Genetic Background Influence on Hippocampal Synaptic Plasticity: Frequency-Dependent Variations between an Inbred and an Outbred Mice Strain.

For almost half a century, acute hippocampal slice preparations have been widely used to investigate anti-amnesic (or promnesic) properties of drug candidates on long-term potentiation (LTP)-a cellular substrate that supports some forms of learning and memory. The large variety of transgenic mice models now available makes the choice of the genetic background when designing experiments crucially important. Furthermore, different behavioral phenotypes were reported between inbred and outbred strains. Notably, some differences in memory performance were emphasized. Despite this, investigations, unfortunately, did not explore electrophysiological properties. In this study, two stimulation paradigms were used to compare LTP in the hippocampal CA1 area of both inbred (C57BL/6) and outbred (NMRI) mice. High-frequency stimulation (HFS) revealed no strain difference, whereas theta-burst stimulation (TBS) resulted in significantly reduced LTP magnitude in NMRI mice. Additionally, we demonstrated that this reduced LTP magnitude (exhibited by NMRI mice) was due to lower responsiveness to theta-frequency during conditioning stimuli. In this paper, we discuss the anatomo-functional correlates that may explain such hippocampal synaptic plasticity divergence, although straightforward evidence is still lacking. Overall, our results support the prime importance of considering the animal model related to the intended electrophysiological experiments and the scientific issues to be addressed.

Long-Term Music Exposure Prevents Age-Related Cognitive Deficits in Rats Independently of Hippocampal Neurogenesis.

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.

Interplay between 5-HT4 Receptors and GABAergic System within CA1 Hippocampal Synaptic Plasticity.

The type 4 serotonin receptor (5-HT4R) is highly involved in cognitive processes such as learning and memory. Behavioral studies have shown a beneficial effect of its activation and conversely reported memory impairments by its blockade. However, how modulation of 5HT4R enables modifications of hippocampal synaptic plasticity remains elusive. To shed light on the mechanisms at work, we investigated the effects of the 5-HT4R agonist RS67333 on long-term potentiation (LTP) within the hippocampal CA1 area. Although high-frequency stimulation-induced LTP remained unaffected by RS67333, the magnitude of LTP induced by theta-burst stimulation was significantly decreased. This effect was blocked by the selective 5-HT4R antagonist RS39604. Further, 5-HT4R-induced decrease in LTP magnitude was fully abolished in the presence of bicuculline, a GABAAR antagonist; hence, demonstrating involvement of GABA neurotransmission. In addition, we showed that the application of a GABABR antagonist, CGP55845, mimicked the effect of 5-HT4R activation, whereas concurrent application of CGP55845 and RS67333 did not elicit an additive inhibition effect on LTP. To conclude, through investigation of theta burst induced functional plasticity, we demonstrated an interplay between 5-HT4R activation and GABAergic neurotransmission within the hippocampal CA1 area.

Environmental Enrichment Duration Differentially Affects Behavior and Neuroplasticity in Adult Mice.

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.

Mechanisms underlying the neuroprotective effect of brain reserve against late life depression.

Depression is common and medically relevant illness that has been associated to a state of "accelerated aging" and can significantly compromise successful aging. In recent years, the concept of "brain reserve" has emerged to describe some individuals having an increased "baseline adaptive neuroplasticity", providing greater dynamic capacity for adjusting and remodeling cortical circuits to various stressors. We hypothesize that brain reserve may have neuroprotective effects against late life depression. Here, we discuss the modulatory capacity of stress and corticosteroid hormones on hippocampal plasticity and neuronal viability in late life depression as well as the anti-depressive of ketamine and scopolamine mediated by stimulation of the mammalian target of rapamycin, increased inhibitory phosphorylation of GSK-3ß, and increased synaptogenesis. This review shall shed light on complex neurobiological mechanisms that underpin late life depression and help to better understand neural correlates of resilience. Investigating how rat models of increased cognitive reserve mitigate a chronic mild stress-elicited depression will afford new insights in the search for new therapeutic targets to treat this neuropsychiatric disorder.

A Dual-Task Paradigm Combining Physical and Cognitive Training in Mice: Application to Aging.

Physical Activity (PA) is often associated with better overall health status, especially in older adults. Numerous pieces of evidence indicate that PA would be more beneficial when applied in conjunction with Cognitive Training (CT) either simultaneously (i.e., in Dual-Task [DT]) or sequentially. Nonetheless, the underlying mechanisms of such benefits remain elusive. To help delve deeper into their understanding, we developed a cognitive-motor DT paradigm in young adult mice and subsequently tested its effect in old age. Three groups of young adults C57BL/6J mice (3.5 months of age; n=10/group) were required. They were given cognitive tasks, either alone (Control) or in combination with PA which was administered either sequentially (SeqT group) or simultaneously (DT group). Mice were trained in a touchscreen chamber: first on a Visual Discrimination (VD) learning task, then on its Reversal (RVD) which assesses cognitive flexibility alongside procedural learning. PA was given through a homemade treadmill, designed to fit in the touchscreen chambers and set at 9 m/min. Fourteen months later, we further evaluated the effects of PA administered in both DT and SeqT groups, on the performance of the now 19-month-old mice. When compared to SeqT and control groups, DT mice significantly displayed better procedural learning in both VD and RVD tasks as young adults. In the RVD task, this enhanced performance was associated with both poorer inhibition and motor performance. Finally, in 19-month-old mice, both DT and SeqT mice displayed better motor and cognitive performances than control mice. This new cognitive-motor DT paradigm in mice yields an interesting framework that should be useful for adapting DT training in aging, including providing knowledge on the neurobiological correlates, to get the most out of its benefits.

Time-course of age-related temporal order memory decline in an object recognition paradigm in mice.

Temporal order memory refers to the ability to remember the order of occurrence of items across time. It is a critical feature of episodic memory that is often tested in rodents using spontaneous object recognition paradigms. However, impact of aging over performances of temporal order memory decline is barely known. Herein, we characterized here the effect of normal aging on the temporal order memory performances in NMRI mice between 3 and 19months of age, with an inter-session interval of 24h.We found that temporal order memory was impaired as soon as7 months of age. These results provide strong evidence that temporal order memory is particularly vulnerable to the deleterious effect of normal aging.

Post-stroke depression: mechanisms, translation and therapy.

The interaction between depression and stroke is highly complex. Post-stroke depression (PSD) is among the most frequent neuropsychiatric consequences of stroke. Depression also negatively impacts stroke outcome with increased morbidity, mortality and poorer functional recovery. Antidepressants such as the commonly prescribed selective serotonin reuptake inhibitors improve stroke outcome, an effect that may extend far beyond depression, e.g., to motor recovery. The main biological theory of PSD is the amine hypothesis. Conceivably, ischaemic lesions interrupt the projections ascending from midbrain and brainstem, leading to a decreased bioavailability of the biogenic amines--serotonin (5HT), dopamine (DA) and norepinephrine (NE). Acetylcholine would also be involved. So far, preclinical and translational research on PSD is largely lacking. The implementation and characterization of suitable animal models is clearly a major prerequisite for deeper insights into the biological basis of post-stroke mood disturbances. Equally importantly, experimental models may also pave the way for the discovery of novel therapeutic targets. If we cannot prevent stroke, we shall try to limit its long-term consequences. This review therefore presents animal models of PSD and summarizes potential underlying mechanisms including genomic signatures, neurotransmitter and neurotrophin signalling, hippocampal neurogenesis, cellular plasticity in the ischaemic lesion, secondary degenerative changes, activation of the hypothalamo-pituitary-adrenal (HPA) axis and neuroinflammation. As stroke is a disease of the elderly, great clinical benefit may especially accrue from deciphering and targeting basic mechanisms underlying PSD in aged animals.

New hypotheses for the binding mode of 4- and 7-substituted indazoles in the active site of neuronal nitric oxide synthase.

Taking into account the potency of 4- and 7-nitro and haloindazoles as nNOS inhibitors previously reported in the literature by our team, a multidisciplinary study, described in this article, has recently been carried out to elucidate their binding mode in the enzyme active site. Firstly, nitrogenous fastening points on the indazole building block have been investigated referring to molecular modeling hypotheses and thanks to the in vitro biological evaluation of N(1)- and N(2)-methyl and ethyl-4-substituted indazoles on nNOS. Secondly, we attempted to confirm the importance of the substitution in position 4 or 7 by a hydrogen bond acceptor group thanks to the synthesis and the in vitro biological evaluation of a new analogous 4-substituted derivative, the 4-cyanoindazole. Finally, by opposition to previous hypotheses describing NH function in position 1 of the indazole as a key fastening point, the present work speaks in favour of a crucial role of nitrogen in position 2.

Effects of chronic tramadol administration on cognitive flexibility in mice.

RATIONALE: Tramadol is widely used for pain relief especially in seniors. However, long-term use of tramadol has serious adverse effects, including cognitive impairment. Besides its memory effects, already demonstrated in animals, a recent clinical report suggests that tramadol could also affect executive function in seniors. Several studies have hypothesized that the anti-muscarinic properties of tramadol could be responsible for the deleterious effects of tramadol on cognition. OBJECTIVES: We aimed at investigating the effects of chronic administration of tramadol on cognitive flexibility in adult male mice, as assessed by a visual discrimination reversal task using a touchscreen device. The effects of tramadol were further compared to those of scopolamine, a reference muscarinic antagonist. RESULTS: We found that, during the early phase of the reversal task, when cognitive flexibility is most in demand, both tramadol-treated mice (20 mg/kg, s.c., twice a day) and scopolamine-treated mice (0.5 mg/kg, s.c., twice a day) needed more correction trials and showed a higher perseveration index than saline-treated mice. Therefore, tramadol affects cognitive flexibility, and its anticholinergic properties could be at least partly involved in these deficits. CONCLUSIONS: In view of these deleterious cognitive effects of tramadol, physicians should be cautious when prescribing this analgesic, especially in seniors who are more vulnerable to adverse drug events and in which alternative prescription should be preferred whenever possible.

Adverse Effects of Anticholinergic Drugs on Cognition and Mobility: Cutoff for Impairment in a Cross-Sectional Study in Young-Old and Old-Old Adults.

BACKGROUND: Drugs with anticholinergic properties are commonly prescribed in older adults despite growing evidence of their adverse outcomes. Several issues regarding these detrimental effects remain unresolved, such as the putative existence of a threshold above which anticholinergic drug consumption impairs cognitive or mobility performance. OBJECTIVES: We aimed to investigate the number of anticholinergic drugs and the anticholinergic burden that leads to mobility or cognitive impairment and compare the effects in community-dwelling older adults in two age groups ("young-old" 55-74 vs. "old-old" ≥ 75 years). METHODS: In a cross-sectional study, we identified drugs with anticholinergic (antimuscarinic) properties using the Anticholinergic Drug Scale. Cognition was assessed using the Mini Mental State Examination (MMSE) and the Trail Making Test (TMT-A and TMT-B), and mobility was assessed using the Timed Up and Go (TUG) test. RESULTS: The study population consisted of 177 volunteers, 114 of whom were classed as young-old and 63 were classed as old-old adults. Despite the lack of cutoff values for impaired outcomes in young-old adults, impaired MMSE were significantly more numerous in users than in nonusers of anticholinergic drugs. In old-old adults, receiver operating characteristic (ROC) curve analysis indicated that taking a single anticholinergic drug per day was associated with impaired TMT-B completion time, TMT difference score (B-A), and TUG scores. The cutoff for anticholinergic burden was also one for these same outcomes. Based on these cutoff values, multivariate logistic regressions in old-old adults showed that the increased risk of impaired cognition and mobility was independent of confounding factors, including comorbidities. They also suggested that anticholinergic drugs would affect mobility through executive functions. CONCLUSIONS: Drugs with anticholinergic (antimuscarinic) properties are associated with cognitive impairment in individuals as young as 55 years, and only one such drug per day, regardless of its anticholinergic burden, is associated with both impaired cognition and impaired mobility in old-old adults. Therefore, wherever possible, clinicians should avoid prescribing drugs with anticholinergic properties.

Delayed hypoxic postconditioning protects against cerebral ischemia in the mouse.

BACKGROUND AND PURPOSE: Inspired from preconditioning studies, ischemic postconditioning, consisting of the application of intermittent interruptions of blood flow shortly after reperfusion, has been described in cardiac ischemia and recently in stroke. It is well known that ischemic tolerance can be achieved in the brain not only by ischemic preconditioning, but also by hypoxic preconditioning. However, the existence of hypoxic postconditioning has never been reported in cerebral ischemia. METHODS: Adult mice subjected to transient middle cerebral artery occlusion underwent chronic intermittent hypoxia starting either 1 or 5 days after ischemia and brain damage was assessed by T2-weighted MRI at 43 days. In addition, we investigated the potential neuroprotective effect of hypoxia applied after oxygen glucose deprivation in primary neuronal cultures. RESULTS: The present study shows for the first time that a late application of hypoxia (5 days) after ischemia reduced delayed thalamic atrophy. Furthermore, hypoxia performed 14 hours after oxygen glucose deprivation induced neuroprotection in primary neuronal cultures. We found that hypoxia-inducible factor-1alpha expression as well as those of its target genes erythropoietin and adrenomedullin is increased by hypoxic postconditioning. Further studies with pharmacological inhibitors or recombinant proteins for erythropoietin and adrenomedullin revealed that these molecules participate in this hypoxia postconditioning-induced neuroprotection. CONCLUSIONS: Altogether, this study demonstrates for the first time the existence of a delayed hypoxic postconditioning in cerebral ischemia and in vitro studies highlight hypoxia-inducible factor-1alpha and its target genes, erythropoietin and adrenomedullin, as potential effectors of postconditioning.

Behavioral deficits after distal focal cerebral ischemia in mice: Usefulness of adhesive removal test.

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.

Intraluminal thread model of focal stroke in the non-human primate.

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.

Characterizing age-related decline of recognition memory and brain activation profile in mice.

Episodic memory decline is one of the earlier deficits occurring during normal aging in humans. The question of spatial versus non-spatial sensitivity to age-related memory decline is of importance for a full understanding of these changes. Here, we characterized the effect of normal aging on both non-spatial (object) and spatial (object location) memory performances as well as on associated neuronal activation in mice. Novel-object (NOR) and object-location (OLR) recognition tests, respectively assessing the identity and spatial features of object memory, were examined at different ages. We show that memory performances in both tests were altered by aging as early as 15 months of age: NOR memory was partially impaired whereas OLR memory was found to be fully disrupted at 15 months of age. Brain activation profiles were assessed for both tests using immunohistochemical detection of c-Fos (neuronal activation marker) in 3and 15 month-old mice. Normal performances in NOR task by 3 month-old mice were associated to an activation of the hippocampus and a trend towards an activation in the perirhinal cortex, in a way that did significantly differ with 15 month-old mice. During OLR task, brain activation took place in the hippocampus in 3 month-old but not significantly in 15 month-old mice, which were fully impaired at this task. These differential alterations of the object- and object-location recognition memory may be linked to differential alteration of the neuronal networks supporting these tasks.

Long-term evaluation of sensorimotor and mnesic behaviour following striatal NMDA-induced unilateral excitotoxic lesion in the mouse.

Excitotoxic lesion of the striatum provides a useful model for evaluating the excitotoxic processes involved in neurological disorders, in particular stroke diseases. The behavioural outcome after such injury is however poorly described. We have therefore investigated the potential behavioural deficits induced by a NMDA-induced excitotoxic unilateral lesion of the lateral part of the striatum, by comparison with a PBS striatal injection (sham procedure), and non-operated mice behaviour. Three groups of male adult Swiss mice were constituted: unilateral NMDA (20 nmol striatal NMDA injection), sham (striatal PBS injection), and control (healthy non-operated mice). From 14 to 29 days post-surgery, sensorimotor and mnesic tests were performed in all groups. After euthanasia, immunohistochemical stainings (NeuN and GFAP) were performed in order to assess the size of the lesion. Straight runway and passive avoidance performances revealed mild deficits related to the excitotoxic NMDA-induced lesion as compared to the sham procedure. Moreover, accelerated rotarod and Morris water maze acquisition performances also revealed deficits related to the surgery, i.e. observed in sham-operated as compared to control mice. NeuN staining revealed no striatal lesion in the sham and non-operated groups in contrast to the NMDA-injected group in which the volume of infarcted striatum was 2.4+/-0.3mm3. GFAP staining revealed a glial reaction in the lesioned striatum of NMDA animals and at the PBS injection site in sham animals. These results suggest that NMDA-induced excitotoxic lesion induces subtle long-term behavioural deficits in mice. Moreover, this study shows the importance of the sham group to investigate the behavioural deficits after excitotoxic lesion models in mice.

Deletion of the serotonin receptor type 7 disrupts the acquisition of allocentric but not egocentric navigation strategies in mice.

Spatial navigation is achieved through both egocentric (body-centered) and allocentric (externally-centered) strategies but decline with age, especially allocentric strategies. A better understanding of the neurobiological mechanisms underlying these strategies would allow the development of new treatments to mitigate this deterioration. Among them, the modulation of 5-HT7 receptor (5-HT7R) may constitute a potential strategy. Indeed, this receptor is known to play a role in spatial navigation, however its precise role in egocentric and allocentric strategies remains unclear. Here, we first examined the effect of 5-HT7 genetic invalidation (knock-out (KO) mice) in two versions of a water cross-maze task in which only egocentric or allocentric strategies were efficient to solve the task. Our results demonstrated that KO mice are able to learn an allocentric strategy. However, contrary to wild-type mice (WT mice), the acquisition rate was slower compared to the task requiring the acquisition of an egocentric strategy. Mice were then trained in a third version of the water maze, allowing the use of both egocentric and allocentric strategies. When facing conflicting spatial information, both KO and WT mice preferentially used an egocentric strategy. However, only WT mice displayed a greater latency to achieve the task. This suggests that WT mice are able to learn both information in parallel, but not KO mice (i.e. only learning an egocentric strategy). Altogether, these results provide evidence for the essential role of the 5HT7R in the acquisition of an allocentric strategy and in the ability to learn concomitantly both strategies.

Long-term functional outcome following transient middle cerebral artery occlusion in the rat: correlation between brain damage and behavioral impairment.

The assessment of both histological and functional long-term outcomes after cerebral ischemia is increasingly recommended for preclinical studies. Whereas correlations between behavioral impairments and primary ischemic lesion are documented, little is known about their relationships with remote nonischemic regions that undergo secondary degeneration, such as the thalamus. Anesthetized rats were subjected to mild (30 min) or severe (60 min) occlusion of the middle cerebral artery. Two months after ischemia, sensorimotor behavior was assessed according to the neurological score, limb-placing, adhesive-removal, and staircase tests; the final histological lesion was measured after this assessment. Cortical damage was correlated to all transient and long-lasting sensorimotor deficits, whereas striatal lesion was more consistently reflected by the forelimb-placing reflexes and adhesive-removal motor deficits. By contrast, the thalamic atrophy was not correlated to early neurological impairment, but rather to the late sensory deficit at the adhesive-removal test and to the skilled forepaw reaching alteration at the staircase test. This suggests that thalamus contributes, albeit moderately, to the ischemia-induced long-lasting sensorimotor deficits, some of which represent relevant targets for therapeutic interventions.

Cerebrovascular effects of sodium nitroprusside in the anaesthetized baboon: a positron emission tomographic study.

The effects of sodium nitroprusside (SNP), a potent hypotensive agent, on cerebral blood flow (CBF) have been extensively studied in clinical and experimental situations but the results remain controversial. Whereas its properties would predict a dilatation of cerebral blood vessels, most studies report either no change or a decrease in CBF. The aim of this study was to investigate the effects of SNP on CBF, cerebral blood volume (CBV), and cerebral oxygen metabolism (CMRO2), by means of positron emission tomography in the anaesthetized baboon. Measurements were performed during normotension (mean arterial pressure (MABP): 97+/-16 mm Hg) and repeated following SNP-induced hypotension (MABP: 44+/-9 mm Hg). Sodium nitroprusside led to an increase in CBF and CBV (+30% and +37%, respectively, P<0.05), whereas no change in CMRO2 was noted. Linear regression analysis of CBF values as a function of MABP confirmed that CBF increases when MABP is reduced by SNP. The comparison between these cerebrovascular changes and those found during trimetaphan-induced hypotension in our previously published studies further argues for a direct dilatatory effect of SNP on cerebral blood vessels.

Time decay of object, place and temporal order memory in a paradigm assessing simultaneously episodic-like memory components in mice.

A common trait of numerous memory disorders is the impairment of episodic memory. Episodic memory is a delay-dependant memory, especially associating three components, the "what", "where" and "when" of a unique event. To investigate underlying mechanisms of such memory, several tests, mainly based on object exploration behaviour, have been set up in rodents. Recently, a three-trial object recognition task has been proposed to evaluate simultaneously the different components of episodic-like memory in rodents. However, to date, the time course of each memory component in this paradigm is not known. We characterised here the time course of memory decay in adult mice during the three-trial object recognition task, with inter-trial interval (ITI) ranging from 1h to 4h. We found that, with 1h and 2h, but not 4h ITI, mice spent more time to explore the displaced "old object" relative to the displaced "recent object", reflecting memory for "what and when". Concomitantly, animals exhibited more exploration time for the displaced "old object" relative to the stationary "old object", reflecting memory for "what and where". These results provide strong evidence that mice establish an integrated memory for unique experience consisting of the "what", "where" and "when" that can persist until 2h ITI.