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Cognitive decline appears across aging. While some studies report beneficial effects of musical listening and practice on cognitive aging, the underlying neurobiological mechanisms remain unknown. This study aims to determine whether chronic (6 h/day, 3 times/week) and long-lasting (4–8 months) music exposure, initiated at middle age in rats (15 months old), can influence behavioral parameters sensitive to age effects and reduce age-related spatial memory decline in rats. Spontaneous locomotor, circadian rhythmic activity, and anxiety-like behavior as well as spatial working and reference memory were assessed in 14-month-old rats and then after 4 and 8 months of music exposure (19 and 23 months old, respectively). Spatial learning and reference memory data were followed up by considering cognitive status of animals prior to music exposure (14 months old) given by K-means clustering of individual Z-score. Hippocampal cell proliferation and brain-derived neurotrophic factor (BDNF) level in the hippocampus and frontal cortex were measured. Results show that music exposure differentially rescues age-related deficits in spatial navigation tasks according to its duration without affecting spontaneous locomotor, circadian rhythmic activity, and anxiety-like behavior. Hippocampal cell proliferation as well as hippocampal and frontal cortex BDNF levels was not affected by music across aging. Cognitive improvement by music in aging rats may require distinct neurobiological mechanisms than hippocampal cell proliferation and BDNF.

International audience; For a better translation from treatment designs of schizophrenia to clinical efficiency, there is a crucial need to refine preclinical animal models. In order to consider the multifactorial nature of the disorder, a new mouse model associating three factors (genetic susceptibility—partial deletion of the MAP6 gene, early-life stress—maternal separation, and pharmacological treatment—chronic Δ-9-tetrahydrocannabinol during adolescence) has recently been described. While this model depicts a schizophrenia-like phenotype, the neurobiological correlates remain unknown. Synaptic transmission and functional plasticity of the CA1 hippocampal region of male and female 3-hit mice were therefore investigated using electrophysiological recordings on the hippocampus slice. While basal excitatory transmission remained unaffected, NMDA receptor (NMDAr)-mediated long-term potentiation (LTP) triggered by theta-burst (TBS) but not by high-frequency (HFS) stimulation was impaired in 3-hit mice. Isolated NMDAr activation was not affected or even increased in female 3-hit mice, revealing a sexual dimorphism. Considering that the regulation of LTP is more prone to inhibitory tone if triggered by TBS than by HFS, the weaker potentiation in 3-hit mice suggests a deficiency of intrinsic GABA regulatory mechanisms. Indeed, NMDAr activation was increased by GABAA receptor blockade in wild-type but not in 3-hit mice. This electrophysiological study highlights dysregulations of functional properties and plasticity in hippocampal networks of 3-hit mice, one of the mechanisms suspected to contribute to the pathophysiology of schizophrenia. It also shows differences between males and females, supporting the sexual dimorphism observed in the disorder. Combined with the previously reported study, the present data reinforce the face validity of the 3-hit model that will help to consider new therapeutic strategies for psychosis.

Schizophrenia is a major psychiatric disease still lacking efficient treatment, particularly for cognitive deficits . To go further in research of new treatments that would encompass all the symptoms associated with this pathology, preclinical animal models need to be improved. To date, the aetiology of schizophrenia is unknown, but there is increasing evidence to highlight its multifactorial nature. We built a new neurodevelopmental mouse model gathering a triple factor combination (3-M): a genetic factor (partial deletion of MAP6 gene), an early stress (maternal separation) and a late pharmacological factor (MK801 administration, 0.05 mg/kg, i.p., daily for 5 days). The effects of each factor and of their combination were investigated on several behaviours including cognitive functions. While each individual factor induced slight deficits in one or another behavioural test, 3-M conditioning induces a wider phenotype with hyperlocomotion and cognitive deficits (working memory and social recognition). This study confirms the hypothesis that genetic, environmental and pharmacological factors, even if not deleterious by themselves, could act synergistically to induce a deleterious behavioural phenotype. It moreover encourages the use of such combined models to improve translational research on neurodevelopmental disorders.

Damage to cochlear primary afferent synapses has been shown to be a key factor in various auditory pathologies. Similarly, the selective lesioning of primary vestibular synapses might be an underlying cause of peripheral vestibulopathies that cause vertigo and dizziness, for which the pathophysiology is currently unknown. To thoroughly address this possibility, we selectively damaged the synaptic contacts between hair cells and primary vestibular neurons in mice through the transtympanic administration of a glutamate receptor agonist. Using a combination of histological and functional approaches, we demonstrated four key findings: (1) selective synaptic deafferentation is sufficient to generate acute vestibular syndrome with characteristics similar to those reported in patients; (2) the reduction of the vestibulo-ocular reflex and posturo-locomotor deficits mainly depends on spared synapses; (3) damaged primary vestibular synapses can be repaired over the days and weeks following deafferentation; and (4) the synaptic repair process occurs through the re-expression and re-pairing of synaptic proteins such as CtBP2 and SHANK-1. Primary synapse repair might contribute to re-establishing the initial sensory network. Deciphering the molecular mechanism that supports synaptic repair could offer a therapeutic opportunity to rescue full vestibular input and restore gait and balance in patients., Summary: The molecular rearrangements of the synaptic proteins that accompany the deafferentation and subsequent reafferentation of the inner ear sensors following an excitotoxic insult are demonstrated for the first time.

International audience; Hypothalamic orexin neurons are involved in various physiological functions, including thermoregulation. The orexinergic system has been considered as a potent mediator of the exercise response. The present study describes how the antagonization of the orexinergic system by a dual orexin receptor antagonist (DORA) modifies the thermoregulatory process during exercise. Core Body Temperature (CBT) and Spontaneous Locomotor Activity (SLA) of 12 male Wistar rats were recorded after either oral administration of DORA (30 mg/kg or 60 mg/kg) or placebo solution, both at rest and in exercise conditions with treadmill running. DORA ingestion decreased SLA for 8 hours (p

d-serine is the major co-agonist of N-methyl-D-aspartate receptors (NMDAR) at CA3/CA1 hippocampal synapses, the activation of which drives long-term potentiation (LTP). The use of mice with targeted deletion of the serine racemase (SR) enzyme has been an important tool to uncover the physiological and pathological roles of D-serine. To date, some uncertainties remain regarding the direction of LTP changes in SR-knockout (SR-KO) mice, possibly reflecting differences in inhibitory GABAergic tone in the experimental paradigms used in the different studies. On the one hand, our extracellular recordings in hippocampal slices show that neither isolated NMDAR synaptic potentials nor LTP were altered in SR-KO mice. This was associated with a compensatory increase in hippocampal levels of glycine, another physiologic NMDAR co-agonist. SR-KO mice displayed no deficits in spatial learning, reference memory and cognitive flexibility. On the other hand, SR-KO mice showed a weaker LTP and a lower increase in NMDAR potentials compared to controls when GABAA receptors were pharmacologically blocked. Our results indicate that depletion of endogenous D-serine caused a reduced inhibitory activity in CA1 hippocampal networks, altering the excitatory/inhibitory balance, which contributes to preserve functional plasticity at synapses and to maintain related cognitive abilities.

Lurasidone is an atypical antipsychotic that has been shown to be effective in reversing schizophrenia-related cognitive impairment. The development of new preclinical models of schizophrenia is a key for improving treatments of cognitive symptoms. This study investigated the effects of chronic lurasidone treatment in C57BL/6 male mice via intraperitoneal injection (1 mg/kg daily at 5 p.m. for 5 weeks). A large battery of behavioural tests was performed (between 9 a.m. and 5 p.m.), which is currently used to assess face validity in animal models of psychiatric diseases. Overall, lurasidone did not interfere with behavioural performances, which characterises very good tolerance to such a high dose. Moreover, pharmacokinetic parameters after i.p. and oral administration were measured. Mean transit time (MTT) values were 1.91 h (1 mg/kg acute i.p.) and 1.74 h (8.3 mg/kg acute oral), respectively, and relative bioavailability comparing these two routes of administration was of 19.8%. This last result gives important data to adapt oral chronic administration of lurasidone with a more ethical perspective in comparison with chronic i.p. injections. This study brings tools to improve pharmacological validity of preclinical models of psychiatric diseases, and to adapt dosage of antipsychotics according to the route used.

The novel object recognition test (NOR) has been exploited to investigate the effects of drugs and the role of their receptors in different stages of memory formation. We review here the roles of the seven serotonin receptors (5-HTRs) in acquisition, consolidation and retrieval using NOR. Evidences from the literature show unambiguous involvement of 5-HT4R in acquisition and of 5-HT2A, 5-HT2C, 5-HT6 and 5-HT7 in both consolidation and retrieval. There are however, some inconsistencies concerning the nature of the modulation of memory processes (facilitation obtained with both 5-HT6R agonist and antagonist, for example). For the other receptors, the evidences are less clear-cut and further investigations are needed. NOR proved to be very sensitive to 5-HT modulation, and pharmacological manipulation of the memory processes may prove useful in determining a specific drug target for treating memory dysfunctions.

Given its predominant expression in the central nervous system (CNS), 5-hydroxytryptamine (5-HT: serotonin) subtype 6 receptor (5-HT6R) has been considered as a valuable target for the development of CNS drugs with limited side effects. After 2 decades of intense research, numerous selective ligands have been developed to target this receptor; this holds potential interest for the treatment of neuropathological disorders. In fact, some agents (mainly antagonists) are currently undergoing clinical trial. More recently, a series of potent and selective agonists have been developed, and preclinical studies have been conducted that suggest the therapeutic interest of 5-HT6R agonists. This review details the medicinal chemistry of these agonists, highlights their activities, and discusses their potential for treating cognitive issues associated with Alzheimer’s disease (AD), depression, or obesity. Surprisingly, some studies have shown that both 5-HT6R agonists and antagonists exert similar procognitive activi...

Dexamphetamine (AMPH) is a psychostimulant drug that is used both recreationally and as medication for attention deficit hyperactivity disorder. Preclinical studies have demonstrated that repeated exposure to AMPH can induce damage to nerve terminals of dopamine (DA) neurons. We here assessed the underlying neurobiological changes in the DA system following repeated AMPH exposure and pre-treated rats with AMPH or saline (4 times 5 mg/kg s.c., 2 hours apart), followed by a 1-week washout period. We then used pharmacological MRI (phMRI) with a methylphenidate (MPH) challenge, as a sensitive and non-invasive in-vivo measure of DAergic function. We subsequently validated the DA-ergic changes post-mortem, using a.o. high-performance liquid chromatography (HPLC) and autoradiography. In the AMPH pre-treated group, we observed a significantly larger BOLD response to the MPH challenge, particularly in DA-ergic brain areas and their downstream projections. Subsequent autoradiography studies showed that AMPH pre-treatment significantly reduced DA transporter (DAT) density in the caudate-putamen (CPu) and nucleus accumbens, whereas HPLC analysis revealed increases in the DA metabolite homovanillic acid in the CPu. Our results suggest that AMPH pre-treatment alters DAergic responsivity, a change that can be detected with phMRI in rats. These phMRI changes likely reflect increased DA release together with reduced DAT binding. The ability to assess subtle synaptic changes using phMRI is promising for both preclinical studies of drug discovery, and for clinical studies where phMRI can be a useful tool to non-invasively investigate DA abnormalities, e.g. in neuropsychiatric disorders. ispartof: PLoS One vol:12 issue:2 pages:1-16 ispartof: location:United States status: published

International audience; The object recognition test is now among the most commonly used behavioral tests for mice. A mouse is presented with two similar objects during the first session, and then one of the two objects is replaced by a new object during a second session. The amount of time taken to explore the new object provides an index of recognition memory. As more groups have used the protocol, the variability of the procedures used in the object recognition test has increased steadily. This protocol provides a necessary standardization of the procedure. This protocol reduces inter-individual variability with the use of a selection criterion based on a minimal time of exploration for both objects during each session. In this protocol, we describe the three most commonly used variants, containing long (3 d), short (1 d) or no habituation phases. Thus, with a short intersession interval (e.g., 6 h), this procedure can be performed in 4, 2 or 1 d, respectively, according to the duration of the habituation phase. This protocol should allow for the comparison of results from different studies, while permitting adaption of the protocol to the constraints of the experimenter.

Recent data suggest that 5-HT7 receptors (5-HT7R) are involved in memory processes and, particularly, those related to novelty-induced arousal, even though this remains so far speculative and controversial. In order to assess the role of 5-HT7R in episodic-like memory, mice were administered 5-carboxamidotryptamine (5-CT, a 5-HT1A/1B/1D/7R agonist) and/or SB-269970 (a selective 5-HT7R antagonist) immediately after the acquisition session of the novel object recognition test. The object recognition test was performed in order to assess the effects of modulation of 5-HT7R during consolidation phase on episodic-like memory performances in mice. A protocol including 3 days of familiarisation to the apparatus has been realised in order to decrease the effect of novelty-induced arousal. With a 2-h delay, SB-269970 (3 and 10 mg/kg, administered subcutaneously) impaired the discrimination of the novel object. With a 4-h delay, while control mice were not able to discriminate the novel object, mice treated with 5-CT (1 mg/kg) showed a significant discrimination. This promnesic effect with a long delay is effectively mediated by 5-HT7R activation since it was blocked by SB-269970 (10 mg/kg), but not by WAY-100135 (10 mg/kg) or by GR-127935 (10 mg/kg). These data suggest that 5-HT7R tonically modulates cognitive processes involved in consolidation performances in object recognition. Therefore, 5-HT7R could be a promising target to treat memory dysfunctions (especially episodically related deficits) related to normal or pathological ageing.

International audience; Domestic horses are regularly subjected to stressful situations due to management practices, such as social isolation, transport and farriery or, in general due to exposure to new/sudden stimuli. These situations may eventually be harmful to the horses’ welfare, possibly altering their relationships with humans and increasing the risk of safety hazards for horses as well as humans. Music has relaxing properties demonstrated in several animal species. We have tested the effect of in-ear classical music diffusion on the intensity of stress reaction when horses were exposed to two stressful situations: short-term transport (n = 24) and farriery (n = 24). Each horse was subjected either to transport or to farriery in three different conditions: ‘music’ (classical music played via an in-ear device), ‘sound attenuation’ (with ear plugs) and ‘control’. During transport, the diffusion of classical music induced a faster post-stress heart rate recovery (P < 0.05). During farriery, the effects on behavior were not significant for post-stress heart rate recovery (t-test: music: t20 = 1.92, P > 0.05). From a physiological point of view, classical music reduces the intensity of stress responses to these common management practices, which can have several applications. Less dangerous behaviors, such as fleeing or kicking, could reduce the risk of injuries for both horses and humans. Reducing the effect of acute stress will also prevent the onset of chronic stress.

Selective antagonists at serotonin 5-HT

International audience; INTRODUCTION: Effects of 3-month continuous environmental enrichment (EE) on cognitive abilities and on theta burst-related synaptic plasticity of CA1 hippocampal neuronal networks have been assessed in 6- and 20-month old NMRI female mice. RESULTS: EE decreased anxiety-like behavior and improved learning and memory performances in adult but not in aged mice. Electrophysiological results in CA1 hippocampal slices showed that basal synaptic transmission was not affected by EE in adult mice whereas it was partially improved in aged animals, even though not sufficient to rescue the decrease related to aging. Besides, no effect of EE on N-methyl-d-aspartate receptor activation and theta-burst-induced long-term potentiation was found in adult or aged animals. DISCUSSION: These results indicate that continuous EE is able to improve cognitive abilities in adult NMRI female mice, that does not correlate with changes in theta burst-related synaptic plasticity within neuronal networks. In addition, the lack of effects in aged animals suggests the existence of a critical delay for the beneficial effects of EE on cognitive aging.

Despite extensive research efforts in the field of cerebral ischemia, numerous disappointments came out. Indeed, even if experimental studies showed up a huge number of promising drugs, most of them unfortunately failed to be efficient in clinical trials. Based on these reports, factors that play a significant role in causing outcome variation were identified and recently reviewed in the Rodent Stroke Model Guidelines for Preclinical Studies. Herein, we provide improvements to this first edition as regards to the functional evaluation section, especially regarding long-term evaluation. Indeed, as in clinical practice (Rothrock et al 1995), animals display a certain degree of spontaneous recovery after stroke (Hunter et al 1998; Roof et al 2001; Zausinger et al 2000; Zhang et al 2000). Typically, the neurological impairment, assessed by basic items, usually disappears during the initial week following stroke in rodents (Bederson et al 1986). As a contrary, more demanding sensorimotor and cognitive tasks underline other deficits, usually long-lasting. Unfortunately, studies addressing such behavioral impairments are less abundant. Therefore, because the characterization of long-term functional recovery is critical for evaluating the efficacy of potential therapeutic agents in experimental stroke, behavioral tests that proved to be sensitive enough to detect long-term deficits are reported here. Overall, since the ultimate goal of any stroke therapy is the restoration of normal functions, an objective appraisal of the behavioral deficits should be done.

International audience; 5-HT4 and 5-HT6 serotonergic receptors are located in brain structures involved in memory processes. Neurochemical and behavioural studies have demonstrated that acute activation of 5-HT4 receptors (5-HT4R) or blockade of 5-HT6 receptors (5-HT6R) improves memory. To evaluate the potential of these two receptors as targets in the treatment of memory disorders encountered in several situations (ageing, Alzheimer's disease, schizophrenia, etc.), it is necessary to assess whether their beneficial effects occur after chronic administration, and if such treatment induces adverse effects. The goal of this study was to assess the effects of chronic 5-HT4R or 5-HT6R modulation on recognition memory, and to observe the possible manifestation of side effects (modification of weight gain, locomotor activity or exploratory behaviour, etc.). Mice were treated for 14 days with a 5-HT4R partial agonist (RS-67333) or a 5-HT6R antagonist (SB-271046) at increasing doses. Memory performances, locomotor activity, and exploration were assessed. Both chronic 5-HT4R activation and 5-HT6R blockade extended memory traces in an object recognition test, and were not associated with any adverse effects in the parameters assessed. Chronic modulation of one or both of these receptors thus seems promising as a potential strategy for the treatment memory deficits

International audience; In this work, we describe the synthesis and in vitro evaluation of a novel series of multitarget-directed ligands (MTDL) displaying both nanomolar dual-binding site (DBS) acetylcholinesterase inhibitory effects and partial 5-HT4R agonist activity, among which donecopride was selected for further in vivo evaluations in mice. The latter displayed procognitive and antiamnesic effects and enhanced sAPPα release, accounting for a potential symptomatic and disease-modifying therapeutic benefit in the treatment of Alzheimer’s disease.

WOS:000348100700001; International audience; Elderly persons often face biological, psychological or social changes over time that may cause discomfort or morbidity. While some cognitive domains remain stable over time, others undergo a decline. Spatial navigation is a complex cognitive function essential for independence, safety and quality of life. While egocentric (body centered) navigation is quite preserved during aging, allocentric (externally centered) navigation based on a cognitive map using distant landmarks declines with age. Recent preclinical studies showed that serotonergic 5-HT7 receptors are localized in brain regions associated with allocentric spatial navigation processing. Behavioral assessments with pharmacological or genetic tools have confirmed the role of 5-HT7 receptors in allocentric navigation. Moreover, few data suggested a selective age-related decrease in the expression of 5-HT7 receptors in pivotal brain structures implicated in allocentric navigation such as the hippocampal CA3 region. We aim to provide a short overview of the potential role of 5-HT7 receptors in spatial navigation, and to argue for their interests as therapeutic targets against age-related cognitive decline.

Item does not contain fulltext Methylphenidate (MPH) is a widely prescribed stimulant drug for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents. Its use in this age group raises concerns regarding the potential interference with ongoing neurodevelopmental processes. Particularly the hippocampus is a highly plastic brain region that continues to develop postnatally and is involved in cognition and emotional behavior, functions known to be affected by MPH. In this study, we assessed whether hippocampal structure and function were affected by chronic oral MPH treatment and whether its effects were different in adolescent or adult rats. Using behavioral testing, resting-state functional MRI, post-mortem structural magnetic resonance imaging (MRI), and immunohistochemistry, we assessed MPH's effects on recognition memory, depressive-like behavior, topological features of functional connectivity networks, hippocampal shape and markers for hippocampal neurogenesis and proliferation. Object recognition memory was transiently impaired in adolescent treated rats, while in animals treated during adulthood, increased depressive-like behavior was observed. Neurogenesis was increased in adolescent treated rats, whereas cell proliferation was decreased following adult treatment. Adolescent treated rats showed inward shape deformations adjacent to ventral parahippocampal regions known to be involved in recognition memory, whereas such deformations were not observed in adult treated animals. Irrespective of the age of treatment, MPH affected topological features of ventral hippocampal functional networks. Thus, chronic oral treatment with a therapeutically relevant dose of MPH preferentially affected the ventral part of the hippocampus and induced contrasting effects in adolescent and adult rats. The differences in behavior were paralleled by opposite effects on adult neurogenesis and granule cell proliferation.

The kinematics of treadmill locomotion in rats conceived, born, and raised in a hypergravity environment (HG: 2 g) until the age of 3 months was investigated for 5 weeks after their exposition to earth’s gravity. The locomotor performance of the HG rats (N=7) was compared to that of age-matched control rats (N=8) housed at 1 g for the same period. Kinematic analysis of treadmill locomotion was performed up to 35 days of terrestrial life by an optoelectronic motion analyzer (ELITE system). Results showed that the HG rats exhibited a faster locomotor rhythm (increased number of steps/s), walked closer to the ground, and had a more dorsiflexed foot position. Also, HG rats had shorter steps. The data also highlight a fast adaptation to normal gravity since all the locomotor parameters returned to normal values within 3 weeks. The locomotor modifications may be seen as the persistence of a hypergravity-induced posturo-locomotor adaptation in the centrifuge and/or to more functional changes of sensorimotor systems. Because locomotor performance of HG rats is not severely affected, it is concluded that early development of locomotion processes is highly resistant to gravito-inertial changes.

International audience; Environmental enrichment is a powerful way to stimulate brain and behavioral plasticity. However the required exposure duration to reach such changes has not been substantially analyzed. We aimed to assess the time-course of appearance of the beneficial effects of enriched environment. Thus, different behavioral tests and neurobiological parameters (such as neurogenesis, brain monoamines levels, and stress-related hormones) were concomitantly realized after different durations of enriched environment (24 h, 1, 3, or 5 weeks). While short enrichment exposure (24 h) was sufficient to improve object recognition memory performances, a 3-week exposure was required to improve aversive stimulus-based memory performances and to reduce anxiety-like behavior; effects that were not observed with longer duration. The onset of behavioral changes after a 3-week exposure might be supported by higher serotonin levels in the frontal cortex, but seems independent of neurogenesis phenomenon. Additionally, the benefit of 3-week exposure on memory was not observed 3 weeks after cessation of enrichment. Thus, the 3-week exposure appears as an optimal duration in order to induce the most significant behavioral effects and to assess the underlying mechanisms. Altogether, these results suggest that the duration of exposure is a keystone of the beneficial behavioral and neurobiological effects of environmental enrichment.

The 5-HT6 receptor (5-HT6R) is one of the most recently discovered serotonin receptors and has received much attention after observations showing its procognition properties. Indeed, 5-HT6R appears to be a promising target to treat cognitive decline, particularly via its modulatory function of cholinergic and glutamatergic systems. 5-HT6Rs are present mostly in the central nervous system, in brain structures known to be particularly involved in memory. Growing evidence suggests that blockade of 5-HT6R can not only improve memory processes in adult rodents but also reverse age-related and pharmacologically induced deficits. 5-HT6R blockade could also have a beneficial effect on neuronal plasticity. Regarding these findings, several 5-HT6R antagonists are currently going through clinical trials. This review provides an overview of the major findings arguing in favour of a role for 5-HT6R antagonists in developing treatment for cognitive disorders related to ageing and neurodegenerative diseases.

International audience; Inbred LOU/C/Jall rats are currently described as a model of successful aging. These rats have a longer healthy median lifespan than many other strains, do not develop obesity, diabetes, or tumor and more importantly they do not show cognitive decline with aging. This is the first study to examine gene expression changes in the inbred LOU/C/Jall rat hippocampus and frontal cortex. Microarray data from animals aged 5 and 26 months were compared to that obtained from the classical Wistar rat strain to potentially identify only the genes associated with successful aging. We have thus identified a set of 15 genes in the hippocampus and 70 genes in the frontal cortex that could be grouped into several clearly delineated clusters of highly correlated genes associated with a diversity of biological processes, including regulation of plasticity, inflammatory response, metabolic, catabolic and homeostatic processes, and transcription. Such a multiplicity of gene networks and diversity of biological functions were not observed in the Wistar rat strain. The gene expression profiles identified in aged the LOU/C/Jall rats' hippocampus and frontal cortex should be related to their intact cognitive abilities, such as those assessed through spontaneous alternation.

International audience; The rescue of cognitive function through environmental enrichment (EE) during aging has been extensively documented. However, the age at onset, the duration of EE, and the cerebral mechanisms required to obtain the greatest benefits still remain to be determined. We have recently shown that EE applied for 3 mo after the median lifespan, i.e., the age at which 50% of the population is still alive (from 17 to 20 mo in NMRI mice), failed to prevent cognitive deficits in senescent animals. In the present study, mice were exposed to EE prior to the median lifespan, and for a longer total duration (from 14 to 20 mo), before the assessment of memory performance and the electrophysiological properties of hippocampal neuronal networks. The EE prevented memory deficits and reduced anxiety as the animal aged. Moreover, EE attenuated the age-related impairment of basal glutamatergic neurotransmission in CA1 hippocampal slices, and reversed the decrease in isolated N-methyl-D-Aspartate receptor (NMDA-R)-dependent synaptic potentials. Surprisingly, EE did not prevent the age-related alteration of theta-burst-induced long-term potentiation (LTP). This study therefore suggests that EE needs to be initiated before the age corresponding to the median lifespan and/or required long duration (> 3 mo) to have an effect on cognitive aging. In addition, we show that EE probably acts through theta-burst-independent mechanisms of synaptic plasticity.

International audience; RATIONALE: Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are increasingly used for the treatment of depression in children. Limited data are, however, available on their effects on brain development and their efficacy remains debated. Moreover, previous experimental studies are seriously hampered in their clinical relevance. OBJECTIVES: The aim of the present study was to investigate putative age-related effects of a chronic treatment with fluoxetine (5 mg/kg, either orally or i.p. for 3 weeks, 1 week washout) using conventional methods (behavioral testing and binding assay using [(123)I]β-CIT) and a novel magnetic resonance imaging (MRI) approach. METHODS: Behavior was assessed, as well as serotonin transporter (SERT) availability and function through ex vivo binding assays and in vivo pharmacological MRI (phMRI) with an acute fluoxetine challenge (10 mg/kg oral or 5 mg/kg i.v.) in adolescent and adult rats. RESULTS: Fluoxetine caused an increase in anxiety-like behavior in treated adult, but not adolescent, rats. On the binding assays, we observed increased SERT densities in most cortical brain regions and hypothalamus in adolescent, but not adult, treated rats. Finally, reductions in brain activation were observed with phMRI following treatment, in both adult and adolescent treated animals. CONCLUSION: Collectively, our data indicate that the short-term effects of fluoxetine on the 5-HT system may be age-dependent. These findings could reflect structural and functional rearrangements in the developing brain that do not occur in the matured rat brain. phMRI possibly will be well suited to study this important issue in the pediatric population.

It has recently been shown that a lack of vestibular sensory information decreases spatial memory performance and induces biochemical changes in the hippocampus in rodents. After vestibular neurectomy, patients display spatial memory deficit and hippocampal atrophy. Our objectives were to explore: (a) spatial (Y maze, radial-arm maze), and non-spatial (object recognition) memory performance, (b) modulation of NMDA receptors within the hippocampus using radioligand binding, and (c) hippocampal atrophy, using MRI, in a rat model of bilateral labyrinthectomy realized in two operations. Chemical vestibular lesions (VLs) were induced in 24 animals by transtympanic injections of sodium arsanilate (30 mg/0.1 ml/ear), one side being lesioned 3 weeks after the other. The control group received transtympanic saline solution (0.1 ml/ear) (n = 24). Spatial memory performance (Y maze and radial maze) decreased after VL. Conversely, non-spatial memory performance (object recognition) was not affected by VL. No hippocampal atrophy was observed with MRI, but density of NMDA receptors were increased in the hippocampus after VL. These findings show that the lack of vestibular information induced specific deficits in spatial memory. Additionally, quantitative autoradiographic data suggest the involvement of the glutamatergic system in spatial memory processes related to vestibular information. When studying spatial memory performances in the presence of vestibular syndrome, two-step labyrinthectomy is a suitable procedure for distinguishing between the roles of the specific components of vestibular input loss and those of impaired locomotor activity. © 2011 Wiley Periodicals, Inc.

1.1 History of the adhesive removal test Long-term consequences of stroke are often dramatically disabling for daily living but also costly for public health. Stroke research is therefore a priority for most industrialized countries. Therefore and paradoxically, the current situation is disappointing for the patients but stimulating for the researchers who have to figure out new therapies and assess their efficiency. The major initial problem to solve for clinicians when a stroke occurs is to rapidly distinguish between ischemia and hemorrhage to decide for the reperfusion of the brain or for the bleeding stop. Therefore, the first step of stroke treatment takes place within a very short-term and tiny time window (even if it was recently extended to 4 hours for thrombolysis). Next steps of the treatments are directed to avoid another stroke and to promote rehabilitation. For this latter, unfortunately, the treatments are scarce and although many different options have been tested (kinesiotherapy, speech therapy etc.), the situation is still unsatisfactory. News fields of research tried to find out new therapies aimed at improving neurogenesis, implanting stem cells or grafts, or stimulating trophic and growth factors, but in vain, transfer from animal to human is still disappointing. Another way to deal with treatment of stroke is to assess what happens in those patients who recover spontaneously. Indeed, around 33% of stroke patients spontaneously recover after stroke but the mechanisms involved in the recovery, not elucidated till now, could be interesting to promote. To assess these mechanisms, it is of a major importance to be able to measure longterm functional deficits in animal models of stroke, which is by the way a strong recommendation from the STAIR Roundtables (STAIR, 1999; STAIRIII, 2001). According to the brain structures infracted, stroke induces many different symptoms affecting physiological, sensori-motor, and/or cognitive functions. In experimental studies, it is possible to induce different models of stroke and to assess with many different ways their consequences. However, given the extraordinary spontaneous recovery displayed by animals, especially rodents, it is not always possible to highlight long-term deficits. Indeed, small brain lesions induce deficits that either cannot be detected by global behavioral tests or only for a short term period after stroke (limb placing test, neurological score). That is the reason why news tests have been designed to assess functional recovery in animals. Among the various behavioral tests developed so far, the adhesive removal test and all its variations (sticky-tape test, bilateral asymmetry test) have been proved to be one of the most efficient to highlight tiny long term sensori-motor deficits. Originally brought back from bedside to

International audience; Environmental enrichment is known to improve learning and memory in adult rodents. Whereas the morphological changes underlying these beneficial effects are well documented, few studies have addressed the influence of this housing condition on the neuronal networks underlying memory processes. We assessed the effects of environmental enrichment on behavioural performances and brain metabolic activation during a memory task in mice. Adult mice were housed in standard (SC) or enriched (EC) conditions for 3 weeks. Then, recent and remote memory performances were measured in the passive avoidance test. After testing, brain metabolic activation was assessed through cytochrome oxidase (CO) activity. EC improved recent memory, in association with an increased metabolic activation in the frontal and prefrontal cortices and a decreased activation in the baso-lateral amygdala and the hippocampus. EC did not improve remote memory, and globally decreased CO activity. Our findings suggest the involvement of regions of pivotal importance during recent memory, such as the frontal cortex, in the beneficial effects of EC.

A series of nitrated 2-substituted-quinolines was synthesized and evaluated in vitro toward Leishmania donovani promastigotes. In parallel, the in vitro cytotoxicity of these molecules was assessed on the murine J774 and human HepG2 cell lines. Thus, a very promising antileishmanial hit molecule was identified (compound 21), displaying an IC(50) value of 6.6 μM and CC(50) values ≥ 100 μM, conferring quite good selectivity index to this molecule, in comparison with 3 drug-compounds of reference (amphotericin B, miltefosine and pentamidine). Compound 21 also appears as an efficient in vitro antileishmanial molecule against both Leishmania infantum promastigotes and the intracellular L. donovani amastigotes (respective IC(50) = 7.6 and 6.5 μM). Moreover, hit quinoline 21 does not show neither significant antiplasmodial nor antitoxoplasmic in vitro activity and though, presents a selective antileishmanial activity. Finally, a structure-activity relationships study enabled to define precisely the antileishmanial pharmacophore based on this nitroquinoline scaffold: 2-hydroxy-8-nitroquinoline.

International audience; Hypoxic-ischemic (HI) brain injury occurring during the perinatal period is still a major cause of mortality and morbidity. We assessed the impact of maternal hypertension, the most common medical disorder of pregnancy, on the anatomical and functional consequences of HI insult in the immature brain. Rat pups from spontaneously hypertensive (SHR) and normotensive (Wistar Kyoto - WKY) dams were subjected to HI brain damage at post-natal day 7 (P7). Brain lesion and functional deficits were analyzed from 10 min to 35 days after HI, using magnetic resonance imaging (MRI), sensorimotor and cognitive tests. MRI data revealed that SHR pups displayed less brain damage than WKY, attested by an initial smaller lesion followed by a reduced tissue loss at chronic stage (57.1±21.6 and 31.1±27% ipsilateral hemisphere atrophy in WKY and SHR, respectively). Behavioral analyses showed less HI-induced behavioral deficits in motor coordination (rotarod test) and spatial learning (Morris water maze test) in pups from hypertensive dams compared to those from normotensive ones. The data suggest that maternal hypertension causes prenatal stress that may render the immature brain more resistant to subsequent hypoxia-ischemia, related to a preconditioning phenomenon.

International audience; Facing inefficiency of current treatments to cure Alzheimer disease (AD), a pharmacological approach is now emerging on the assumption that a single compound may be able to hit multiple targets, namely Multi-Target-Directed Ligands (MTDLs). Displaying numerous advantages, several MTDL for AD have been recently described but none associating an inhibition of AChE and an activation of 5-HT(4)R. The aim of this study was to validate the concept of a synergistic action of these two targets on episodic-like memory performances in mice. Among potent molecules, RS67333, a reference 5-HT(4)R agonist and donepezil (DNPZ), a reference acetylcholinesterase inhibitor, have been particularly chosen because of their close chemical structure. Administered separately, RS67333 (0.3 and 1mg/kg) and DNPZ (1mg/kg) improved recognition performances compared to saline treated animals but not with lower doses. Co-administration of subactive doses of RS67333 (0.1mg/kg) and DNPZ (0.3mg/kg) improved memory, moreover, this improvement is prevented if a 5-HT(4)R antagonist (GR125487, 10mg/kg) is also administered. Activation of 5-HT(4)R combined with inhibition of AChE with subactive doses of RS67333 and of DNPZ has synergistic effects on memory performances in mice. These molecules having close chemical structures, the synergistic effect of their combination affords new hope to chemist for the synthesis of MTDL.

International audience; Erythropoietin (EPO), a well known haematopoietic growth factor, possesses neuroprotective and neurotrophic effects which have been recently reported to improve cognition and to modulate emotional processing. We investigated the effects of EPO and of its non-erythropoietic carbamylated derivative (CEPO) on memory- and emotion-related behaviour in the adult mouse. Locomotor activity, memory performances (place and object recognition tasks), anxiety- (light/dark transition test) and despair-like behaviours (tail suspension test) were assessed over 6 weeks of repeated EPO or CEPO administration (40 μg/kg, twice a week). Given the potential involvement of hippocampal neurogenesis in memory, we also assessed the effects of EPO and CEPO on neurogenesis in the dentate gyrus. Both treatments improved spatial and non-spatial recognition memory and increased the number of NeuN/BrdU double-labeled cells in the dentate gyrus. These effects seem to be, at least partly, independent from an haematopoietic action since administration of CEPO leads to the similar results. Moreover, CEPO decreased, albeit modestly, despair-related behaviour and tended to decrease anxiety-like behaviour. These results suggest that CEPO is as an attractive molecule for the treatment of neuropsychiatric diseases associating memory and/or emotional disorders.

International audience; Environmental factors are involved to various degrees in psychiatric diseases. Unfortunately, early-life manipulations have been rarely investigated in mice. Interestingly, given the advances in genetics, combination of environmental and genetic factors to get construct validity is now possible. Herein, spontaneous activity, anxiety-like behaviour, social behaviour and short term spatial working memory were assessed in mice after maternal separation or social isolation. Of note, social withdrawal was observed in both models suggesting that this aspect needs to be better considered in future studies, particularly in testing new treatments for schizophrenia.

International audience; Among experimental models of perinatal ischemic stroke, Renolleau's model mimics selected types of stroke at birth, including ischemia and reperfusion. However, its behavioural consequences on development have been poorly described. Here, ischemia-reperfusion was performed in 7-day-old Wistar rats. Between the ages of 9 and 40 days, sensorimotor and memory functions were assessed. The infarcted area was analysed by immunohistochemistry at 40 days of age. The remaining lesion was in the parietal cortex, in the form of a cone-shaped area. This area contained glial cells but neither neurons nor macrophages. Transient focal neonatal ischemia led to sensorimotor alterations in early adulthood, such as postural asymmetry, motor coordination and somatosensory deficits, and hyperactivity, as well as cognitive impairments, such as spatial reference memory deficits. Based on these results, we propose here a selection of behavioural tests that should constitute meaningful tools for assessing sensory and cognitive functions after experimental neonatal ischemic stroke.

International audience; We found that recombinant human erythropoietin (rhEPO) reduced significantly the development of brain edema in a rat model of diffuse traumatic brain injury (TBI) (impact-acceleration model). In this study, we investigated the molecular and intracellular changes potentially involved in these immediate effects. Brain tissue nitric oxide (NO) synthesis, phosphorylation level of two protein kinases (extracellular-regulated kinase (ERK)-1/-2 and Akt), and brain water content were measured 1 (H1) and 2 h (H2) after insult. Posttraumatic administration of rhEPO (5,000 IU/kg body weight, intravenously, 30 mins after injury) reduced TBI-induced upregulation of ERK phosphorylation, although it increased Akt phosphorylation at H1. These early molecular changes were associated with a reduction in brain NO synthesis at H1 and with an attenuation of brain edema at H2. Intraventricular administration of the ERK-1/-2 inhibitor, U0126, or the Akt inhibitor, LY294002, before injury showed that ERK was required for brain edema formation, and that rhEPO-induced reduction of edema could involve the ERK pathway. These results were obtained in the absence of any evidence of blood-brain barrier damage on contrast-enhanced magnetic resonance images. The findings of our study indicate that the anti edematous effect of rhEPO could be mediated through an early inhibition of ERK phosphorylation after diffuse TBI.

International audience; Neurosteroids have been reported to modulate memory processes in rodents. Three analogues of dehydroepiandrosterone (DHEA), two of them previously described (7beta-aminoDHEA and 7beta-amino-17-ethylenedioxy-DHEA), and a new one (3beta-hydroxy-5alpha-androstane-6,17-dione) were synthesized, and their effects were evaluated on memory. This study examined their effects on long term and short term memory in male (6 weeks old) NMRI mice in comparison with the reference drug. Long term memory was assessed using the passive avoidance task and short term memory (spatial working memory) using the spontaneous alternation task in a Y maze. Moreover, the effects of DHEA and its analogues on spontaneous locomotion were measured. In all tests, DHEA and analogues were injected at three equimolar doses (0.300-1.350-6.075 microM/kg). DHEA and its three analogues administered immediately post-training at the highest doses (6.075 microM/kg, s.c.) improved retention in passive avoidance test. Without effect per se in the spatial working memory task, the four compounds failed to reverse scopolamine (1mg/kg, i.p.)-induced deficit in spontaneous alternation. These data suggested an action of DHEA and analogues in consolidation of long term memory particularly when emotional components are implied. Moreover, data indicated that pharmacological modulation of DHEA as performed in this study provides derivatives giving the same mnemonic profile than reference molecule.

International audience; Long-term functional deficits after a brain injury are difficult to assess in the mouse. If no deficit is observed, researchers could conclude either that the animal has fully recovered or that the tests they used were not appropriate or sensitive enough to the modality of the deficits. We present here a detailed protocol describing how to conduct an adhesive removal test for this species. It consists of applying adhesive tape on each forepaw of the animal and measuring the time-to-contact and the time-to-remove them. This behavior implies correct paw and mouth sensitivity (time-to-contact) and correct dexterity (time-to-remove). To decrease interindividual differences, we recommend a training session (1 week, 1 trial per day) before surgical procedures so that mice to reach optimal performances.

International audience; Distal occlusion of the middle cerebral artery (dMCAo), which closely mimics human stroke, is one of the most used animal models. However, although assessment of histological and functional outcome is increasingly recommended for preclinical studies, the latter is often excluded because of the high difficulties to estimate, especially in mice, behavioral impairments. The aim of our study was to deeply screen functional consequences of distal permanent MCAo in mice to target relevant behaviors for future studies. A set of sensorimotor and cognitive tests were performed during 3 weeks postsurgery in 2 groups of mice. Afterward, brain infarctions were estimated by histological staining or magnetic resonance imaging. Overall, while no long-term functional impairments could be detected, the adhesive removal was the only test showing a deficit. Interestingly, this sensorimotor impairment was correlated to cortical damage 3 weeks after surgery. In conclusion, despite the fact that dMCAo-induced deficits could not be evidenced by most of our behavioral tests, the authors showed that the adhesive removal test was the only one, sensitive enough, to highlight a long-term deficit. This result suggests therefore that this mouse model of ischemia is relevant to efficiently assess therapeutic strategies with histological but also behavioral analysis, provided that relevant tests are used.

The common marmoset ( Callithrix jacchus), a New World monkey, has recently been used as a model of focal cerebral ischaemia. Here, we sought to develop a stroke model in this species using an intraluminal approach to occlude the middle cerebral artery (MCA). This technically simple procedure allows both transient and permanent ischaemia with minimal morbidity. Ten common marmosets underwent either transient (3 h) or permanent ischaemia by the insertion of a nylon filament through the external carotid artery up to the origin of the MCA. Cerebral blood flow (CBF) was monitored by the laser-Doppler flowmetry technique. Sensorimotor functions were regularly evaluated, and histologic, immunohistochemical, and magnetic resonance imaging analyses were performed 8 days after the occlusion. The surgical procedure was achieved straightforwardly without postoperative mortality or cerebral haemorrhage. All animals displayed a consistent decrease in CBF that remained stable over 3 h. Infarction affected both cortical and subcortical structures. Although not statistically significant, the volume of infarction was smaller in marmosets subjected to transient ischaemia compared to those permanently occluded (237±139 and 358±118 mm3, respectively). In all the behavioural tests used, reperfused marmosets exhibited fewer neurologic and functional impairments compared to permanently occluded ones. We show the feasibility of the induction of permanent or transient focal cerebral ischaemia in the marmoset using an intraluminal approach with minimal invasion. This model could be suitable as an advanced screening for potential stroke therapies in which behavioural, imaging, and histologic analyses can be compared.