 mg/kg i.p. for 21 days). Such chronic treatment reduced in PS rats immobility time in the forced swim test. These findings suggest that the PS rat is an interesting animal model for the evaluation of antidepressant treatment.

01/05/2003 | Sleep   IF 4.6
Sleep in female mice: a strain comparison across the estrous cycle.
Koehl M, Battle SE, Turek FW

STUDY OBJECTIVE: Studying inbred strains of mice has proven useful in uncovering genetic variation in the expression of sleep patterns. However, although genetic influence on many behaviors has been shown to be gender specific, to date, sleep patterns in different strains of female mice have not been reported. In order to perform such studies in female mice, the estrous cycle must be taken into account in view of the effects of reproductive hormones on sleep. The aim of this study was thus to determine sleep patterns in female mice of different inbred strains over the estrous cycle. DESIGN: Three strains of mice were used. Vaginal smears were performed to determine the estrous cycle stage; electroencephalographic and electromyographic activity, as well as body temperature and locomotor activity collected during a full estrous cycle, were analyzed. MEASUREMENTS AND RESULTS: We report a major impact of the genetic background in the regulation of non-rapid eye movement sleep over a 24-hour period and clear strain differences in rapid eye movement sleep distribution over the light-dark cycle. In contrast, the estrous cycle had less influence on non-rapid eye movement sleep and rapid eye movement sleep, and these effects were dependent on the genotype of the mice. CONCLUSIONS: Sleep regulation in female mice is influenced primarily by genetic background and, to a lesser extent, by hormonal variations associated with the estrous cycle.

12/2002 | Peptides   IF 2.7
Measurement of hypocretin/orexin content in the mouse brain using an enzyme immunoassay: the effect of circadian time, age and genetic background.
Lin L, Wisor J, Shiba T, Taheri S, Yanai K, Wurts S, Lin X, Vitaterna M, Takahashi J, Lovenberg TW, Koehl M, Uhl G, Nishino S, Mignot E

The hypocretins (1 and 2) have emerged as key regulators of sleep and wakefulness. We developed a high-throughput enzyme immunoassay (EIA) to measure total brain hypocretin levels from large numbers of mice. Hypocretin levels were not altered by circadian time or age. However, significant differences in one or both hypocretin peptides were observed between different mouse strains. We studied hypocretin levels in knockout and transgenic mouse models with obesity, circadian gene mutations or monoaminergic defects. Compared to controls, only histamine receptor knockouts had lower hypocretin levels. This was most pronounced in H1 receptor knockouts suggesting the existence of a positive feedback loop between hypocretin and histaminergic neurons.

08/2002 | Mol Pharmacol   IF 3.9
Behavioral characterization of mice lacking histamine H(3) receptors.
Toyota H, Dugovic C, Koehl M, Laposky AD, Weber C, Ngo K, Wu Y, Lee DH, Yanai K, Sakurai E, Watanabe T, Liu C, Chen J, Barbier AJ, Turek FW, Fung-Leung WP, Lovenberg TW

Brain histamine H(3) receptors are predominantly presynaptic and serve an important autoregulatory function for the release of histamine and other neurotransmitters. They have been implicated in a variety of brain functions, including arousal, locomotor activity, thermoregulation, food intake, and memory. The recent cloning of the H(3) receptor in our laboratory has made it possible to create a transgenic line of mice devoid of H(3) receptors. This paper provides the first description of the H(3) receptor-deficient mouse (H(3)(-/-)), including molecular and pharmacologic verification of the receptor deletion as well as phenotypic screens. The H(3)(-/-) mice showed a decrease in overall locomotion, wheel-running behavior, and body temperature during the dark phase but maintained normal circadian rhythmicity. H(3)(-/-) mice were insensitive to the wake-promoting effects of the H(3) receptor antagonist thioperamide. We also observed a slightly decreased stereotypic response to the dopamine releaser, methamphetamine, and an insensitivity to the amnesic effects of the cholinergic receptor antagonist, scopolamine. These data indicate that the H(3) receptor-deficient mouse represents a valuable model for studying histaminergic regulation of a variety of behaviors and neurotransmitter systems, including dopamine and acetylcholine.

06/2002 | Neurotox Res   IF 3.3
Individual vulnerability to substance abuse and affective disorders: role of early environmental influences.
Koehl M, Lemaire V, Mayo W, Abrous DN, Maccari S, Piazza PV, Le Moal M, Vallee M

One of the most important questions raised by modern psychiatry and experimental psychopathology is the origin of mental diseases. More concisely, clinical and experimental neurosciences are increasingly concerned with the factors that render one individual more vulnerable than another to a given pathological outcome. Animal models are now available to understand the sources of individual differences for specific phenotypes prone to behavioral disadaptations. Over the last 10 years we have explored the consequences of environmental perinatal manipulations in the rat. We have shown that prenatal stress is at the origin of a wide range of physiological and behavioral aberrances such as alterations in the activity of the hormonal stress axis, increased vulnerability to drug of abuse, emotional liability, cognitive impairments and predisposition to pathological aging. Taken together, these abnormalities define a bio-behavioral syndrome. Furthermore, the cognitive disabilities observed in prenatally-stressed rats were recently related to an alteration of neurogenesis in the dentate gyrus, thus confirming the impact of early life events on brain morphology. A second model (handling model) has also been developed in which pups are briefly separated from their mothers during early postnatal life. In contrast with prenatally-stressed animals, handled rats exhibited a reduced emotion response when confronted with novel situations and were protected against age-induced impairments of both the hormonal stress axis and cognitive functions. Taken together, the results of these investigations show that the bio-behavioral phenotype that characterizes each individual is strongly linked to the nature and timing of perinatal experience. Furthermore, data collected in prenatally-stressed animals indicate that this model could be used profitably to understand the etiology and pathophysiology of affective disorders.

24/05/2002 | Brain Res   IF 2.9
The effect of restraint stress on paradoxical sleep is influenced by the circadian cycle.
Koehl M, Bouyer JJ, Darnaudery M, Le Moal M, Mayo W

It is well known that the physiological impact imposed by events or behaviors displayed during the waking period determines the way organisms sleep. Among the situations known to affect sleep both in its duration and quality, stress has been widely studied and it is now admitted that its effects on sleep architecture depend on several factors specific to the stressor or the individual itself. Although numerous reports have highlighted the prominent role of the circadian cycle in the physiological, endocrine and behavioral consequences of restraint stress, a possible circadian influence in the effects of stress on the sleep-wake cycle has never been studied. Thus the present study was designed to compare the effects on sleep of a 1 h-lasting restraint stress applied at light onset to those observed after the same stressor was applied at light offset. We report that in both conditions stress induced a marked paradoxical sleep increase, whereas wakefulness displayed a moderate decrease and slow wave sleep a moderate augmentation. Although the effects of stress at lights on were of similar magnitude than those of stress at lights off, important differences in the sleep rebound latencies were observed: whatever the time of day the stress was applied, its effects on sleep always occurred during the dark period. This result thus shows that restraint stress could be efficiently used to study the interaction between the circadian and homeostatic components of sleep regulation.

05/2002 | J Neuroendocrinol   IF 3
Sleep restriction alters the hypothalamic-pituitary-adrenal response to stress.
Meerlo P, Koehl M, van der Borght K, Turek FW

Chronic sleep restriction is an increasing problem in many countries and may have many, as yet unknown, consequences for health and well being. Studies in both humans and rats suggest that sleep deprivation may activate the hypothalamic-pituitary-adrenal (HPA) axis, one of the main neuroendocrine stress systems. However, few attempts have been made to examine how sleep loss affects the HPA axis response to subsequent stressors. Furthermore, most studies applied short-lasting total sleep deprivation and not restriction of sleep over a longer period of time, as often occurs in human society. Using the rat as our model species, we investigated: (i) the HPA axis activity during and after sleep deprivation and (ii) the effect of sleep loss on the subsequent HPA response to a novel stressor. In one experiment, rats were subjected to 48 h of sleep deprivation by placing them in slowly rotating wheels. Control rats were placed in nonrotating wheels. In a second experiment, rats were subjected to an 8-day sleep restriction protocol allowing 4 h of sleep each day. To test the effects of sleep loss on subsequent stress reactivity, rats were subjected to a 30-min restraint stress. Blood samples were taken at several time points and analysed for adrenocorticotropic hormone (ACTH) and corticosterone. The results show that ACTH and corticosterone concentrations were elevated during sleep deprivation but returned to baseline within 4 h of recovery. After 1 day of sleep restriction, the ACTH and corticosterone response to restraint stress did not differ between control and sleep deprived rats. However, after 48 h of total sleep deprivation and after 8 days of restricted sleep, the ACTH response to restraint was significantly reduced whereas the corticosterone response was unaffected. These results show that sleep loss not only is a mild activator of the HPA axis itself, but also affects the subsequent response to stress. Alterations in HPA axis regulation may gradually appear under conditions of long total sleep deprivation but also after repeated sleep curtailment.

01/2001 | Neurotox Res   IF 3.3
Long term neurodevelopmental and behavioral effects of perinatal life events in rats.
Koehl M, Lemaire V, Vallee M, Abrous N, Piazza PV, Mayo W, Maccari S, Le Moal M

Modern neurosciences are now able to open new avenues concerning an experimental approach to clinical neurosciences and psychiatry. Detection and prediction of potential vulnerabilities such as behavioral disturbances and neurodegenerative diseases, are urgent tasks leading to prevention that must be encouraged in parallel to the enormous efforts displayed for treatments. Besides possible genetic origins of diseases, environmental factors are now coming under scrutiny, and especially deleterious and challenging life events and stress occurring during prenatal and postnatal critical periods may orient brain functions towards deleterious developments. The hypothesis that will be examined is that early events might be at the origin of pathological transformations and symptoms after long periods of apparent normal abilities and behavioral homeostasis. We used models of prenatal stress and postnatal manipulations such as cross-fostering. It will be demonstrated that such events induce long-term changes, cognitive and emotional modifications appearing first, when offspring are adults, followed by cognitive defects later in life. Increased sensitivity of the hypothalamic pituitary-adrenal axis (HPA), the endocrine system controlling the secretion of stress hormones (corticoids), appears to be a major element of pathogenesis. HPA axis dysfunction appears very early after birth (3 days) and lasts for months. Cumulative exposure to high levels of hormones seems to be detrimental for some brain regions, especially the hippocampus and major neurotransmitter systems such as dopamine neurons. We evidenced that neuronal modifications in hippocampal region are correlated with behavioral and cognitive defects, relating environment, stress in early life, hormonal changes, long-term neuropathological processes and impaired cognition in aging. Moreover appears in offspring, when adults, a proneness to engage in drug dependence. These data emphasize the need to consider early environmental life events as etiological factors for delayed neuropsychiatric disturbances, neurodegenerative defects included. Moreover, they strengthen the interest for a longitudinal approach to promote experimental psychopathology.

03/11/2000 | Brain Res   IF 2.9
Nicotine-induced locomotor activity is increased by preexposure of rats to prenatal stress.
Koehl M, Bjijou Y, Le Moal M, Cador M

Genetic factors are believed to play a predominant role in the individual differences observed in behavioral and pharmacological responses to drugs of abuse. An increasing literature indicates, however, that epigenetic factors can be involved as well. In this report we examined whether developmental changes induced by prenatal stress could alter the way animals respond to the psychostimulant effect of nicotine when adults. The results show that nicotine induces a dose-dependent increase of locomotor activity in both groups, and that prenatally-stressed animals exhibit a higher behavioral response at all doses. This study emphasizes the importance of early environment in the later development of drug-related behavior.

26/09/2000 | Proc Natl Acad Sci U S A   IF 9.6
Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus.
Lemaire V, Koehl M, Le Moal M, Abrous DN

Early experiences such as prenatal stress significantly influence the development of the brain and the organization of behavior. In particular, prenatal stress impairs memory processes but the mechanism for this effect is not known. Hippocampal granule neurons are generated throughout life and are involved in hippocampal-dependent learning. Here, we report that prenatal stress in rats induced lifespan reduction of neurogenesis in the dentate gyrus and produced impairment in hippocampal-related spatial tasks. Prenatal stress blocked the increase of learning-induced neurogenesis. These data strengthen pathophysiological hypotheses that propose an early neurodevelopmental origin for psychopathological vulnerabilities in aging.