Lentiviral Delivery of a Vesicular Glutamate Transporter 1 (VGLUT1)-Targeting Short Hairpin RNA Vector Into the Mouse Hippocampus Impairs Cognition

Glutamate is the principle excitatory neurotransmitter in the mammalian brain, and dysregulation of glutamatergic neurotransmission is implicated in the pathophysiology of several psychiatric and neurological diseases. This study utilized novel lentiviral short hairpin RNA (shRNA) vectors to target expression of the vesicular glutamate transporter 1 (VGLUT1) following injection into the dorsal hippocampus of adult mice, as partial reductions in VGLUT1 expression should attenuate glutamatergic signaling and similar reductions have been reported in schizophrenia. The VGLUT1-targeting vector attenuated tonic glutamate release in the dorsal hippocampus without affecting GABA, and selectively impaired novel object discrimination (NOD) and retention (but not acquisition) in the Morris water maze, without influencing contextual fear-motivated learning or causing any adverse locomotor or central immune effects. This pattern of cognitive impairment is consistent with the accumulating evidence for functional differentiation along the dorsoventral axis of the hippocampus, and supports the involvement of dorsal hippocampal glutamatergic neurotransmission in both spatial and nonspatial memory. Future use of this nonpharmacological VGLUT1 knockdown mouse model could improve our understanding of glutamatergic neurobiology and aid assessment of novel therapies for cognitive deficits such as those seen in schizophrenia.     

Riluzole enhances the activity of glutamate transporters GLAST, GLT1 and EAAC1

Riluzole exerts a neuroprotective effect through different mechanisms, including action on glutamatergic transmission. We investigated whether this drug affects glutamate transporter-mediated uptake, using clonal cell lines stably expressing the rat glutamate transporters GLAST, GLT1 or EAAC1. We found that riluzole significantly increased glutamate uptake in a dose-dependent manner; kinetic analysis indicated that the apparent affinity of glutamate for the transporters was significantly increased, with similar effects in the three cell lines. This may facilitate the buffering of excessive extracellular glutamate under pathological conditions suggesting that riluzole's neuroprotective action might be partly mediated by its activating effect on glutamate uptake.     

The effects of chronic administration of ethosuximide on learning and memory: a behavioral and biochemical study on nonepileptic rats

Long-term use of antiepileptic drugs is common in the treatment of epilepsy. Clinical reports exist of cognitive impairment attributed to antiepileptic drugs. Hence, this study evaluates the effect of chronic administration of one antiepileptic drug, ethosuximide, on spatial and fear learning and memory in nonepileptic rats. High performance liquid chromatography with electrochemical detection was used for quantification of glutamate, glycine, taurine, gamma-aminobutyric acid, dopamine, and serotonin in the frontal cortex and hippocampus to elucidate the neurobiological basis of the effect of ethosuximide on learning and memory. We found that 21 days of ethosuximide treatment produced negative effects on fear memory (passive avoidance) at all doses (100, 200 and 250 mg/kg body weight), but had no effect on spatial learning (T-maze). Fear memory impairment was associated with decreased hippocampal dopamine levels. Ethosuximide (at all doses) had a minimal effect on the GABAergic and glutamatergic systems in all brain regions studied, with the exception of elevated levels of gamma-aminobutyric acid in the frontal cortex with the 250 mg/kg body weight dose. We have shown that long-term administration of ethosuximide adversely affects fear memory, but does not affect spatial learning and memory.     

Dexibuprofen (S(+)-isomer ibuprofen) reduces microglial activation and impairments of spatial working memory induced by chronic lipopolysaccharide infusion

Non-steroidal anti-inflammatory drugs (NSAIDs) have been proposed as a therapeutics to reduce the risk of Alzheimer's disease (AD). The present study shows that the peripheral administration of dexibuprofen (S(+)-isomer ibuprofen), which causes less gastric damage and has better anti-inflammatory effects than ibuprofen, reduces the microglial activation in the cortex and hippocampus, and reduces the phosphorylation of extracellular signal-regulated kinases in the hippocampus, which has been induced by chronic infusion of lipopolysaccharide (LPS) into the fourth ventricle of Wistar rats. The effects of dexibuprofen on impairments of spatial working memory induced by LPS infusions were measured with a trial-unique matching-to-place task in a water maze which assessed memory for place information over varying delays. When performing the water maze task, the rats with the LPS infusions showed spatial working memory impairments relative to the rats with the artificial cerebrospinal fluid. Daily administrations of dexibuprofen reduced the spatial working memory impairment induced by the chronic LPS infusion. The results indicate that NSAID treatments using dexibuprofen significantly attenuate the processes that drive the pathology associated with AD and that this process may involve the suppression of microglial activation.     

Low corticosterone levels attenuate late life depression and enhance glutamatergic neurotransmission in female rats

Sustained elevation of corticosterone (CORT) is one of the common causes of aging and major depression disorder. However, the role of elevated CORT in late life depression (LLD) has not been elucidated. In this study, 18-month-old female rats were subjected to bilateral adrenalectomy or sham surgery. Their CORT levels in plasma were adjusted by CORT replacement and the rats were divided into high-level CORT (H-CORT), low-level CORT (L-CORT), and Sham group. We showed that L-CORT rats displayed attenuated depressive symptoms and memory defects in behavioral tests as compared with Sham or H-CORT rats. Furthermore, we showed that glutamatergic transmission was enhanced in L-CORT rats, evidenced by enhanced population spike amplitude (PSA) recorded from the dentate gyrus of hippocampus in vivo and increased glutamate release from hippocampal synaptosomes caused by high frequency stimulation or CORT exposure. Intracerebroventricular injection of an enzymatic glutamate scavenger system, glutamic-pyruvic transmine (GPT, 1 μM), significantly increased the PSA in Sham rats, suggesting that extracelluar accumulation of glutamate might be the culprit of impaired glutamatergic transmission, which was dependent on the uptake by Glt-1 in astrocytes. We revealed that hippocampal Glt-1 expression level in the L-CORT rats was much higher than in Sham and H-CORT rats. In a gradient neuron–astrocyte coculture, we found that the expression of Glt-1 was decreased with the increase of neural percentage, suggesting that impairment of Glt-1 might result from the high level of CORT contributed neural damage. In sham rats, administration of DHK that inhibited Glt-1 activity induced significant LLD symptoms, whereas administration of RIL that promoted glutamate uptake significantly attenuated LLD. All of these results suggest that glutamatergic transmission impairment is one of important pathogenesis in LLD induced by high level of CORT, which provide promising clues for the treatment of LLD.     

Prenatal exposure to the cannabinoid receptor agonist WIN 55,212-2 increases glutamate uptake through overexpression of GLT1 and EAAC1 glutamate transporter subtypes in rat frontal cerebral cortex

Prenatal exposure to the CB1 receptor agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)-pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone) mesylate (WIN) at a daily dose of 0.5 mg/kg, and Delta9-tetrahydrocannabinol (Delta9-THC) at a daily dose of 5 mg/kg, reduced dialysate glutamate levels in frontal cerebral cortex of adolescent offspring (40-day-old) with respect to those born from vehicle-treated mothers. WIN treatment induced a statistically significant enhancement of Vmaxl-[3H]glutamate uptake, whereas it did not modify glutamate Km, in frontal cerebral cortex synaptosomes of adolescent rats. Western blotting analysis, performed either in membrane proteins derived from homogenates and in proteins extracted from synaptosomes of frontal cerebral cortex, revealed that prenatal WIN exposure enhanced the expression of glutamate transporter 1 (GLT1) and excitatory amino acid carrier 1 (EAAC1). Moreover, immunocytochemical analyses of frontal cortex area revealed a more intense GLT1 and EAAC1 immunoreactivity (ir) distribution in the WIN-treated group. Collectively these results show that prenatal exposure to the cannabinoid CB1 receptor agonist WIN increases expression and functional activity of GLT1 and EAAC1 glutamate transporters (GluTs) associated to a decrease of cortical glutamate outflow, in adolescent rats. These findings may contribute to explain the mechanism underlying the cognitive impairment observed in the offspring of mothers who used marijuana during pregnancy.     

头孢曲松对甲基苯丙胺致大鼠伏隔核神经元和谷氨酸转运体改变的影响

目的观察头孢曲松对甲基苯丙胺(METH)急性、亚急性处理时致神经损伤情况的影响,以及对伏隔核中谷氨酸转运体1(GLT1)与囊泡型谷氨酸转运体1(VGLUT1)的变化的影响。方法建立METH急性毒性模型,同时利用谷氨酸转运体调节剂头孢曲松调控谷氨酸转运体的表达,尼氏染色实验观测神经元中尼氏小体的变化,利用Western blot实验检测其谷氨酸转运体蛋白表达的变化。结果 METH急性给药组与盐水对照组相比,刻板行为明显增加(P<0.01),尼氏小体明显减少;伏隔核中GLT1和VGLUT1的表达增加分别为53.7%和102%(P<0.05);头孢曲松预防给药组与METH组相比,大鼠刻板行为明显减少,伏隔核中GLT1的表达增加36%(P<0.05);VGLUT1的表达下调56%(P<0.05);METH亚急性处理后,与盐水对照组相比,伏隔核中GLT1的蛋白表达增加40.9%,VGLUT1蛋白表达增加52.9%;预防给予头孢曲松后,头孢曲松预防给药组与METH组相比,GLT1和VGLUT1蛋白表达差异没有显著性。结论 METH处理导致神经损伤,引起伏隔核中谷氨酸转运体的表达变化;头孢曲松能激活谷氨酸转运体的表达,缓解METH引起的神经损伤。     

Blockade of Astrocytic Glutamate Uptake in Rats Induces Signs of Anhedonia and Impaired Spatial Memory

Mood disorders are associated with regional brain abnormalities, including reductions in glial cell and neuron number, glutamatergic irregularities, and differential patterns of brain activation. Because astrocytes are modulators of neuronal activity and are important in trafficking the excitatory neurotransmitter glutamate, it is possible that these pathologies are interrelated and contribute to some of the behavioral signs that characterize depression and related disorders. We tested this hypothesis by determining whether depressive-like signs were induced by blocking central astrocytic glutamate uptake with the astrocytic glutamate transporter (GLT-1) inhibitor, dihydrokainic acid (DHK), in behavioral tests that quantify aspects of mood, including reward and euthymia/dysthymia: intracranial self-stimulation (ICSS) and place conditioning. We found that DHK elevated ICSS thresholds, a depressive-like effect that could reflect reduced sensitivity to reward (anhedonia) or increased aversion (dysphoria). However, DHK treatment did not establish conditioned place aversions, suggesting that this treatment does not induce dysphoria. To identify the brain regions mediating the behavioral effects of DHK, we examined c-Fos expression in areas implicated in motivation and emotion. DHK increased c-Fos expression in many of these regions. The dentate gyrus of the hippocampus was robustly activated, which led us to explore whether DHK alters hippocampal learning. DHK impaired spatial memory in the MWM. These findings identify disruption of astrocyte glutamate uptake as one component of the complex circuits that mediate anhedonia and cognitive impairment, both of which are common symptoms of depression. These finding may have implications for the etiology of depression and other disorders that share the features of anhedonia and cognitive impairment.     

甲基苯丙胺急性处理对大鼠纹状体中神经元和谷氨酸转运体的影响

目的:观察甲基苯丙胺(METH)急性处理致神经损伤情况,以及纹状体中谷氨酸转运体1(GLT1)与囊泡型谷氨酸转运体1(VGLUT1)的变化。方法:建立METH急性毒性模型,同时利用谷氨酸转运体激动剂头孢曲松调控谷氨酸转运体的表达,尼氏染色实验观测神经元中尼氏小体的变化,利用Western blot实验检测其谷氨酸转运体蛋白表达的变化。结果:与盐水对照组相比,METH给药组刻板行为明显增加(P<0.01),尼氏小体显著减少,纹状体中GLT1和VGLUT1的表达增加分别为23.1%和66.1%(P<0.05);与METH组相比,头孢曲松预防给药组大鼠刻板行为明显减少,纹状体中GLT1的表达增加15.2%(P<0.05),VGLUT1的表达降低,但没有统计学意义(P>0.05)。结论:METH急性处理能导致神经损伤,引起纹状体中谷氨酸转运体的表达变化;头孢曲松能激活谷氨酸转运体的表达,缓解METH引起的神经损伤。     

Centrophenoxine improves chronic cerebral ischemia induced cognitive deficit and neuronal degeneration in rats

AIM:To study the effects of centrophenoxine (CPH, meclofenoxate) on chronic cerebral hypoperfusion induced deficits in rats. METHODS: Chronic hypoperfusion in rats was performed by permanent bilateral ligation of the common carotid arteries. Morris water maze was used to measure spatial memory performance. Spectrophoto-metrical techniques were used to assay SOD, GPx activities, MDA content, TXB2, and 6-keto-PGF1α levels. Morphological change was examined by HE staining. The expression of Bax and p53 protein were assayed by immunohistochemistry analysis. RESULTS: Chronic hypoperfusion in rats resulted in spatial memory impairments shownby longer escape latency and shorter time spent in the target quadrant. These behavioral dysfunction were accom-panied by increase in SOD and GPx activities, the content of MDA, the levels of pro-inflammatory mediators(TXB2, 6-keto-PGF1α, overexpression of Bax and P53 protein, and delayed degeneration of neurons in cortex andhippocampus. Oral administration of CPH (100 mg/kg, once per day for 37 d) markedly improved the memory impairment, reduced the increase in antioxidant enzyme activities, MDA content and the levels of pro-inflammatorymediators to their normal levels, and attenuated neuronal damage. CONCLUSION: The abilities of CPH to attenuate memory deficits and neuronal damage after ischemia may be beneficial in cerebrovascular type dementia.     

Chotosan,a Kampo Formula,Ameliorates Hippocampal LTD and Cognitive Deficits in Juvenile-Onset Diabetes Rats

Childhood-onset type 1 diabetes is associated with modest impairments in cognition and has an elevated risk of cognitive decline. Our previous study showed that working memory and hippocampal long-term depression (LTD) were impaired in juvenile-onset diabetes mellitus (JDM) rats. In this study, we investigated the effect of chotosan (CTS), a traditional herbal formula called a Kampo medicine, which has been clinically demonstrated to be effective for the treatment of vascular dementia, on JDM rats. The repeated treatment with CTS (1 g/kg per day) for 3 – 7 days restored spatial working memory and hippocampal LTD in JDM rats. The expression level of NR2B glutamate receptor subunits, but not other glutamate receptor subunits was enhanced in the hippocampus of JDM rats, and repeated treatment with CTS reversed these changes. These results suggest that CTS improves diabetes-induced cognitive deficits by modulating NMDA-receptor subunit expression.     

Protective effect of buckwheat polyphenols against long-lasting impairment of spatial memory associated with hippocampal neuronal damage in rats subjected to repeated cerebral ischemia

In the present experiment, we studied the action of buckwheat polyphenol (BWP, from Fagopyrum esculentum MOENCH) in a repeated cerebral ischemia model, which induced a strong and long-lasting impairment of spatial memory in 8-arm radial maze with hippocampal CA1 cell death in rats. BWP (600 mg/kg, continuous 21-day p.o.) significantly ameliorated not only the impairment of spatial memory in the 8-arm radial maze, but also necrosis and TUNEL-positive cells in the hippocampal CA1 area subjected to repeated cerebral ischemia (10 min x 2 times occlusion, 1-h interval) in rats. In order to investigate the mechanism of BWP protective action, we measured the release of glutamate and NO(x)(-) (NO(2)(-) + NO(3)(-)) production induced by repeated cerebral ischemia in the rat dorsal hippocampus using microdialysis. A 14-day BWP treatment significantly inhibited the excess release of glutamate after the second occlusion. In addition, the BWP remarkably suppressed a delayed increase in NO(x)(-) (NO(2)(-) + NO(3)(-)) induced by repeated cerebral ischemia in the dorsal hippocampus as determined in vivo by microdialysis. However, the 14-day treatment did not affect hippocampal blood flow in either intact rats or rats subjected to repeated ischemia measured by lasser Doppler flowmeter. These results suggested that BWP might ameliorate spatial memory impairment by inhibiting glutamate release and the delayed generation of NO(x)(-) in rats subjected to repeated cerebral ischemia.     

Neonatal exposure to monosodium glutamate disrupts place learning ability in adult rats

The activation of glutamatergic NMDA receptors of the hippocampus is closely associated with expression of place learning. Neonatal exposure to monosodium glutamate leads to abnormal expression of NMDA receptor subunits in the hippocampus, but its effect on place learning is unknown. Place learning acquisition and retrieval were assessed in mature adult rats after subcutaneous injection of monosodium glutamate (4 mg/g body weight) in eight neonatal rat pups at postnatal days one, three, five, and seven. Eight untreated rats were used as controls. At four months of age, the rats were challenged over a period of nine days with a place learning task. The task used an acquisition-retrieval paradigm in a Morris maze. Place learning acquisition was impaired in the experimental rats, which were unable to reduce their escape latencies during the nine training days. Controls improved between the fifth and ninth days of training. Test trials showed that retrieval of spatial information was also impaired in the experimental animals. These results show that both place learning acquisition and retrieval abilities in mature rats are impaired by neonatal treatment with monosodium glutamate. These findings may be related to the abnormal expression of NMDA receptor subunits in the hippocampus.     

Changes in the Neuronal Glutamate Transporter EAAT3 in Rat Brain after Exposure to Methamphetamine

Methamphetamine (METH), an addictive psychostimulant, can induce glutamate release in several brain areas such as cerebral cortex, hippocampus and striatum. Excess glutamate is ordinarily removed from the synaptic cleft by glutamate transporters for maintaining homoeostasis. EAAT3, a subtype of glutamate transporter expressed mainly by neurons, is a major glutamate transporter in the hippocampus and cortex. Therefore, this study examined the effects of acute and sub‐acute METH administration on the expression of the EAAT3 in the hippocampal formation, striatum and frontal cortex. Male Sprague–Dawley rats received vehicle injections (i.p.) for 13 days followed by one injection of METH (8 mg/kg, i.p.) on day 14 in acute group. Animals received METH (4 mg/kg, i.p.) or vehicle for 14 days in sub‐acute and control groups, respectively. EAAT3 immunoreactivity was determined by western blotting followed by measurement of the integrated optical density. A significant increase in EAAT3 was found in the hippocampal formation after sub‐acute, but not acute, METH administration. Conversely, a significant decrease in EAAT3 in striatum was observed in both acute and sub‐acute groups. A trend towards a decrease in EAAT3 was also found in frontal cortex in the sub‐acute group. Our results of decreased EAAT3 in striatum and frontal cortex suggest deficits of cortico‐striatal glutamatergic synapses after METH exposure. Increased EAAT3 expression in the hippocampus may be a compensatory response to possible deficits of glutamatergic neurotransmission induced by METH. Moreover, our findings provide further support for glutamatergic dysfunction with abnormalities involving a transporter important in the regulation of neuronal glutamate.     

Acetyl-L-carnitine ameliorates hypobaric hypoxic impairment and spatial memory deficits in rats

Inadequate oxygen availability at high altitude causes oxidative stress and generation of reactive oxygen species, which may lead to memory impairment. Hippocampus, which plays a key role in the learning and memory processes, is especially vulnerable to hypoxic damage. The present study was aimed at investigating the effect of acetyl-L-carnitine on spatial working and reference memory deficits along with oxidative and apoptotic damage, caused by hypobaric hypoxia in male Sprague Dawley rats. Rats were trained in Morris Water Maze for eight days after which they were submitted to chronic hypobaric hypoxia exposure at a simulated altitude of 6100 m for three days. Rats received daily acetyl-L-carnitine at a dosage of 75 mg/kg body weight orally during exposure. Subsequent to exposure, performance of the animals was tested in Morris Water Maze, which revealed working memory impairment that was significantly improved by acetyl-L-carnitine. However, there was no change in the reference memory after hypobaric hypoxia exposure. Following behavioral study animals were sacrificed and biomarkers of oxidative damage like free radical production, lactate dehydrogenase activity, lipid peroxidation, antioxidant status and expression of apoptotic [viz. caspase-3, Apoptosis activating factor (Apaf-1), bax, cytochrome c] and anti-apoptotic protein-Bcl-2 were studied in the hippocampus. There was a significant increase in oxidative stress along with increased expression of apoptotic proteins and NR1 subunit of glutamate receptor indicating occurrence of excitotoxicity in hypoxia exposed rats. These results suggested that supplementation with acetyl-L-carnitine improves spatial working memory deficits reduces oxidative stress and inhibits apoptotic cascade induced by hypoxia.     

Repeated methamphetamine treatment impairs spatial working memory in rats: reversal by clozapine but not haloperidol

Rationale Although chronic use of methamphetamine (METH) leads to long-lasting cognitive dysfunction in humans, there are few reports about an animal model that reflects METH-induced impairment of working memory. Objectives In this study, we investigated the effect of repeated METH treatment on spatial working memory in rats. Materials and methods Rats were repeatedly administered METH (2 mg/kg) once a day for 7 days, and their memory function was assessed with a delayed spatial win-shift task in a radial arm maze. The task consisted of two phases, a training phase and a test phase, separated by a delay. Results METH-treated animals showed an impairment of performance in the test phase when the delay time was increased from 5 to 30 min or longer. The effect of METH persisted for at least 14 days after the drug withdrawal. METH-induced impairment of working memory was reversed by clozapine (3 and 10 mg/kg, for 7 days), but not haloperidol (1 and 2 mg/kg, for 7 days). The improving effect of clozapine diminished 7 days after the withdrawal. Phosphorylated extracellular signal-regulated kinase1/2 (ERK1/2) levels were significantly increased in the hippocampus of saline-treated control rats from 5 to 60 min after the training phase. In contrast, hyperphosphorylation of ERK1/2 was abolished in the hippocampus of rats treated with METH. Conclusions These findings suggest that repeated METH treatment induces impairment of working memory, which is associated with a dysfunctional ERK1/2 pathway in the hippocampus. Furthermore, clozapine may be effective for the treatment of METH-induced cognitive dysfunction. Taku Nagai and Kazuhiro Takuma contributed equally to the work.     

Tianeptine: An Antidepressant with Memory-Protective Properties

The development of effective pharmacotherapy for major depression is important because it is such a widespread and debilitating mental disorder. Here, we have reviewed preclinical and clinical studies on tianeptine, an atypical antidepressant which ameliorates the adverse effects of stress on brain and memory. In animal studies, tianeptine has been shown to prevent stress-induced morphological sequelae in the hippocampus and amygdala, as well as to prevent stress from impairing synaptic plasticity in the prefrontal cortex and hippocampus. Tianeptine also has memory-protective characteristics, as it blocks the adverse effects of stress on hippocampus-dependent learning and memory. We have further extended the findings on stress, memory and tianeptine here with two novel observations: 1) stress impairs spatial memory in adrenalectomized (ADX), thereby corticosterone-depleted, rats; and 2) the stress-induced impairment of memory in ADX rats is blocked by tianeptine. These findings are consistent with previous research which indicates that tianeptine produces anti-stress and memory-protective properties without altering the response of the hypothalamic-pituitary-adrenal axis to stress. We conclude with a discussion of findings which indicate that tianeptine accomplishes its anti-stress effects by normalizing stress-induced increases in glutamate in the hippocampus and amygdala. This finding is potentially relevant to recent research which indicates that abnormalities in glutamatergic neurotransmission are involved in the pathogenesis of depression. Ultimately, tianeptine’s prevention of depression-induced sequelae in the brain is likely to be a primary factor in its effectiveness as a pharmacological treatment for depression.     

Chronic stress in adulthood followed by intermittent stress impairs spatial memory and the survival of newborn hippocampal cells in aging animals: prevention by FGL, a peptide mimetic of neural cell adhesion molecule

In this study, we examined whether chronic stress in adulthood can exert long-term effects on spatial-cognitive abilities and on the survival of newborn hippocampal cells in aging animals. Male Wistar rats were subjected to chronic unpredictable stress at midlife (12 months old) and then reexposed each week to a stress stimulus. When evaluated in the water maze at the early stages of aging (18 months old), chronic unpredictable stress accelerated spatial-cognitive decline, an effect that was accompanied by a reduction in the survival of newborn cells and in the number of adult granular cells in the hippocampus. Interestingly, spatial-memory performance in the Morris water maze was positively correlated with the number of newborn cells that survived in the dentate gyrus: better spatial memory in the water maze was associated with more 5-bromo-2-deoxyuridine (BrdU)-labeled cells. Administration of FGL, a peptide mimetic of neural cell adhesion molecule, during the 4 weeks of continuous stress not only prevented the deleterious effects of chronic stress on spatial memory, but also reduced the survival of the newly generated hippocampal cells in aging animals. FGL treatment did not, however, prevent the decrease in the total number of granular neurons that resulted from prolonged exposure to stress. These findings suggest that the development of new drugs that mimic neural cell adhesion molecule activity might be of therapeutic relevance to treat stress-induced cognitive impairment.