Deprivation of endogenous brain-derived neurotrophic factor results in impairment of spatial learning and memory in adult rats

Brain-derived neurotrophic factor (BDNF) is abundantly expressed in the hippocampus and cerebral cortex and is involved in synaptic plasticity and long-term potentiation (LTP). The present study was under taken to investigate whether endogenous BDNF was required for spatial learning and memory in a rat model. Antibodies to BDNF (anti-BDNF, n=7) or control immunoglobulin G (control, n=6) were delivered into the rat brain continuously for 7 days with an osmotic pump. The rats were then subjected to a battery of behavioral tests. The results show that the average escape latencies in the BDNF antibody treated group were dramatically longer than those of the control (F=13.3, p<0.001). The rats treated with control IgG swam for a significantly longer distance in the P quadrant (where the escape plane had been placed) compared with the other three quadrants (p<0.05). In contrast, anti-BDNF-treated rats swam an equivalent distance in all four quadrants. The average percentage of swimming distance in the P quadrant by anti-BDNF-treated rats was much less than that by control IgG treated rats (p<0.001). These results suggest that endogenous BDNF is required for spatial learning and memory in adult rats.     

Spatial memory impairment in ventral subicular lesioned rats

The present study examined the effects of ibotenic acid lesions of the ventral subiculum (SUB) on the ability of rats to memorize a rewarded alternation test in a T-maze. Results indicated that rats with ibotenic acid lesions (IL) of the ventral subiculum were impaired in postoperative acquisition of the spatial discrimination task, making more errors than the vehicle treated and normal control rats. In addition, all rats, including the IL group of rats, were able to memorize an acquired spatial behaviour. These findings suggest that the SUB play an important role in spatial information processing in rats.     

Nicotine ameliorates impairment of working memory in methamphetamine-treated rats

Nicotine is hypothesized to have therapeutic effects on attentional and cognitive abnormalities in psychosis. In this study, we investigated the effect of nicotine on impaired spatial working memory in repeated methamphetamine (METH)-treated rats. Rats were administered METH (4 mg/kg, s.c.) once a day for 7 days, and their working memory 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. Control animals showed impaired performance in the test phase when the delay time was increased to 120 min or longer, while METH-treated rats showed impaired performance with a shorter delay time of 90 min. Memory impairment in METH-treated rats persisted for at least 14 days after drug withdrawal. METH-induced impairment of working memory was reversed by nicotine (0.3mg/kg, p.o., for 7 days), but the effect was diminished 7 days after the withdrawal. In control rats, nicotine decreased the number of working memory errors in the test with delay time of 120 min when administered before the training phase. Neither post-training nor pre-test administration of nicotine had any effect on working memory. These findings suggest that nicotine may have some protective effect against the impairment of working memory.     

Short-term memory impairment following chronic alcohol consumption in rats

Prolonged alcohol consumption (20 weeks), concomitant with adequate nutrition, was found to result in a residual short-term memory deficit after a 2-month alcohol-free period. Alcohol was administered in a liquid diet containing 35–37% ethanol-derived calories. One control group was pair-fed the same diet, except that sucrose was isocalorically substituted for ethanol. A second control group received pelleted laboratory food. After a 60-day alcohol-free period, short-term memory was assessed by training the rats on a discrete-trial temporal-alternation task in which bar presses were reinforced on alternate trials. Performance of the alternation problem was evaluated under conditions of short (20 sec) and long (50 sec) between-trial retention intervals. Although alcohol-treated-rats were relatively unimpaired when the retention interval was short, they were severely impaired with the long retention interval. In addition, the performance of alcohol-treated rats was severely disrupted when a distractor task was introduced during the short retention interval. The results were discussed relative to the similar short-term memory impairments of chronic alcoholic and alcoholic Korsakoff patients.     

Mitochondrial involvement in memory impairment induced by scopolamine in rats

Objective: Scopolamine (SCO) administration to rats induces molecular features of AD and other dementias, including impaired cognition, increased oxidative stress, and imbalanced cholinergic transmission. Although mitochondrial dysfunction is involved in different types of dementias, its role in cognitive impairment induced by SCO has not been well elucidated. The aim of this work was to evaluate the in vivo effect of SCO on different brain mitochondrial parameters in rats to explore its neurotoxic mechanisms of action.

Methods: Saline (Control) or SCO (1 mg/kg) was administered intraperitoneally 30 min prior to neurobehavioral and biochemical evaluations. Novel object recognition and Y-maze paradigms were used to evaluate the impact on memory, while redox profiles in different brain regions and the acetylcholinesterase (AChE) activity of the whole brain were assessed to elucidate the amnesic mechanism of SCO. Finally, the effects of SCO on brain mitochondria were evaluated both ex vivo and in vitro, the latter to determine whether SCO could directly interfere with mitochondrial function.

Results: SCO administration induced memory deficit, increased oxidative stress, and increased AChE activities in the hippocampus and prefrontal cortex. Isolated brain mitochondria from rats administered with SCO were more vulnerable to mitochondrial swelling, membrane potential dissipation, H₂O₂ generation and calcium efflux, all likely resulting from oxidative damage. The in vitro mitochondrial assays suggest that SCO did not affect the organelle function directly.

Conclusion: In conclusion, the present results indicate that SCO induced cognitive dysfunction and oxidative stress may involve brain mitochondrial impairment, an important target for new neuroprotective compounds against AD and other dementias.     

Cerebral hypoperfusion and amyloid-induced synergistic impairment of hippocampal CA1 synaptic efficacy and spatial memory in young adult rats

Alzheimer's disease (AD) is characterized by amyloid plaques, neurofibrillary tangles in the brain, cerebral hypoperfusion/hypometabolism, and amyloid angiopathy. The former two and cell loss occur late in the disease and are probably not the leading causes for the initial memory decline. Cerebral hypoperfusion is a pre-clinical event in AD and represents the most accurate indicator predicting the probable AD patients to develop AD in a future time. However, in young animals, cerebral hypoperfusion as those matching the reduction in AD has no significant effects on learning and memory. Here, we report that association of cerebral hypoperfusion (2-vessel occlusion) with cerebrovascular amyloid (internal-carotid 0.5 mg beta(25-35), an active fragment of Abeta) significantly impaired spatial learning and memory of young adult rats, while neither the same insult alone had significant impact. At the time when the spatial memory was impaired, in vitro recording revealed that the associated cerebral hypoperfusion and internal-carotid amyloid reduced the ability of the hippocampal CA1 network to generate cholinergic theta and the synaptic modification evoked by associative activation of cholinergic and GABAergic inputs. The results suggest that cerebral hypoperfusion and amyloid angiopathy may play an important role as associated events in initiating the early memory decline in AD.     

Selegiline protects against recognition memory impairment induced by neonatal iron treatment

Excess of iron in the brain has been implicated in the pathogenesis of several human neurodegenerative diseases, for example Alzheimer's disease and Parkinson's disease. It has been shown that the neonatal period is critical for the establishment of normal iron content in the adult brain. Moreover, it is known that aging alters the cerebral distribution of this metal. We have recently described that neonatal administration of iron severely impaired novel object recognition memory in rats. The aim of the present study was to determine whether selegiline, a monoamine oxidase (MAO) inhibitor known for its neuroprotective properties, could protect rats against cognitive impairment induced by neonatal administration of iron. In the first experiment, male Wistar rats received vehicle (5% sorbitol in water) or iron (10.0 mg/kg) orally from postnatal days 12 to 14 and saline (0.9% NaCl) or selegiline (1.0 or 10.0 mg/kg) intraperitoneally for 21 days, starting 24 h before the first iron dosing. In the second experiment, rats were given either vehicle or iron (10.0 mg/kg) orally from postnatal days 12 to 14 followed by saline or selegiline (1.0 or 10.0 mg/kg) intraperitoneally for 21 days, starting when rats reached adulthood (50th day after birth). Iron-treated rats given selegiline in both doses showed no deficits in recognition memory. Rats receiving iron but no selegiline presented memory deficits. This is the first study reporting the reversion of iron-induced memory impairment, supporting the view that our model can be considered as a useful tool in the search for new drugs with neuroprotective and/or memory enhancing properties.     

Central catecholaminergic dysfunction and behavioural disorders following hypoxia in adult rats

Wistar male rats, 3-4 months old, were made to breathe for 6 h a sub-lethal hypoxic atmosphere consisting of 8% oxygen and 92% nitrogen. Following this treatment, these rats were subjected to a series of behavioral and biochemical tests starting 30 days and ending at about 180 days after the hypoxic insult. an age-matched control group was subjected to the same series of tests. The following findings were made at the time interval indicated, relative to controls: (1) At 30-35 days, diurnal (3 h) and nocturnal (12 h) locomotor activities decreased by about 25%. (2) At 40-45 days, amphetamine in the dose range of 0.25-1 mg/kg proved less effective in eliciting an increase in motor activity and stereotypic behavior. (3) At about 50 days, apomorphine in the dose range 0.25-0.5 mg/kg caused an increase in stereotypic behavior. (4) At 60-65 days, alpha-methyl-p-tyrosine at the dose of 50 mg/kg caused a more pronounced hypoactive syndrome and a slower rate of recovery of motor activity. (5) At 75-90 days, performance in the active avoidance test was inferior to that of controls. (6) At 180 days, and one hour after a dose of 200 mg/kg alpha-methyl-p-tyrosine, the turnover rates of hippocampal norepinephrine and caudate-putamen dopamine were much below control. One may tentatively conclude that one of the effects of hypoxia in adult rats is a lesion producing long-term behavioral disorders which are partly ascribed to dopaminergic and, possibly noradrenergic, dysfunction.     

Anastrozole improved testosterone-induced impairment acquisition of spatial learning and memory in the hippocampal CA1 region in adult male rats

Neurohormones like testosterone and estrogen have an important role in learning and memory. Many biological effects of androgens in the brain require the local conversion of these steroids to an estrogen. The current research has conducted to assess the effect of testosterone, estrogen and aromatase inhibitor (anastrozole) on spatial discrimination of rats, using Morris water maze and also the pathway of the effect of testosterone by using anastrozole. Adult male rats were bilaterally cannulated into CA1 region of hippocampus and divided into 15 groups. Different groups received DMSO 0.5 microl and DMSO 0.5 microl + DMSO 0.5 microl as control groups and different doses of testosterone enanthate (TE) (20, 40 and 80 microg/0.5 microl), estradiol valerat (EV) (1, 2.5, 5, 10, and 15 microg/0.5 microl), anastrozole (An) (0.25, 0.5, 1 microg/0.5 microl), TE 80 microg/0.5 microl + anastrozole 0.5 microg/0.5 microl and EV 15 microg/0.5 microl + anastrozole 0.5 microg/0.5 microl all days before training. TE and EV were injected 30-35 min before training and anastrozole was injected 25-30 min before training. Our results have shown both TE 80 microg/0.5 microl and EV 15 microg/0.5 microl groups increase in escape latency and traveled distance to find invisible platform. Also we have shown that anastrozole dose dependently decreases escape latency and traveled distance. We resulted that both TE and EN impaired acquisition of spatial learning and memory but anastrozole improved it. Anastrozole also could be buffered TE-induced impairment effect but not EV.     

Systemic insulin-like growth factor-I administration prevents cognitive impairment in diabetic rats, and brain IGF regulates learning/memory in normal adult rats

Diabetic patients have impaired learning/memory, brain atrophy, and two-fold increased risk of dementia. The cause of cognitive disturbances that progress to dementia is unknown. Because neurotrophic insulin-like growth factor (IGF) levels are reduced in diabetic patients and rodents, and IGF can cross the blood-central nervous system barrier (B-CNS-B), the hypothesis was tested that IGF administered systemically can prevent cognitive disturbances, independently of hyperglycemia and a generalized catabolic state. Latency to escape to a hidden platform in the Morris Water Maze is used widely to test spatial memory, a hippocampus-dependent task. Adult rats were rendered diabetic with streptozotocin and implanted 4 weeks later with subcutaneous pumps that released either vehicle (D + Veh) or 20 microg/day IGF-I (D + IGF). Latency to escape to the hidden platform was prolonged in (D + Veh) versus non-diabetic rats (P < 0.003) 10.5 weeks after the onset of diabetes. Such prolongation was prevented in (D + IGF) versus (D + Veh) rats (P < 0.03). The data show that IGF-I can act across the B-CNS-B to prevent loss of cognition-related performance in the water maze independently of ongoing hyperglycemia and reduction in brain (P < 0.001) and whole body weight (P < 0.001) in diabetic rats. The hypothesis that brain IGF contributes to learning/memory was tested. An anti-IGF antibody, or preimmune serum, was infused into the lateral ventricles in non-diabetic rats. Learning in a passive avoidance task was impaired significantly in the IGF antibody versus preimmune serum-treated groups on test Days 1, 2, and 3 (P = 0.04, 0.02 and 0.004, respectively). The data together are consistent with a model in which brain IGF is essential for learning/memory, and a loss of IGF activity due to diabetes may contribute to cognitive disturbances.     

Status epilepticus in immature rats leads to behavioural and cognitive impairment and epileptogenesis

It remains under dispute whether status epilepticus (SE) in the perinatal period or early childhood or the underlying neuropathology is the cause of functional impairment later in life. The present study examined whether SE induced by LiCl-pilocarpine in normal immature brain (at the age of 12 or 25 days; P12 or P25) causes cognitive decline and epileptogenesis, and the data were compared to those of rats undergoing SE as adults. Rats in the P12 group had impaired memory (repeated exposure to open-field paradigm) and emotional behaviour (lower proportion of open-arm entries and higher incidence of risk assessment period in elevated plus-maze) when assessed 3 months after SE, although not as severe as in the older age groups. Importantly, video-electroencephalography monitoring 3 months after SE demonstrated that 25% of rats in the P12 and 50% in P25 group developed spontaneous seizures. Only nonconvulsive seizures (ictal activity in hippocampus accompanied by automatisms) were recorded in the P12 group whereas rats in the P25 group exhibited clonic convulsions. The present findings indicate that SE is harmful to the immature brain as early as P12, which might be compared with early infancy in humans.     

Hilar interneuron vulnerability distinguishes aged rats with memory impairment

Hippocampal interneuron populations are reportedly vulnerable to normal aging. The relationship between interneuron network integrity and age‐related memory impairment, however, has not been tested directly. That question was addressed in the present study using a well‐characterized model in which outbred, aged, male Long‐Evans rats exhibit a spectrum of individual differences in hippocampal‐dependent memory. Selected interneuron populations in the hippocampus were visualized for stereological quantification with a panel of immunocytochemical markers, including glutamic acid decarboxylase‐67 (GAD67), somatostatin, and neuropeptide Y. The overall pattern of results was that, although the numbers of GAD67‐ and somatostatin‐positive interneurons declined with age across multiple fields of the hippocampus, alterations specifically related to the cognitive outcome of aging were observed exclusively in the hilus of the dentate gyrus. Because the total number of NeuN‐immunoreactive hilar neurons was unaffected, the decline observed with other markers likely reflects a loss of target protein rather than neuron death. In support of that interpretation, treatment with the atypical antiepileptic levetiracetam at a low dose shown previously to improve behavioral performance fully restored hilar SOM expression in aged, memory‐impaired rats. Age‐related decreases in GAD67‐ and somatostatin‐immunoreactive neuron number beyond the hilus were regionally selective and spared the CA1 field of the hippocampus entirely. Together these findings confirm the vulnerability of hippocampal interneurons to normal aging and highlight that the integrity of a specific subpopulation in the hilus is coupled with age‐related memory impairment. J. Comp. Neurol. 521:3508‐3523, 2013. © 2013 Wiley Periodicals, Inc.     

Effect of naloxone on aluminum-induced learning and memory impairment in rats

BACKGROUND: Uptake of aluminum may disturb the learning and memory of humans or animals. Naloxone (NAL) has been shown to exert beneficial effects on memory deficits. AIMS: We investigated the effects of naloxone on aluminum-induced learning and memory impairment in rats. SETTINGS AND DESIGN: Aluminum-induced learning and memory impairment model was established by gavage of Aluminum chloride (600 mg/kg) for 3 months. Rats were divided into three groups viz. naloxone-treated rats (NAL 0.8 mg/kg, i.p. daily for 7 days), non-treated model rats and normal controls. MATERIALS AND METHODS: The Morris water maze test was performed to study spatial learning and memory. Long-term potentiation (LTP) of the Schaffer collateral-CA1 synapse was recorded. Aluminum and zinc contents in the hippocampus were assayed with atomic absorption spectrophotometry. STATISTICAL ANALYSIS: Parameters of the hidden and visible platform trials and data of LTP were analyzed using two-way repeated measures ANOVA. RESULTS: In the hidden platform trials, escape latencies of the NAL rats were significantly shorter than that of the non-treated rats (P=0.000, 95% confidential interval low bound 14.31, upper bound 22.68). In probe trails, the number of entries in the target area of the NAL rats (6.75+/-1.28 times/min) was more than that of non-treated model rats (4.56+/-2.16 times/min, P=0.004, 95% confidence interval low bound -3.65, upper bound -0.788). The magnitudes of LTP recorded in the CA1 pyramidal neurons of the NAL-treated rats were significantly augmented when compared to the non-treated model rats (P=0.005, 95% confidence interval low bound 0.16, upper bound 0.84). CONCLUSIONS: NAL could facilitate spatial learning and memory and enhance LTP in the CA1 region of the hippocampus in aluminum-induced learning and memory impairment in rats.     

Electroencephalographic activity in neonatal ventral hippocampus lesion in adult rats

A neonatal ventral hippocampal lesion (NVHL) in rats has been commonly used as a neurodevelopmental model to mimic schizophrenia-like behaviors. Recently, we reported that NVHL resulted in dendritic retraction and spine loss in pyramidal neurons of the prefrontal cortex (PFC). In addition, the hippocampus and PFC are important structures in the regulation of the electroencephalographic (EEG) activity. Patients with PFC lesions show deficits in the EEG activity. This study aimed to determine whether the EEG activity was altered in NVHL rats. In addition, we also analyzed the locomotor activity induced by a novel environment and exploratory behavior using the hole-board test. Consistent with the behavioral findings, the EEG analysis of the cortical regions showed that the NVHL rats displayed a lower power in cortical bands. At 1-8 Hz, 9-14 Hz, and 15-30 Hz bands, our findings showed a decrease in the absolute power of the parietal and occipital cortices recordings. In addition, the NVHL rats also showed a reduction in the exploratory behavior tested using the hole-board test. In conclusion, this study demonstrated that the EEG activity was reduced in adult NVHL rats and suggests that this may play a role in the behavioral changes observed in this neurodevelopmental model of schizophrenia.     

Learning and memory impairment in rats with chronic atypical absence seizures

Atypical absence seizures (AASs) represent a pediatric malignant seizure type that commonly exists as a component of Lennox-Gastaut syndrome. AAS involves both the hippocampal and thalamocortical circuitry in slow spike-and-wave discharges (SSWD) and is associated with cognitive dysfunction. The electrographic, behavioral, and pharmacological features of clinical AAS have been reproduced in rats chronically in the AY-9944 (AY) model. AY rats show spontaneous SSWD involving the hippocampus, a structure that is highly implicated in learning and memory. The purpose of the present study was to determine whether AY rats exhibit cognitive deficits that mirror those observed in AAS clinically. Hippocampal function was examined in AY animals both in vitro with electrophysiology (i.e., synaptic plasticity) and in vivo with a hippocampus-dependent radial arm maze (RAM) task that is designed to assess spatial cognition. In vitro tests of synaptic plasticity revealed impairments in long-term potentiation (LTP), paired-pulse facilitation (PPF), and presynaptic depression (PD). Consistently, performance of AY animals in RAM revealed fewer perfect entries, a greater number of errors, and required more training days to learn the task than saline-treated controls. The abolishment of spontaneous seizures by ethosuximide failed to recover the perturbed spatial learning and working memory in AY animals. AY rats demonstrate altered hippocampal functioning as manifested by altered synaptic plasticity and cognition. The relationship between AAS and cognitive deficit remains uncertain and the pathophysiology of both in AY treated requires further investigation.     

Spatial memory impairment in OLETF rats without cholecystokinin - a receptor

Cholecystokinin (CCK) is one of the most abundant neurotransmitter peptides in the brain. As Otsuka Long-Evans Tokushima Fatty (OLETF) rats lack CCK-A receptor because of a genetic abnormality, we examined whether learning and memory were impaired in these animals using both Morris water maze (MWM) and step-through type passive avoidance (PA) learning test. In the MWM test, memory impairment was observed in OLETF rats. The number of errors was also significantly higher, and that of the correct choices was significantly lower in OLETF rats compared to the controls [Long-Evans Tokushima Otsuka (LETO)] rats. In PA, OLETF rats did not show facilitating response 24 h after training. From these observations, we concluded that a spatial memory was impaired in the OLETF rats.     

Constraints on decay of environmental sound memory in adult rats

When adult rats are pretreated with a 48-h-long 'repetitive nonreinforced sound exposure', performance in two-sound discriminative operant conditioning transiently improves. We have already proven that this 'sound exposure-enhanced discrimination' is dependent upon enhancement of the perceptual capacity of the auditory cortex. This study investigated principles governing decay of sound exposure-enhanced discrimination decay. Sound exposure-enhanced discrimination disappeared within approximately 72 h if animals were deprived of environmental sounds after sound exposure, and that shortened to less than approximately 60 h if they were exposed to environmental sounds in the animal room. Sound-deprivation itself exerted no clear effects. These findings suggest that the memory of a passively exposed behaviorally irrelevant sound signal does not merely pass along the intrinsic lifetime but also gets deteriorated by other incoming signals.