Memory In Adult Mice Research Articles

Recombinant human thioredoxin-1 promotes neurogenesis and facilitates cognitive recovery following cerebral ischemia in mice

Cerebral ischemia (CI) can induce loss of hippocampal neurons, causing cognitive dysfunction such as learning and memory deficits. In adult mammals, the hippocampal dentate gyrus contains neural stem cells (NSCs) that continuously generate newborn neurons and integrate into the pre-existing networks throughout life, which may ameliorate cognitive dysfunction following CI. Recent studies have demonstrated that recombinant human thioredoxin-1 (rhTrx-1) could promote proliferation of human adipose tissue-derived mesenchymal stem cells and angiogenesis. To investigate whether rhTrx-1 also regulates hippocampal neurogenesis following CI and its underlying mechanisms, adult mice were subjected to bilateral common carotid arteries occlusion (BCCAO) to induce CI and treated with rhTrx-1 before reperfusion. Mice treated with rhTrx-1 showed shortened escape latencies in Morris water maze by 30 days and improvements in spatial memory demonstrated by probe trial test. Enhanced NSCs proliferation was observed at day 14, indicated by BrdU and Ki67 immunostaining. Doublecortin (DCX)+ cells were also significantly increased following rhTrx-1 treatment. Despite increases in BrdU+/NeuN+ cells by day 30, the double-labeling to total BrdU+ ratio was not affected by rhTrx-1 treatment. The promotive effects of rhTrx-1 on NSCs proliferation and differentiation were further confirmed in in vitro assays. Western blot revealed increased ERK1/2 phosphorylation after rhTrx-1 treatment, and the ERK inhibitor U0126 abrogated the effects of rhTrx-1 on NSCs proliferation. These results provide initial evidence that rhTrx-1 effects neurogenesis through the ERK signaling pathway and are beneficial for improving spatial learning and memory in adult mice following global CI.

Ghrelin administration enhances neurogenesis but impairs spatial learning and memory in adult mice

Ghrelin, an orexigenic brain-gut hormone promoting feeding and regulating energy metabolism in human and rodents, was reported to enhance both adult neurogenesis and hippocampus-dependent memory formation. However, it is still unclear whether ghrelin-induced hippocampus neurogenesis is responsible for its memory improvement. Using 5-bromo-2′ deoxyuridien (BrdU) to birth-date newborn neurons and c-Fos expression to identify dentate gyrus (DG) neurons involved in memory processes, we checked here the effect of ghrelin treatment on adult neurogenesis and cognitive behaviors in mice. We further examined the possible effect of ghrelin on the recruitment of new neurons into the spatial memory traces in intact mice. We found that systemic ghrelin treatment (80μg/kg, ip injection once daily for 8days) stimulated neurogenesis in the adult hippocampus, but had no effect on spatial memory formation. Consistently, it did not affect the incorporation of newborn neurons into the spatial memory circuits. On the contrary, local infusion of ghrelin (8ng/0.5μl into CA1 region of the hippocampus) impaired spatial memory formation, but did not affect adult neurogenesis. Our results thus suggested that ghrelin plays distinct roles in modulating adult neurogenesis and the memory acquisition in the hippocampus, the two processes may not be correlated and may be mediated by different mechanisms.

F3/Contactin promotes hippocampal neurogenesis, synaptic plasticity, and memory in adult mice

F3/contactin, a cell-adhesion molecule belonging to the immunoglobulin supergene family, is involved in several aspects of neural development including synapse building, maintenance and functioning. Here, we examine F3/contactin function in adult hippocampal neurogenesis, synaptic plasticity, and memory, using as a model TAG/F3 transgenic mice, where F3/contactin overexpression was induced under control of regulatory sequences from the human TAG-1 (TAX-1) gene. Transgenic mice aged 5 (M5) and 12 (M12) months exhibited an increase in hippocampal size, which correlated with positive effects on precursor proliferation and NeuN expression, these data suggesting a possible role for F3/contactin in promoting adult hippocampal neurogenesis. On the functional level, TAG/F3 mice exhibited increased CA1 long-term potentiation and improved spatial and object recognition memory, notably at 12 months of age. Interestingly, these mice showed an increased expression of the phosphorylated transcription factor CREB, which may represent the main molecular correlate of the observed morphological and functional effects. Altogether, these findings indicate for the first time that F3/contactin plays a role in promoting adult hippocampal neurogenesis and that this effect correlates with improved synaptic function and memory.

Inhibition of brain ST8SiaIII sialyltransferase leads to impairment of procedural memory in mice

Several glycoproteins in mammalian brains contain α2,8-linked disialic acid residues. We previously showed a constant expression of disialic acid (DiSia) in the hippocampus, olfactory bulb and cortex, and a gradual decrease of expression in the cerebellum from neonatal to senile mice. Previous publications indicate that neurite extension of neuroblastoma-derived Neuro2A cells is inhibited in the presence of DiSia antibody. Based on this, we treated Neuro2A cell cultures with RNA interference for ST8SiaIII mRNA, the enzyme responsible for DiSia formation. We observed that neurite extension was inhibited by this treatment.Taking this evidence into consideration and the relationship of the cerebellum with learning and memory, we studied the role of DiSia expression in a learning task.Through delivery of pST8SiaIII into the brains of C57BL/6 neonatal mice, we inhibited the expression of ST8SiaIII. ST8SiaIII mRNA and protein expressions were analyzed by real-time PCR and western blot, respectively.In this work, we showed that pST8SiaIII-treated mice presented a significantly reduced level of ST8SiaIII mRNA in the cerebellum (p<0.01) in comparison to control mice at 8days after treatment. It is also noted that these levels returned to baseline values in the adulthood. Then, we evaluated behavioural performance in the T-Maze, a learning task that estimates procedural memory. At all ages, pST8SiaIII-treated mice showed a lower performance in the test session, being most evident at older ages (p<0.001). Taken all together, we conclude that gene expression of ST8SiaIII is necessary for some cognitive tasks at early postnatal ages, since reduced levels impaired procedural memory in adult mice.

Neurotoxicity of perfluorooctane sulfonate to hippocampal cells in adult mice.

Perfluorooctane sulfonate (PFOS) is a ubiquitous pollutant and found in the environment and in biota. The neurotoxicity of PFOS has received much concern among its various toxic effects when given during developing period of brain. However, little is known about the neurotoxic effects and potential mechanisms of PFOS in the mature brain. Our study demonstrated the neurotoxicity and the potential mechanisms of PFOS in the hippocampus of adult mice for the first time. The impairments of spatial learning and memory were observed by water maze studies after exposure to PFOS for three months. Significant apoptosis was found in hippocampal cells after PFOS exposure, accompanied with a increase of glutamate in the hippocampus and decreases of dopamine (DA) and 3,4-dihydrophenylacetic acid (DOPAC) in Caudate Putamen in the 10.75 mg/kg PFOS group. By two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE) analysis, seven related proteins in the hippocampus that responded to PFOS exposure were identified, among which, Mib1 protein (an E3 ubiquitin-protein ligase), Herc5 (hect domain and RLD 5 isoform 2) and Tyro3 (TYRO3 protein tyrosine kinase 3) were found down-regulated, while Sdha (Succinate dehydrogenase flavoprotein subunit), Gzma (Isoform HF1 of Granzyme A precursor), Plau (Urokinase-type plasminogen activator precursor) and Lig4 (DNA ligase 4) were found up-regulated in the 10.75 mg/kg PFOS-treated group compare with control group. Furthermore, we also found that (i) increased expression of caspase-3 protein and decreased expression of Bcl-2, Bcl-XL and survivin proteins, (ii) the increased glutamate release in the hippocampus. All these might contribute to the dysfunction of hippocampus which finally account for the impairments of spatial learning and memory in adult mice.

Tau Phosphorylation and Sevoflurane Anesthesia

BACKGROUND There is a growing interest in the involvement of anesthetic agents in the etiology of postoperative cognitive dysfunction. Recent animal studies suggest that acute anesthesia induces transient hyperphosphorylation of tau, an effect essentially ascribed to hypothermia. The main aim of the present study was to investigate effects, in normothermic conditions, of acute or repeated exposure to sevoflurane, a halogenated anesthetic agent, on hippocampal tau phosphorylation and spatial memory in adult mice. METHODS 5 to 6-month-old C57Bl6/J mice were submitted to acute (1 h) or repeated (five exposures of 1h every month) anesthesia using 1.5 or 2.5% sevoflurane, in normothermic conditions. In the acute protocol, animals were sacrificed 1 and 24 h after exposure. In the chronic protocol, spatial memory was evaluated using the Morris water maze following the fourth exposure, and tau phosphorylation evaluated 1 month following the last exposure using bi- and mono-dimensional electrophoresis. RESULTS Acute sevoflurane anesthesia in normothermic conditions led to a significant dose-dependent and reversible hippocampal tau phosphorylation, 1 h following the end of exposure (P < 0.001). Conversely, repeated anesthesia led to persistent tau hyperphosphorylation and significant memory impairments, as seen in the retention phase of the Morris water maze in sevoflurane-anesthesized animals. These pathologic features may be related to the activation of both Akt and Erk pathways. CONCLUSIONS The present study demonstrates, in mice, that sevoflurane exposure is associated with increased tau phosphorylation through specific kinases activation and spatial memory deficits. These data support a correlation between exposures to this anesthetic agent and cognitive decline.

Effect of intermittent exposure to ethanol and MDMA during adolescence on learning and memory in adult mice

BackgroundHeavy binge drinking is increasingly frequent among adolescents, and consumption of 3,4-methylenedioxymethamphetamine (MDMA) is often combined with ethanol (EtOH). The long-lasting effects of intermittent exposure to EtOH and MDMA during adolescence on learning and memory were evaluated in adult mice using the Hebb-Williams maze.MethodsAdolescent OF1 mice were exposed to EtOH (1.25 g/kg) on two consecutive days at 48-h intervals over a 14-day period (from PD 29 to 42). MDMA (10 or 20 mg/kg) was injected twice daily at 4-h intervals over two consecutive days, and this schedule was repeated six days later (PD 33, 34, 41 and 42), resulting in a total of eight injections. Animals were initiated in the Hebb-Williams maze on PND 64. The concentration of brain monoamines in the striatum and hippocampus was then measured.ResultsAt the doses employed, both EtOH and MDMA, administered alone or together, impaired learning in the Hebb-Williams maze, as treated animals required more time to reach the goal than their saline-treated counterparts. The groups treated during adolescence with EtOH, alone or plus MDMA, also presented longer latency scores and needed more trials to reach the acquisition criterion score. MDMA induced a decrease in striatal DA concentration, an effect that was augmented by the co-administration of EtOH. All the treatment groups displayed an imbalance in the interaction DA/serotonin.ConclusionsThe present findings indicate that the developing brain is highly vulnerable to the damaging effects of EtOH and/or MDMA, since mice receiving these drugs in a binge pattern during adolescence exhibit impaired learning and memory in adulthood.

Tau Phosphorylation and Sevoflurane Anesthesia

There is a growing interest in the involvement of anesthetic agents in the etiology of postoperative cognitive dysfunction. Recent animal studies suggest that acute anesthesia induces transient hyperphosphorylation of tau, an effect essentially ascribed to hypothermia. The main aim of the present study was to investigate effects, in normothermic conditions, of acute or repeated exposure to sevoflurane, a halogenated anesthetic agent, on hippocampal tau phosphorylation and spatial memory in adult mice. 5 to 6-month-old C57Bl6/J mice were submitted to acute (1 h) or repeated (five exposures of 1h every month) anesthesia using 1.5 or 2.5% sevoflurane, in normothermic conditions. In the acute protocol, animals were sacrificed 1 and 24 h after exposure. In the chronic protocol, spatial memory was evaluated using the Morris water maze following the fourth exposure, and tau phosphorylation evaluated 1 month following the last exposure using bi- and mono-dimensional electrophoresis. Acute sevoflurane anesthesia in normothermic conditions led to a significant dose-dependent and reversible hippocampal tau phosphorylation, 1 h following the end of exposure (P < 0.001). Conversely, repeated anesthesia led to persistent tau hyperphosphorylation and significant memory impairments, as seen in the retention phase of the Morris water maze in sevoflurane-anesthesized animals. These pathologic features may be related to the activation of both Akt and Erk pathways. The present study demonstrates, in mice, that sevoflurane exposure is associated with increased tau phosphorylation through specific kinases activation and spatial memory deficits. These data support a correlation between exposures to this anesthetic agent and cognitive decline.

Nimodipine-Induced Hypotension but Not Nitroglycerin-Induced Hypotension Preserves Long- and Short-Term Memory in Adult Mice

Acute hypotension may be implicated in cognitive dysfunction. L-type calcium channel blockers in the setting of hypoxia are protective of learning and memory. We tested the hypothesis that hypotension induced by nimodipine (NIMO) and nicardipine (NICA) would be protective of long- and short-term memory compared to hypotension induced by nitroglycerin (NTG). Forty Swiss-Webster mice (30 to 35 g, 6 to 8 weeks) were randomized into 4 groups for i.p. injection immediately after passive avoidance (PA) learning on day 0: (1) NTG (30 mg/kg); (2) NICA (40 mg/kg); (3) NIMO (40 mg/kg); and (4) saline. PA training latencies (seconds) were recorded for entry from a suspended platform into a Plexiglas tube where a shock (0.3 mA; 2-second duration) was automatically delivered. On day 2 latencies were recorded during a testing trial during which no shock was delivered. Latencies >900 seconds were assigned this value. Lower testing latency is indicative of an impairment of long-term associative memory. Forty-nine additional mice were randomized into similar groups for object recognition testing (ORT) and given i.p. injections on day 0. ORT measures short-term memory by exploiting the tendency of mice to prefer novel objects where a familiar object is present. On day 5 during training, 2 identical objects were placed in a circular arena and mice explored both for 15 minutes. A testing trial was conducted 1 hour later for 3 minutes after a novel object replaced a familiar one. Mice with intact memory spend about 65% of the time exploring the novel object. Mice with impaired memory devote equal time to each object. Recognition index (RI) is defined as the ratio of time spent exploring the novel object to time spent exploring both objects was the measure of memory. Mean arterial blood pressure (MAP), cerebral bloodflow, and body and brain oxygenation (PO(2)) studies were done in separate groups of mice to determine the dosages for matched degrees of hypotension and the physiological profile of each treatment. The median PA latencies for the different conditions were as follows: NTG (219.5 ± 93.5 second semi-interquartile range [SIQR]), NICA (372.5 ± 75.5 second SIQR), NIMO (540 ± 200 second SIQR) and saline (804 ± 257.5 second SIQR). Rank methods were used to analyze the PA latencies for significant differences. NTG latency was significantly shorter than NIMO latency (P = 0.012) and saline latency (P = 0.006), but not NICA latency (P = 0.126). ORT RI values showed a similar pattern. We found that NTG RI (47.2 ± 5.9% SEM) was different from NIMO RI (60.2 ± 4.6% SEM, P = 0.031) and different from saline RI (66.9 + 3.7% SEM, P = 0.006). Physiological experiments showed that MAP decreased to 45 to 50 mm Hg in all animals who became minimally responsive to external stimuli within 10 to 15 minutes of injection. Intergroup differences for MAP, body and brain oxygenation, and cerebral bloodflow were not statistically significant. Acute hypotension induced by NIMO was protective of 2 categories of memory formation relevant to the clinical posttreatment period. Both immediate long-term associative memory consolidation as measured by the PA learning paradigm and delayed short-term working memory function as measured by the ORT paradigm were significantly improved compared to matched levels of hypotension induced by NTG. These results indicate the utility of further investigation of l-type calcium channel blockers as a potential means of preserving cognition in the setting of hypotensive and low flow states.

Differences in neonatal neurotoxicity of brominated flame retardants, PBDE 99 and TBBPA, in mice

Flame retardants such as polybrominated diphenyl ethers (PBDE) and tetrabromobisphenol A are used as flame retardants and detected in the environmental, wildlife species and human tissues. Exposure to PBDEs during the neonatal development of the brain has been shown to affect behavior and learning and memory in adult mice, while neonatal exposure to TBBPA (another brominated flame retardant) did not affect behavioral variables in the adult. In this study, we hypothesized that the effects of these compounds could be reflected by changes in biochemical substrates and cholinergic receptors and have examined the levels of four proteins involved in maturation of the brain, neuronal growth and synaptogenesis and the densities of both muscarinic and nicotinic cholinergic receptors. We measured the levels of radioactivity in the brain after administration of 14C-labelled TBBPA at different time points and saw that levels of TBBA peaked earlier and decreased faster than the earlier reported levels of PBDE 99. The protein analysis in the neonatal brain showed changes in the levels of calcium/calmodulin-dependent protein kinase II (CaMKII), growth associated protein-43 (GAP-43) and synaptophysin following neonatal exposure to PBDE 99 (21μmol/kg body weight), but not following exposure TBBPA. Furthermore, neonatal exposure to PBDE 99 and TBBPA caused a decrease in binding sites of the nicotinic ligand cytisine in frontal cortex. These results confirm earlier reported data that PBDE 99 can act as a developmental neurotoxicant, possibly due to its different uptake and retention in the brain compared to TBBPA. In addition, the changes in protein levels are interesting leads in the search for mechanisms behind the developmental neonatal neurotoxicity of PBDEs in general and PBDE 99 in particular, since also other compounds inducing similar adult behavioral disturbances as PBDE 99, affect these proteins during the period of rapid brain development.

Influence of early stress on social abilities and serotonergic functions across generations in mice.

Exposure to adverse environments during early development is a known risk factor for several psychiatric conditions including antisocial behavior and personality disorders. Here, we induced social anxiety and altered social recognition memory in adult mice using unpredictable maternal separation and maternal stress during early postnatal life. We show that these social defects are not only pronounced in the animals directly subjected to stress, but are also transmitted to their offspring across two generations. The defects are associated with impaired serotonergic signaling, in particular, reduced 5HT1A receptor expression in the dorsal raphe nucleus, and increased serotonin level in a dorsal raphe projection area. These findings underscore the susceptibility of social behaviors and serotonergic pathways to early stress, and the persistence of their perturbation across generations.

Hippocampal endocannabinoids play an important role in induction of long-term potentiation and regulation of contextual fear memory formation

Recent studies show contradictory results regarding the contribution of endocannabinoids in fear memory formation and long-term synaptic plasticity. In this study, we investigated the effects of both cannabinoid receptor type 1 (CB1 receptor) antagonist AM281 and anandamide reuptake inhibitor AM404 on the formation of contextual fear memory in adult mice. Both i.p. and intra-hippocampal injections of AM281 promoted contextual fear memory while a high dose of AM404 inhibited it. These findings demonstrate that CB1 receptor-mediated signaling negatively contributes to contextual fear memory formation. We further investigated the induction of long-term potentiation (LTP) in CA1 pyramidal neurons of hippocampal slices and found that AM281 impaired the induction of LTP. Additionally, the blockade of LTP by AM281 was completely prevented by bath application of picrotoxin, a selective antagonist of GABAA receptor. Taken together, these results indicate that activation of CB1 receptor contributes to induction of LTP via a GABAA receptor-mediated mechanism.

Blockade of adenosine A1 receptors prevents methylphenidate-induced impairment of object recognition task in adult mice

Methylphenidate (MPH) is the preferred treatment used for attention-deficit/hyperactivity disorder (ADHD). Recently, misuse for MPH due to its apparent cognitive enhancer properties has been reported. Adenosine is a neuromodulator known to exert influence on the dopaminergic neurotransmission, which is the main pharmacological target of MPH. We have reported that an overdosage of MPH up-regulates adenosine A1 receptors in the frontal cortex, but this receptor was not involved in its anxiolytic effects. In this study, the role of adenosine A1 receptor was investigated on MPH-induced effects on aversive and recognition memory in adult mice. Adult mice received acute and chronic (15days) administration of methylphenidate (5mg/kg, i.p.), or an acute overdosage (50mg/kg, i.p) in order to model misuse. Memory was assessed in the inhibitory avoidance and object recognition task. Acute administration 5mg/kg improved whereas 50mg/kg disrupted recognition memory and decreased performance in the inhibitory avoidance task. Chronic administration did not cause any effect on memory, but decreased adenosine A1 receptors immunocontent in the frontal cortex. The selective adenosine A1 receptor antagonist, (DPCPX 1mg/kg, i.p.), prevented methylphenidate-triggered recognition memory impairment. Our findings showed that recognition memory rather than aversive memory was differently affected by acute administration at both doses. Memory recognition was fully impaired by the overdosage, suggesting that misuse can be harmful for cognitive functions. The adenosinergic system via A1 receptors may play a role in the methylphenidate actions probably by interfering with dopamine-enhancing properties of this drug.

Young hippocampal neurons are critical for recent and remote spatial memory in adult mice

New granule cells are continuously generated throughout adulthood in the mammalian hippocampus. These newly generated neurons become functionally integrated into existing hippocampal neuronal networks, such as those that support retrieval of remote spatial memory. Here, we sought to examine whether the contribution of newly born neurons depends on the type of learning and memory task in mice. To do so, we reduced neurogenesis with a cytostatic agent and examined whether depletion of young hippocampal neurons affects learning and/or memory in two hippocampal-dependent tasks (spatial navigation in the Morris water maze and object location test) and two hippocampal-independent tasks (cued navigation in the Morris water maze and novel object recognition). Double immunohistofluorescent labeling of the birth dating marker 5-bromo-2'deoxyuridine (BrdU) together with NeuN, a neuron specific marker, was employed to quantify reduction of hippocampal neurogenesis. We found that depletion of young adult-generated neurons alters recent and remote memory in spatial tasks but spares non-spatial tasks. Our findings provide additional evidence that generation of new cells in the adult brain is crucial for hippocampal-dependent cognitive functions.

P.6.c.001 Cortisol levels and MDMA-induced memory impairment

The present study was undertaken to evaluate the immediate and long-term effects of a single-day exposure to 5-Azacytidine (5-AzaC), a DNA methyltransferase inhibitor, on neurobehavioral abnormalities in mice. Our findings suggest that the 5-AzaC treatment significantly inhibited DNA methylation, impaired extracellular signal-regulated kinase (ERK1/2) activation and reduced expression of the activity-regulated cytoskeleton-associated protein (Arc). These events lead to the activation of caspase-3 (a marker for neurodegeneration) in several brain regions, including the hippocampus and cortex, two brain areas that are essential for memory formation and memory storage, respectively. 5-AzaC treatment of P7 mice induced significant deficits in spatial memory, social recognition, and object memory in adult mice and deficits in long-term potentiation (LTP) in adult hippocampal slices. Together, these data demonstrate that the inhibition of DNA methylation by 5-AzaC treatment in P7 mice causes neurodegeneration and impairs ERK1/2 activation and Arc protein expression in neonatal mice and induces behavioral abnormalities in adult mice. DNA methylation-mediated mechanisms appear to be necessary for the proper maturation of synaptic circuits during development, and disruption of this process by 5-AzaC could lead to abnormal cognitive function.

Caffeine prevents disruption of memory consolidation in the inhibitory avoidance and novel object recognition tasks by scopolamine in adult mice

Caffeine is a psychostimulant with positive effects on cognition. Recent studies have suggested the participation of the cholinergic system in the effects of caffeine on wakefulness. However, there are few studies assessing the contribution of cholinergic system in the cognitive enhancer properties of caffeine. In the present study, the effects of a dose and schedule of administration of caffeine that improved memory recognition were investigated on scopolamine-induced impairment of memory in adult mice. Inhibitory avoidance and novel object recognition tasks were used to assess learning and memory. Caffeine (10 mg/kg, i.p.) was administered during 4 consecutive days, and the treatment was interrupted 24 h before scopolamine administration (2 mg/kg, i.p.). Scopolamine was administered prior to or immediately after training. Short-term and long-term memory was evaluated in both tasks. In the novel object recognition task, pre treatment with caffeine prevented the disruption of short- and long-term memory by scopolamine. In the inhibitory avoidance task, caffeine prevented short- but not long-term memory disruption by pre training administration of scopolamine. Caffeine prevented short- and long-term memory disruption by post training administration of scopolamine. Both treatments did not affect locomotor activity of the animals. These findings suggest that acute treatment with caffeine followed by its withdrawal may be effective against cholinergic-induced disruption of memory assessed in an aversive and non-aversive task. Finally, our results revealed that the cholinergic system is involved in the positive effects of caffeine on cognitive functions.

Cyclophosphamide impairs hippocampus-dependent learning and memory in adult mice: Possible involvement of hippocampal neurogenesis in chemotherapy-induced memory deficits

Cyclophosphamide (CYP) is an anti-neoplastic agent as well as an immunosuppressive agent. In order to elucidate the alteration in adult hippocampal function following acute CYP treatment, hippocampus-related behavioral dysfunction and changes in adult hippocampal neurogenesis in CYP-treated (intraperitoneally, 40 mg/kg) mice (8–10-week-old ICR) were analyzed using hippocampus-dependent learning and memory tasks (passive avoidance and object recognition memory test) and immunohistochemical markers of neurogenesis (Ki-67 and doublecortin (DCX)). Compared to the vehicle-treated controls, mice trained at 12 h after CYP injection showed significant memory deficits in passive avoidance and the object recognition memory test. The number of Ki-67- and DCX-positive cells began to decrease significantly at 12 h post-injection, reaching the lowest level at 24 h after CYP injection; however, this reverted gradually to the vehicle-treated control level between 2 and 10 days. We suggest that the administration of a chemotherapeutic agent in adult mice interrupts hippocampal functions, including learning and memory, possibly through the suppression of hippocampal neurogenesis.

Administration of midazolam in infancy does not affect learning and memory of adult mice

1. Midazolam is a common fast-acting GABA(A) receptor agonist. Recent data suggest that exposure to midazolam in early life may cause long-term effects on brain function through stable epigenetic reprogramming. The aim of the present study was to determine whether the administration of midazolam to infant mice would affect their learning and memory in adulthood. 2. An open-field test was conducted before and then 3, 24, 48 and 72 h after administration of midazolam (50 mg/kg, i.p.) to infant mice. Saline control mice received an equal volume of saline i.p. 3 h before the open-field test. Total movements, total movement time, total movement distance and velocity were analysed. Novel object recognition (NOR), Morris water-maze and passive avoidance tests were performed when the treated mice grew to adulthood (105 days of age). 3. The results of open-field test showed that midazolam significantly reduced locomotor activity (total movements, total movement time, total movement distance and velocity) in infant mice 3 and 24 h after drug administration and that these effects had disappeared by 72 h after drug administration. The results of the water-maze, NOR and passive avoidance tests in adulthood (at 105 days of age) indicated that administration of midazolam in infancy had no long-term effects on the learning and memory behaviours of adult mice compared with the saline control. 4. Acute midazolam administration to infant mice affected spontaneous locomotor activity for approximately 2 days, but did not seem to have any significant impact on cognitive functioning that lasted into adulthood.

Selective 5-HT6 Receptor Blockade Improves Spatial Recognition Memory and Reverses Age-Related Deficits in Spatial Recognition Memory in the Mouse

Studies have recently suggested that blockade of 5-HT6 receptors (5-HT6R) improves memory processes. As episodic memory alteration is one of the first deficits observed during normal aging and in neurological and neuropsychiatric disorders (Alzheimer's disease, schizophrenia), the present study sought to characterize the effects of 5-HT6R blockade on spatial recognition memory, which can be considered as 'episodic-like' memory, in rodents. We quantified the effects of the selective 5-HT6R antagonist SB-271046 (10 mg/kg, i.p.), using the two-trial place recognition task in the Y-maze, on acquisition, consolidation, and retrieval of spatial recognition memory in young adult mice (6-week-old; intertrial intervals (ITIs) 30, 60, 120, 240, and 360 min) and on the consolidation of spatial recognition memory in aged mice (3-, 12-, 18-, and 21-month-old; ITI 60 and 240 min). SB-271046-treated young adult mice explored the new arm more after a 240-min (pre-acquisition) and 360-min (post-acquisition) ITI, whereas vehicle-treated animals failed to discriminate the new arm when the ITI exceeded 120 min (pre-acquisition) or 240 min (post-acquisition). Aged mice, which expressed spatial memory deficits, explored the new arm more after a 60-min ITI (21-month-old) and a 240-min ITI (18- and 21-month-old) when treated with SB-271046. Consequently, 5-HT6R blockade improves spatial recognition memory in adult mice and reverses age-related consolidation deficits of episodic-like memory. This study provides further support for the use of 5-HT6R antagonists in the treatment of episodic memory disorders related to aging as well as neurological disorders such as Alzheimer's disease and schizophrenia.

Isoflurane Preserves Spatial Working Memory in Adult Mice After Moderate Hypoxia

Perioperative hypoxia may contribute to postoperative cognitive impairment. It is unknown, however, whether anesthetics exacerbate or protect against hypoxia-related central nervous system impairment. We sought to determine whether hypoxia alone or in combination with isoflurane disrupts working memory in mice. To this extent, we assigned adult mice to one of four treatments for 1 h: oxygen 21%, oxygen 21% + isoflurane 1.2%, oxygen 8%, or oxygen 8% + isoflurane 1.2%. Mice breathed spontaneously throughout the experiment. Body temperature was maintained at 37 degrees C + 0.5 degrees C. Mice were allowed to recover for 24 h to avoid the confounding influence of residual anesthetics on neurobehavioral performance. Working memory was assessed by use of a Y maze modified for mice. For the training trial, entry to one arm was blocked and mice were permitted to run between the two open arms for 15 min and inspect the objects outside. For the test trial, carried out 1 h later, all arms were open. Time spent in each arm was automatically recorded by a camera and associated software. Mice were tested 1, 4, and 7 days after anesthesia. A different arm was used as the novel arm for each test. Performance was analyzed with repeated-measurements analysis of variance, followed by analysis of simple main effects and by post hoc comparison using Newman-Keuls test when appropriate. P values <0.05 were considered significant. Animals subjected to hypoxia (8% oxygen for 1 h) spent significantly less time in the novel arm 1 day after the insult. The impairment, however, was transient. Hypoxic mice performance improved to the level of the control animals on the fourth post-treatment day. Mice subjected to hypoxia plus isoflurane exhibited no impairment and were comparable to the control group at all time points. Hypoxia transiently impairs performance in a spatial memory task. It appears that isoflurane protects against this deleterious effect of hypoxia.