Hippocampal damage impairs long-term spatial memory in rats: comparison between electrolytic and neurotoxic lesions

In previous studies we have suggested that the dorsal hippocampus is involved in spatial consolidation by showing that rats with electrolytic hippocampal lesions exhibit a profound deficit in the retention of an allocentric task 24 days after the acquisition. However, in various hippocampal-dependent tasks, several studies have shown an overestimation of the behavioral deficit when electrolytic versus axon-sparing cytotoxic lesions has been used. For this reason, in this report we compare the effects on spatial retention of electrolytic and neurotoxic lesions to the dorsal hippocampus. Results showed a similar deficit in spatial retention in both groups 24 days after acquisition. Thus, the hippocampus proper and not fibers of passage or extrahippocampal damage is directly responsible for the deficit in spatial retention seen in rats with electrolytic lesions.     

Brain serotonin depletion impairs short-term memory, but not long-term memory in rats

Intracerebroventricular injection of 5,7-dihydroxytryptamine (5,7-DHT) (150 microg; 4.5 microl/ventricle), a serotonergic neurotoxin, significantly decreased spontaneous alternation in Y-maze task and working memory in radial 8 arm-maze task, suggesting effects on short-term memory, without affecting long-term memory, explored by reference memory in radial 8 arm-maze task and step-through latency in multi-trial passive avoidance task. Parachlorophenylalanine (PCPA) (3 days treatment 200 microg, i.c.v.), a serotonin synthesis inhibitor, did not impair step-through-latency in multi-trial passive avoidance task, suggesting no effects on long-term memory. These results suggest that serotonin, among other neurotransmitters, play an important role in cognitive functions, especially short-term memory.     

Early chronic aluminium exposure impairs long-term potentiation and depression to the rat dentate gyrus in vivo

As an important neurotoxin, aluminium can cause cognitive dysfunctions and mental diseases. Previous studies have reported that aluminium impaired long-term potentiation (LTP) in vivo and in vitro. Here, we utilise two models of synaptic plasticity, LTP and long-term depression (LTD) to study the effects of aluminium on synaptic plasticity in vivo. Neonatal Wistar rats were chronically exposed to aluminium from birth to weaning via the milk of dams fed with 0.3% aluminium chloride solution. Excitatory postsynaptic potential (EPSP) and population spikes (PS) were recorded from the dentate gyrus (DG) of adult rats by electrically stimulating the perforant path.THE FOLLOWING RESULTS WERE OBTAINED: (1) The input/output function indicated that, as compared to controls, aluminium increased the baseline amplitude of the PS, but decreased the baseline slope of EPSP. (2) Aluminium significantly prevented LTD in PS (controls: 77.36+/-6.7%, n=7; aluminium-exposed: 102.01+/-9.1%, n=7; P<0.05) and decreased the LTD amplitude in EPSP (controls: 76.61+/-4.1%, n=7; aluminium-exposed: 94.31+/-7.9% n=7, P<0.05). (3) Aluminium reduced the amplitude of LTP in both PS (controls: 190+/-16.1%, n=7; aluminium-exposed: 135+/-9.7%, n=7; P<0.05) and EPSP (control: 132+/-9.3%, n=7; aluminium-exposed: 115+/-10.6%, n=7; P<0.05). As for LTD and LTP, PS was impaired more seriously than EPSP in aluminium-exposed rats. (4) Aluminium exposure decreased the paired-pulse facilitation (PPF) of PS at 30-150 ms interpulse interval (IPI), and reduced 93.5% of PPF at 80 ms IPI in PS (controls: 243.4+/-39.8%, n=7; aluminium-exposed: 149.9+/-12.3%, n=7). There was no significant difference in EPSP of PPF.From these results we conclude that aluminium exposure in neonatal rats thus reduces the amplitude of LTP and PPF and blocks the induction of LTD in the DG. We suggest that aluminium affects both presynaptic and postsynaptic mechanisms of synaptic transmission.     

Effect of acute and chronic hypertension on short- and long-term spatial and avoidance memory in male rats

It has been demonstrated that hypertension can lead to coronary heart disease, heart failure, stroke, and memory loss. In this study we investigated the effect of acute and chronic hypertension on the avoidance and spatial learning and memory in rats. The forty male rats were divided into acute hypertensive, chronic hypertensive and control for each group rats. Hypertension was induced by Deoxy Corticosterone Acetate (DOCA)-salt method. DOCA was injected 30 mg/kg of body weight subcutaneously, twice a week. These rats received NaCl 1% instead of tap water for drinking throughout the experiment. The control group received normal saline injection with usual drinking water. Spatial learning and memory was investigated by Morris water maze test and passive avoidance learning by Shuttle box test in the rats after hypertension induction. Results showed that acute hypertension impaired short-term memory in passive avoidance learning. However, acute and chronic hypertension did not affect spatial learning and memory. These data suggest that simple uncomplicated hypertension does not remarkably alter cognition.     

Temporary inactivation of the supramammillary area impairs spatial working memory and spatial reference memory retrieval

The aim of our study was to examine the supramammillary (SuM) area involvement in spatial memory. Sprague-Dawley rats with chronically implanted cannula in the supramammillary area were trained in two spatial memory tasks with different memory demands: reference and working memory. In the spatial reference memory task, the rats received microinjections in the SuM area of tetrodotoxin (TTX) (0.5 ng diluted in 0.5 microL of saline) or saline (0.5 microL). The microinjections were administered 30 min before the spatial training (day 4) (to assess the effect on acquisition) and on the following two days (days 5 and 6) the training was conducted without microinjections (to study the effect on consolidation). On the last training day (day 7), in order to assess the retrieval of spatial information, the rats received the microinjections 30 min before the spatial training. The spatial working memory used was a delayed-matching-to-position (DMTP) task. Spatial training was performed for seven days. During the first three days of the spatial training, the rats achieved a good spatial knowledge and learnt the working memory rule necessary to solve the spatial task. On days 4 and 6, the rats received microinjections to study involvement of the SuM area in working memory. The results showed that temporary inactivation of SuM area impairs both the rat's ability to solve a spatial working memory task with DMTP demands and the recovery of spatial information in a spatial reference memory task. We suggest that SuM area is involved in the rearrangement of spatial information during spatial working memory tasks with DMTP memory demands.     

Scopolamine impairs spatial maze performance in rats

Male Wistar rats given repeated daily injections of scopolamine (0.3 mg/kg), or isotonic saline, over a 15 day acquisition period were trained in an 8-arm radial maze using a confinement procedure in which the animal was detained in the centre of the maze for 10 sec between each arm choice. Confinement was used to reduce the likelihood that animals would resort to non-spatial strategies to solve the maze. All scopolamine treated animals failed to learn over the 15 day period, since their performance never exceeded that of saline treated animals early in learning. On two days when treatments were reversed, the animals which had previously received scopolamine improved performance significantly, and those which had been given saline were impaired under scopolamine treatment.     

Exposure to light at night and risk of depression in the elderly

Background

Recent advances in understanding the fundamental links between chronobiology and depressive disorders have enabled exploring novel risk factors for depression in the field of biological rhythms. Increased exposure to light at night (LAN) is common in modern life, and LAN exposure is associated with circadian misalignment. However, whether LAN exposure in home settings is associated with depression remains unclear.

Methods

We measured the intensities of nighttime bedroom light and ambulatory daytime light along with overnight urinary melatonin excretion (UME) in 516 elderly individuals (mean age, 72.8). Depressive symptoms were assessed using the Geriatric Depression Scale.

Results

The median nighttime light intensity was 0.8 lx (interquartile range, 0.2–3.3). The depressed group (n=101) revealed significantly higher prevalence of LAN exposure (average intensity, ≥5 lx) compared with that of the nondepressed group (n=415) using a multivariate logistic regression model adjusted for daytime light exposure, insomnia, hypertension, sleep duration, and physical activity [adjusted odds ratio (OR): 1.89; 95% confidence interval (CI), 1.10–3.25; P=0.02]. Consistently, another parameter of LAN exposure (duration of intensity ≥10 lx, ≥30 min) was significantly more prevalent in the depressed than in the nondepressed group (adjusted OR: 1.71; 95% CI, 1.01–2.89; P=0.046). In contrast, UME was not significantly associated with depressive symptoms.

Limitation

Cross-sectional analysis.

Conclusion

These results suggested that LAN exposure in home settings is significantly associated with depressive symptoms in the general elderly population. The risk of depression may be reduced by keeping nighttime bedroom dark.     

A specific role for group II metabotropic glutamate receptors in hippocampal long-term depression and spatial memory

Activity-dependent and sustained alterations in synaptic efficacy are widely regarded as the cellular correlates underlying learning and memory. Metabotropic glutamate receptors (mGluRs) are intrinsically involved in both hippocampal synaptic plasticity and spatial learning. Group II mGluRs are required for persistent hippocampal long-term depression (LTD), but are not required for long-term potentiation (LTP) in the hippocampal CA1 region in vivo. The role of these receptors in spatial learning, and in synaptic plasticity in the dentate gyrus in vivo has not yet been the subject of close scrutiny. We investigated the effects of group II mGluR antagonism on LTP and LTD in the adult rat, at medial perforant path-dentate gyrus synapses, and on spatial learning in the eight-arm radial maze. Daily application of the group 2 mGluR antagonist (2S)-alpha-ethylglutamic acid (EGLU) resulted in impairment of long-term (reference) memory with effects becoming apparent 6 days after training and drug-treatment began. Short-term (working) memory was unaffected throughout the 10-day study. Acute injection of EGLU did not affect either LTD or LTP in the dentate gyrus in vivo. Following six daily applications of EGLU a clear impairment of LTD but not LTP was apparent however. These data support that prolonged antagonism of group II mGluRs results in an impairment of LTD that parallels the appearance of spatial memory deficits arising from group II mGluR antagonism. These findings support the importance of group II mGluRs for spatial memory formation and offer a further link between LTD and the encoding of spatial information in the hippocampus.     

Experimental sleep fragmentation impairs spatial reference but not working memory in Fischer/Brown Norway rats

Sleep fragmentation is a common symptom in sleep disorders and other medical complaints resulting in excessive daytime sleepiness. The present study seeks to explore the effects of sleep fragmentation on learning and memory in a spatial reference memory task and a spatial working memory (WM) task. Fischer/Brown Norway rats lived in custom treadmills designed to induce locomotor activity every 2 min throughout a 24-h period. Separate rats were either on a treadmill schedule that allowed for consolidated sleep or experienced no locomotor activation. Rats were tested in one of two water maze-based tests of learning and memory immediately following 24 h of sleep interruption. Rats tested in a spatial reference memory task (eight massed acquisition trials) with a 24-h follow-up probe trial to assess memory retention showed no differences in acquisition performance but were impaired on the 24 h retention of the platform location. In contrast, the performance of rats tested in a spatial WM task (delayed matching to position task) was not impaired. Therefore, sleep fragmentation prior to testing impairs the ability to retain spatial reference memories but does not impair spatial reference memory acquisition or spatial WM in Fischer-Norway rats.     

Long-term study of chronic oral aluminum exposure and spatial working memory in rats

The authors report an effort to advance animal models that mimic the cognitive decline of Alzheimer's disease. Rats were trained and repeatedly tested in a spatial delayed matching-to-position paradigm in the water maze, with the location of the submerged platform changing between, but not within, days. After Trial 1 (random search) and intertrial intervals of 30 s or 1 hr, memory was tested in Trial 2. Young rats quickly acquired this task and were repeatedly tested after different intervals over 7 months, with a slight increase in performance toward the end of testing, but no difference in latencies between delays. Oral long-term treatment of 1 group with 0.1% aluminum caused no delay-dependent working memory deficit. This testing protocol may enable between- and within-subject long-term assessment of spatial working memory before and after drug treatment and may prove useful in animal models of progressive cognitive decline.     

The stress experience dependent long-term depression disassociated with stress effect on spatial memory task

Behavioral stress can either block or facilitate memory and affect the induction of long-term potentiation (LTP) and long-term depression (LTD). However, the relevance of the stress experience-dependent long-term depression (SLTD) to spatial memory task is unknown. Here we have investigated the effects of acute and sub-acute elevated platform (EP) and foot shock (FS) stress on LTD induction in CA1 region of the hippocampus of anesthetized rats and spatial memory in Morris water maze. We found that LTD was facilitated by acute EP stress, but not by sub-acute EP stress that may be due to the fast adaptation of the animals to this naturalistic mild stress. However, FS stress, an inadaptable strong stress, facilitated LTD induction both in acute and sub-acute treatment. In addition, with the same stress protocols, acute EP stress impaired spatial memory but the sub-acute EP stressed animals performed the spatial memory task as well as the controls, may due to the same reason of adaptation. However, acute FS stress slightly impaired learning but sub-acute FS even enhanced memory retrieval. Our results showed that SLTD was disassociated with the effect of stress on memory task but might be related to stress experience-dependent form of aberrant memory.     

The hormone therapy,Premarin, impairs hippocampus-dependent spatial learning and memory and reduces activation of new granule neurons in response to memory in female rats

Estrogens have been implicated as possible therapeutic agents for improving cognition in postmenopausal women and have been linked to neurodegenerative disorders such as Alzheimer's disease. However, the utility of Premarin (Wyeth Pharmaceuticals, Markham, ON, Canada), a conjugated equine estrogen and the most commonly prescribed hormone therapy, has recently been questioned. The purpose of this study was to investigate the effects of Premarin at 2 different doses (10 or 20 μg) on hippocampus-dependent spatial learning and memory, hippocampal neurogenesis, and new neuronal activation using a rodent model of surgical menopause. Rats were treated daily with subcutaneous injections of Premarin and trained on the spatial working/reference memory version of the radial arm maze. Premarin impaired spatial reference and working learning and memory, increased hippocampal neurogenesis, but either decreased or increased activation of new neurons in response to memory retrieval as indexed by the expression of the immediate early gene product zif268, depending on the maturity of cells examined. This activation of new neurons was related to impaired performance in Premarin-treated but not control-treated female rats. These results indicate that Premarin may be impairing hippocampus-dependent learning and memory by negatively altering the neurogenic environment in the dentate gyrus thus disrupting normal activity of new neurons.     

Aging impairs hippocampus-dependent long-term memory for object location in mice

The decline in cognitive function that accompanies normal aging has a negative impact on the quality of life of the elderly and their families. Studies in humans and rodents show that spatial navigation and other hippocampus-dependent functions are particularly vulnerable to the deleterious effects of aging. However, reduced motor activity and alterations in the stress response that accompany normal aging can hinder the ability to study certain cognitive behaviors in aged animals. In an attempt to circumvent these potential confounds, we used a hippocampus-dependent object-place recognition task to show that long-term spatial memory is impaired in aged mice. Aged animals performed similarly to young adult mice on an object recognition task that does not rely on hippocampal function.     

Galanin impairs acquisition but not retrieval of spatial memory in rats studied in the Morris swim maze

The effect of intraventricular administration of the neuropeptide galanin on acquisition and retrieval in a modified Morris swim maze was studied in rats. Galanin induced a significant deficit in the acquisition of the task while no effects on the retrieval were observed. No deficits were seen 24 h after the last treatment. Galanin did not increase the number of failures to reach the platform. It is suggested that endogenous galanin modulates learning possibly via the galanin-containing cholinergic neurons in the septum-basal forebrain area projecting to the hippocampus and cortex.     

Spared unconscious influences of spatial memory in diencephalic amnesia

Spatial memory is crucial to our daily lives and in part strongly depends on automatic, implicit memory processes. This study investigates the neurocognitive basis of conscious and unconscious influences of object–location memory in amnesic patients with Korsakoff’s syndrome (N = 23) and healthy controls (N = 18) using a process-dissociation procedure in a computerized spatial memory task. As expected, the patients performed substantially worse on the conscious memory measures but showed even slightly stronger effects of unconscious influences than the controls. Moreover, a delayed test administered after 1 week revealed a strong decline in conscious influences in the patients, while unconscious influences were not affected. The presented results suggest that conscious and unconscious influences of spatial memory can be clearly dissociated in Korsakoff’s syndrome.     

Cerebellar nodulectomy impairs spatial memory of vestibular and optokinetic stimulation in rabbits

Natural vestibular and optokinetic stimulation were used to investigate the possible role of the cerebellar nodulus in the regulation and modification of reflexive eye movements in rabbits. The nodulus and folium 9d of the uvula were destroyed by surgical aspiration. Before and after nodulectomy the vertical and horizontal vestibuloocular reflexes (VVOR, HVOR) were measured during sinusoidal vestibular stimulation about the longitudinal (roll) and vertical (yaw) axes. Although the gain of the HVOR (G(HVOR) = peak eye movement velocity/peak head velocity) was not affected by the nodulectomy, the gain of the VVOR (G(VVOR)) was reduced. The gains of the vertical and horizontal optokinetic reflexes (G(VOKR), G(HOKR)) were measured during monocular, sinusoidal optokinetic stimulation (OKS) about the longitudinal and vertical axes. Following nodulectomy, there was no reduction in G(VOKR) or G(HOKR). Long-term binocular OKS was used to generate optokinetic afternystagmus, OKAN II, that lasts for hours. After OKAN II was induced, rabbits were subjected to static pitch and roll, to determine how the plane and velocity of OKAN II is influenced by a changing vestibular environment. During static pitch, OKAN II slow phase remained aligned with earth-horizontal. This was true for normal and nodulectomized rabbits. During static roll, OKAN II remained aligned with earth-horizontal in normal rabbits. During static roll in nodulectomized rabbits, OKAN II slow phase developed a centripetal vertical drift. We examined the suppression and recovery of G(VVOR) following exposure to conflicting vertical OKS for 10-30 min. This vestibular-optokinetic conflict reduced G(VVOR) in both normal and nodulectomized rabbits. The time course of recovery of G(VVOR) after conflicting OKS was the same before and after nodulectomy. In normal rabbits, the head pitch angle, at which peak OKAN II velocity occurred, corresponded to the head pitch angle maintained during long-term OKS. If the head was maintained in a "pitched-up" or "pitched-down" orientation during long-term OKS, the subsequently measured OKAN II peak velocity occurred at the same orientation. This was not true for nodulectomized rabbits, who had OKAN II peak velocities at head pitch angles independent of those maintained during long-term OKS. We conclude that the nodulus participates in the regulation of compensatory reflexive movements. The nodulus also influences "remembered" head position in space derived from previous optokinetic and vestibular stimulation.     

Chronic prenatal lead exposure impairs long-term memory in day old chicks

Environmental exposure to lead during developmental stages has been established as a potential cause of intellectual deficits. The high susceptibility of rapidly developing fetal and infant brains to external factors suggests that impairment of later cognitive functions may arise from relatively minor prenatal exposure to environmental lead levels. In this study, we used the one-trial passive avoidance learning paradigm with day old chicks to evaluate memory function and memory consolidation in response to prenatal lead exposure. Lead acetate (5.5 mg/kg, 11 mg/kg, 16.5 mg/kg) was administered daily from E9 to E16 via direct injection into the airspace in chick eggs. Higher doses of lead acetate (11 mg/kg, 16.5 mg/kg) administration had significant effects on the hatching success (23.4 and 17, respectively) and hatch weight (∼10% decrease) of chicks when compared to equivalent treatments of sodium acetate (11 mg/kg, 16.5 mg/kg) (p < 0.001). Low doses of lead acetate (5.5 mg/kg) did not significantly affect chick hatching, weight or morphology compared to equivalent sodium acetate treatments (5.5 mg/kg) and controls. However, lead acetate (5.5 mg/kg) was found to significantly impair long-term memory after 120 min following training in the one-trial passive avoidance learning task (p < 0.05). These findings add to a growing body of evidence that suggests lead toxicity during fetal development leads to impairment in cognitive and memory processes.     

Excess protein synthesis in Drosophila fragile X mutants impairs long-term memory

We used Drosophila olfactory memory as a model to study the molecular basis of cognitive defects in Fragile X syndrome in vivo. We observed that fragile X protein was acutely required and interacted with argonaute1 and staufen in the formation of long-term memory. Occlusion of long-term memory formation in Fragile X mutants could be rescued by protein synthesis inhibitors, suggesting that excess baseline protein synthesis could negatively affect cognition.     

Early undernutrition impairs hippocampal long-term potentiation in adult rats

Following high-frequency stimulation of hippocampal dentate granule cells, potentiation was difficult to achieve in undernourished animals, showed a significant decline within 3 to 6 hr, and was completely absent at 24 hr. Further trains of stimulation resulted in only small benefits in undernourished animals. Coupled with previously reported morphological and behavioral deficits, these findings indicate a marked hippocampal dysfunction resulting from early undernutrition and provide a potentially valuable approach for relating nutritionally induced behavioral impairments to brain function.