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Michel LE-MOAL

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415 publication(s) since Janvier 1966:

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The aim of this study was to investigate the noradrenergic regulation of mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) in high responder (HR) and low responder (LR) male rats, an animal model of individual differences in hypothalamo-pituitary-adrenal axis activity and vulnerability to drugs of abuse. The effects of a chronic treatment with the noradrenergic alpha(1) antagonist (1-[4-amino-6,7-dimethoxy-2-quinazolinyl]-4-[2-furanylcarbonyl] piperazine) hydrochloride (prazosin) (0.5 mg/kg, i.p., 35 days) were assessed on stress-induced corticosterone (CORT) secretion and on hippocampal MRs and GRs in adrenally intact rats. In order to ascertain whether the effects of chronic prazosin treatment on hippocampal MRs and GRs were direct or indirect, through prazosin-induced CORT secretion, we also assessed the effects of the same treatment on adrenalectomized rats with CORT substitutive therapy. When compared with LR rats, HR rats exhibited a delayed return to the basal level of CORT following acute restraint stress; this was associated with a lower binding of MRs and GRs in HR rats than in LR rats. Chronic prazosin treatment had no effect in HR animals but markedly reduced hippocampal MRs and GRs, and increased stress-induced CORT secretion in LR rats. In LR adrenalectomized rats, prazosin reduced hipppocampal MRs but did not change GRs. Our results provide evidence of a differential regulation by noradrenaline of hippocampal MRs and GRs in HR and LR rats. These data could have clinical implications in terms of individual differences in the resistance to antidepressant treatments and individual differences in drug abuse.

2007 | Eur Neuropsychopharmacol   IF 4.5
Drug addiction: pathways to the disease and pathophysiological perspectives
Le Moal M, Koob G F

Drug addiction is a medical condition, a chronic relapsing disease. As in other domains of experimental medicine, appropriate experimental investigations are needed in order to better understand the disease. However, to understand the diverse facets of drug effects and of the underlying pathophysiology it is necessary to keep in mind the complexity of the psychopathological processes. The main symptoms that characterize addiction correspond to expressions of dysfunctions within specific circuits and regions. Pathways to addiction are numerous and comorbidity and in the real world poly-drug use are common. Some of these aspects will be examined as well as the role of life events and stress. Theoretical considerations will be proposed [see also: Koob, G.F., & Le Moal, M.. 2005a. Neurobiology of Addiction. Elsevier. 570 pp] to account for the stages of the disease from impulse control disorder to compulsive disorders, for affective dynamics and for the relations between the symptoms and pathophysiology.

12/2006 | Neurobiol Aging   IF 4.4
Smad-dependent alterations of PPT cholinergic neurons as a pathophysiological mechanism of age-related sleep-dependent memory impairments
George O, Parducz A, Dupret D, Kharouby M, Le Moal M, Piazza P V, Mayo W

In humans, memory impairments are highly prevalent in the aged population, but their functional and structural origins are still unknown. We hypothesized that circadian rhythm alterations may predict spatial memory impairment in aged rats. We demonstrate an association between sleep/wake circadian rhythm disturbances (non-REM sleep fragmentation) and spatial memory impairments in aged rats. We show by light and electron microscopy that these age-related disruptions in circadian rhythm and spatial memory are also associated with degeneration of cholinergic neurons of the pedunculopontine nucleus (PPT), a structure known to be involved in sleep and cognitive functions and which is altered during aging. Finally, we demonstrate that a trophic deregulation of the PPT occur in aged impaired rats, involving an over activation of the TGFbeta-Smad cascade, a signalling pathway involved in neurodegeneration. In conclusion these results provide a new pathophysiological mechanism for age-related sleep-dependent memory impairments opening the ground for the development of new therapeutic approaches of these pathologies.

10/08/2006 | Behav Brain Res   IF 2.8
Chronic exposure of rats to noise: relationship between long-term memory deficits and slow wave sleep disturbances
Rabat A, Bouyer J J, George O, Le Moal M, Mayo W

Noise is now recognized as a serious health problem in our modern societies. Although its deleterious and direct effects on cognitive tasks (long-term memory, mental arithmetic activity, visual tasks, etc.) are clearly admitted, no studies have determined a delayed indirect effect of noise on cognitive processes. Furthermore, the link between sleep disturbances related to environmental noise (EN) exposure and these indirect deteriorations of human performances has never been demonstrated. This could be due to inappropriate evaluation of sleep as well as to uncontrolled and confounding factors such as sex, age, and also inter-individual vulnerability. Based on a recently validated animal model [Rabat A, Bouyer JJ, Aran JM, Le Moal M, Mayo W. Chronic exposure to an environmental noise permanently disturbs sleep in rats: inter-individual vulnerability. Brain Res 2005;1059:72-82], aims of the present study were (i) to determine long-term memory (LTM) deficits following a chronic exposure to EN and (ii) to link these behavioral problems to sleep disturbances related to EN. For this purpose in a first experiment, LTM performances were evaluated before and following 9 days of EN. Results show LTM deficits following a chronic exposure to EN with inter-individual vulnerability. Vulnerability profile was related to the psychobiological profile of rats. Results of the second experiment show LTM deficits correlated to both debt of slow wave sleep (SWS) and to daily decrease of SWS bout duration. Our results demonstrate that chronic exposure to noise indirectly disturbs LTM possibly through SWS disturbances and suggest a possible role of the stress hormonal axis in these biological effects of noise.

06/2006 | Eur J Neurosci   IF 2.8
Motherhood-induced memory improvement persists across lifespan in rats but is abolished by a gestational stress
Lemaire V, Billard J M, Dutar P, George O, Piazza P V, Epelbaum J, Le Moal M, Mayo W

Motherhood modifies the biology and behavior of the female, a process which prepares the mother's cognitive systems that are needed for nurturance. It has recently been shown that motherhood enhances hippocampal-mediated spatial learning and synaptic plasticity. Deleterious and long-term effects of a stress experienced during gestation have been demonstrated on progeny. Surprisingly little is known about the effect of such stress on mothers. Here, we investigated the effect of gestational stress on the adaptive changes due to motherhood. Female rats were mated and stressed during the last week of gestation. Two weeks after weaning, they were submitted to behavioral tests or electrophysiological study. A group of females were then kept for 16 months after motherhood experience to study the long-term effect of gestational stress and motherhood on memory when they were 22 months old. We confirm that a single motherhood experience selectively increases hippocampal-mediated spatial memory during the entire lifespan of female rats and protects them from age-associated memory impairments. However, we demonstrate that a stressful experience during gestation totally abolishes the positive effects of motherhood both on spatial memory and on hippocampal synaptic plasticity (long-term potentiation). Environmental factors that induce biological vulnerability have negative effects even for fundamental biological behaviors.


RATIONALE: The neurosteroids pregnenolone sulfate (PREGS), dehydroepiandrosterone sulfate (DHEAS) and allopregnanolone (3alpha,5alpha THPROG) have been implicated as powerful modulators of memory processes and sleep states in young and aged subjects with memory impairment. As these processes depend on the integrity of cholinergic systems, a specific effect of neurosteroids on these systems may account for their effects on sleep and memory. OBJECTIVE: To review the evidence for a specific and differential effect of neurosteroids on cholinergic systems. METHODS: We carried out keyword searches in 'Medline' to identify articles concerning (1) the effects of neurosteroids on cholinergic systems, sleep and memory processes, and (2) changes in neurosteroid concentrations during aging. Few results are available for humans. Most data concerned rodents. RESULTS: Peripheral and central administrations of PREGS, DHEAS, and 3alpha,5alpha THPROG modulate the basal forebrain and brainstem projection cholinergic neurons but not striatal cholinergic interneurons. Local administration of neurosteroids to the basal forebrain and brainstem cholinergic neurons alters sleep and memory in rodents. There are a few conflicting reports concerning the effects of aging on neurosteroid concentrations in normal and pathological conditions. CONCLUSIONS: The specific modulation of basal forebrain and brainstem cholinergic systems by neurosteroids may account for the effects of these compounds on sleep and memory processes. To improve our understanding of the role of neurosteroids in cholinergic systems during normal and pathological aging, we need to determine whether there is specific regionalization of neurosteroids, and we need to investigate the relationship between neurosteroid concentrations in cholinergic nuclei and age-related sleep and memory impairments.

01/05/2006 | Biol Psychiatry   IF 11.5
Postnatal stimulation of the pups counteracts prenatal stress-induced deficits in hippocampal neurogenesis.
Lemaire V, Lamarque S, Le Moal M, Piazza PV, Abrous DN

BACKGROUND: Prenatal stress constitutes a developmental risk factor for later psychopathology. The behavioral disorders are sustained by neurobiological alterations including long-term reduction of hippocampal neurogenesis; its deregulation has been involved in cognitive impairments, mood disorders and addiction. A major goal is to define periods in development and strategies for intervening to prevent the effects of early stressful events. We investigated the ability of a postnatal infantile stimulation to prevent prenatal stress-induced alteration in hippocampal neurogenesis. METHODS: The influence of postnatal handling on prenatal stress-induced changes in hippocampal neurogenesis was examined in 4 and 26 month-old male rats. Three distinct phases of the neurogenesis were studied: proliferation, survival and neuronal differentiation. RESULTS: Prenatal stress reduced hippocampal cell proliferation all throughout life. Furthermore, the survival rate of newborn cells, the number of immature neurons and the number of differentiated new neurons were reduced in young and old prenatally-stressed rats. All those deleterious effects were counteracted by neonatal handling. CONCLUSIONS: These data show that finer aspects of brain shaping can be rewired by environmental influences occurring at sensitive phase of development. They also suggest that infantile stimulation may reverse the appearance of behavioral disorders induced by early life stress.

04/2006 | Neurobiol Aging   IF 4.4
Lifelong corticosterone level determines age-related decline in neurogenesis and memory.
Montaron MF, Drapeau E, Dupret D, Kitchener P, Aurousseau C, Le Moal M, Piazza PV, Abrous DN

Ageing is accompanied by an alteration of spatial memory, a decline in hippocampal neurogenesis and a dysregulation of the hypothalamic-pituitary axis (HPA) leading to elevated levels of circulating corticosterone. However, the role of the HPA axis in age-related decline in cognitive functions and in neurogenesis decline remains unclear. We found that suppression of glucocorticoids secretion from midlife to the rest of the animals' life increases neurogenesis in old animals and prevents the emergence of age-related memory disorders. Reciprocally, aged rats with a chronic upregulation of the HPA axis exhibit not only spatial memory impairments but also very low levels of hippocampal cell proliferation and survival. Altogether, these results indicate that the extent of lifetime exposure to glucocorticoids determines the extent of age-related decline in hippocampal neurogenesis and consequently age-related cognitive dysfunctions.

03/2006 | Addict Biol   IF 4.2
Glucocorticoid negative feedback in methadone-maintained former heroin addicts with ongoing cocaine dependence: dose-response to dexamethasone suppression
Aouizerate B, Ho A, Schluger J H, Perret G, Borg L, Le Moal M, Piazza P V, Kreek M J

Combined cocaine and illicit opiate use is common. This study aimed to test the hypothesis that cocaine dependence in former heroin-addicted patients maintained on methadone treatment is associated with enhanced glucocorticoid negative feedback. Multiple dose dexamethasone suppression tests, using a conventional 2.0 mg dose, and two lower doses, 0.5 mg and 0.125 mg, were performed in 10 methadone-maintained former heroin addicts with ongoing cocaine dependence (C-MM), 10 stabilized methadone-maintained former heroin addicts with no ongoing drug or alcohol use (MM), and 22 normal volunteers (NV). At 9 hours, there was no difference in plasma adrenocorticotropin hormone (ACTH) and/or cortisol levels among groups on the baseline day, as well as after the two lower doses of dexamethasone. At 17 hours, C-MM and MM had significantly lower plasma ACTH and/or cortisol levels than NV. However, C-MM did not significantly differ from MM in their hormonal levels. When the hormonal responses to dexamethasone are expressed as magnitude of lowering from baseline, there was no significant difference at any dose among groups. Therefore, C-MM exhibited a normal glucocorticoid negative feedback in the morning. Using the standard interpretation of dexamethasone suppression testing based on the examination of the actual hormonal levels rather than the difference from baseline condition, C-MM appear to have glucocorticoid effects similar to MM, yet were both greater than NV in the late afternoon. Thus, further studies are needed to know whether altered glucocorticoid negative feedback is related to chronic cocaine exposure, or is the result of former heroin addiction and/or its long-term treatment with methadone.