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PubMed2004

Impaired set-shifting and dissociable effects on tests of spatial working memory following the dopamine D2 receptor antagonist sulpiride in human volunteers.

RATIONALE: Dopamine (DA) D(2) receptor antagonists have been shown to produce similar impairments to those seen in Parkinson's disease. These include working memory and set-shifting deficits. Theories of DA function have predicted that distraction or impaired switching may be important determinants of such deficits. OBJECTIVES: In order to test these hypotheses, we have followed up our previous findings with more refined tests (1) that allow measurement of spatial working memory (SWM) and distraction, (2) that allow separation of executive and mnemonic components of SWM and (3) that allow isolation of set-shifting from learning deficits. METHODS: Thirty-six young healthy male volunteers were tested on two occasions after oral administration of either 400 mg sulpiride or placebo. All participants performed the delayed response task. Sixteen participants received task-irrelevant distractors during this task, and were also given a self-ordered SWM test. The remaining participants were given delayed response tasks with task-relevant distractors, and tests of attentional and task set-shifting. RESULTS: Sulpiride impaired performance of the delayed-response task both without distraction and with task-relevant distraction. By contrast, the drug protected against deficits from task-irrelevant distraction seen in the placebo group. Task set-switching was also impaired by sulpiride, with participants being slower to respond on switch trials compared with non-switch trials. There was also a trend for attentional set-shifting to be impaired following sulpiride. In contrast, self-ordered SWM performance was enhanced by sulpiride on the second test session only. CONCLUSIONS: These results support models of central DA function that postulate a role in switching behaviour, and in certain aspects of working memory.

Adult↗
PubMed2005

Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice.

Accumulation of beta-amyloid (Abeta) peptides in the cerebral cortex is considered a key event in the pathogenesis of Alzheimer's disease (AD). Presenilin 1 (PS1) plays an essential role in the gamma-secretase cleavage of the amyloid precursor protein (APP) and the generation of Abeta peptides. Reduction of Abeta generation via the inhibition of gamma-secretase activity, therefore, has been proposed as a therapeutic approach for AD. In this study, we examined whether genetic inactivation of PS1 in postnatal forebrain-restricted conditional knock-out (PS1 cKO) mice can prevent the accumulation of Abeta peptides and ameliorate cognitive deficits exhibited by an amyloid mouse model that overexpresses human mutant APP. We found that conditional inactivation of PS1 in APP transgenic mice (PS1 cKO;APP Tg) effectively prevented the accumulation of Abeta peptides and formation of amyloid plaques and inflammatory responses, although it also caused an age-related accumulation of C-terminal fragments of APP. Short-term PS1 inactivation in young PS1 cKO;APP Tg mice rescued deficits in contextual fear conditioning and serial spatial reversal learning in a water maze, which were associated with APP Tg mice. Longer-term PS1 inactivation in older PS1 cKO;APP Tg mice, however, failed to rescue the contextual memory and hippocampal synaptic deficits and had a decreasing ameliorative effect on the spatial memory impairment. These results reveal that in vivo reduction of Abeta via the inactivation of PS1 effectively prevents amyloid-associated neuropathological changes and can, but only temporarily, improve cognitive impairments in APP transgenic mice.

Aging↗
PubMed2002

Time-dependent hierarchical organization of spatial working memory: a transcranial magnetic stimulation study.

The performance of memory-guided saccades with two different delays (3 and 30 s of memorization) was studied in seven healthy subjects. Double-pulse transcranial magnetic stimulation (dTMS) with an interstimulus interval of 100 ms was applied over the right dorsolateral prefrontal cortex (DLPFC) early (1 s after target presentation) and late (28 s after target presentation). Early stimulation significantly increased in both delays the percentage of error in amplitude (PEA) of contralateral memory-guided saccades compared to the control experiment without stimulation. dTMS applied late in the delay had no significant effect on PEA. Furthermore, we found a significantly smaller effect of early stimulation in the long-delay paradigm. These results suggest a time-dependent hierarchical organization of the spatial working memory with a functional dominance of DLPFC during the early memorization, independent from the memorization delay. For a long memorization delay, however, working memory seems to have an additional, DLPFC-independent component.

Adult↗
PubMed1999

Treatment with the noradrenergic alpha-2 agonist clonidine, but not diazepam, improves spatial working memory in normal young rhesus monkeys.

Noradrenergic alpha-2 agonists such as clonidine and guanfacine improve working memory performance in aged monkeys. Guanfacine also improves cognition in young monkeys, but there are conflicting reports of the effects of clonidine in young adult human and nonhuman primates. In the present study, high doses of clonidine (0.02-0.1 mg/kg) significantly improved performance of the delayed response task, a test of spatial working memory, in young adult monkeys. Lower doses (0.0001-0.01 mg/kg), similar to those used in human studies (0.001-0.003 mg/kg), had no effect on task performance. In contrast, monkeys experimentally depleted of catecholamines by chronic reserpine treatment have been improved by both dose ranges. These results provide further support for the hypothesis that alpha-2 agonists improve cognition via actions at post-synaptic alpha-2 receptors, and suggest that conflicting results with clonidine in previous studies of prefrontal cortical function may result from insufficient dosage.

Adrenergic Uptake Inhibitors↗
PubMed2005

Pentoxifylline and insulin-like growth factor-I (IGF-I) abrogate kainic acid-induced cognitive impairment in mice.

Hippocampal insults involving neuroimmune mechanisms can impair learning and memory in a variety of tasks. The present study was designed to assess the effect of pentoxifylline, an inhibitor of tumor necrosis factor alpha (TNFalpha), and insulin-like growth factor-I (IGF-I) on kainate (KA)-induced impairment in spatial memory. Male mice received a subcutaneous injection of a dose of KA (15 mg/kg) that had no cytotoxic effect on hippocampal neurons as confirmed by Fluorojade B staining. This dose resulted in an impairment of spatial memory in a two-trial recognition task 11 days later. Intraperitoneal administration of pentoxifylline (200 mg/kg) abrogated this effect. Repeated intracerebroventricular injection of IGF-I (2 microg/mouse on day 1 followed by 1 microg/mouse on days 2-5) abrogated KA-induced deficits in spatial memory whereas acute IGF-I (2 microg/mouse on day 1 only) had mixed effects. These findings indicate that endogenous TNFalpha is probably involved in the detrimental effects of kainate on cognition and that exogenous IGF-I can oppose these effects, probably by antagonizing TNFalpha-induced neurotoxicity.

Analysis of Variance↗
PubMed2000

Long-term memory for spatial and temporal mental models includes construction processes and model structure.

There is a strong case that people construct and manipulate mental models in working memory but relatively little evidence that mental models are preserved in long-term memory. Instead people may remember an episodic construction trace: a record of the operations used to construct a mental model (Payne, 1993). Experiment 1 investigated memory for determinate spatial descriptions (which describe a single configuration of objects) and indeterminate spatial descriptions (which describe two equally plausible configurations). Recognition performance was impaired when the overlap between the episodic construction trace of a description at learning and at test was disrupted by reordering the sentences within a description. Participants were better at remembering the gist of determinate descriptions than that of indeterminate descriptions. For indeterminate descriptions, provided differences in gist recognition were controlled, participants showed better memory for the original description. Experiment 2 showed a similar pattern of results with temporal descriptions. A third experiment manipulated the similarity between foils in the recognition test and the original descriptions to provide further evidence for both episodic construction trace and remembered mental models. In combination, these results favour a hybrid account of memory for mental models, which includes information about both construction processes and model structure.

Adult↗
PubMed2006

Saying versus touching: age differences in short-term memory are affected by the type of response.

We examined whether the type of response used to report items recalled from short-term memory affects the age difference in verbal and spatial memory spans. Younger and older adults viewed either a series of letters or a series of locations in a grid, and then they reported their memory for the items either vocally or by using a touch screen. Overall, age differences were larger for spatial memory spans than for verbal memory spans, replicating previous results. Changing the response modality affected only older adults' verbal spans, which were approximately one item higher with a vocal response than with a manual response. This resulted in a smaller age difference for verbal items reported vocally than for any other condition. The results can best be explained by age-related difficulties in both spatial processing and in dealing with stimulus-response incongruity.

Age Factors↗
PubMed1996

Reduced evoked release of acetylcholine in the rodent hippocampus following traumatic brain injury.

The chronic effects of traumatic brain injury on acetylcholine release were evaluated by using in vivo microdialysis. Acetylcholine release was measured in the hippocampus of anesthetized rats 2 weeks after lateral controlled cortical impact (n = 10) or sham surgery (n = 10). Prior to microdialysis, behavioral assessments of motor and spatial memory were performed. Cortical impact (6 meter/s, 2 mm deformation) produced beam balance deficits that persisted for 1 day and beam walking deficits that persisted for 3 days after injury. In addition, spatial memory, as measured by swim latencies in a Morris water maze, was compromised between 10-14 days after injury. Immediately following behavioral testing, the animals were anesthetized with halothane, and a microdialysis probe was placed into the dorsal hippocampus. After a 160 min equilibration period, extracellular levels of acetylcholine were measured prior to and after an intraperitoneal administration of scopolamine (1 mg/kg), which evokes acetylcholine release by blocking autoreceptors. Prior to scopolamine administration, there were no differences in extracellular levels of acetylcholine between injured and sham animals. However, there was a significant reduction of hippocampal acetylcholine release evoked by scopolamine in injured animals as compared to sham controls. In separate control groups, saline administration alone did not change hippocampal acetylcholine release in injured (n = 5) or sham (n = 5) animals. This study represents the first application of in vivo microdialysis to evaluate chronic neurotransmission deficits following TBI. The present study demonstrates that a magnitude of traumatic brain injury (TBI) sufficient to produce spatial memory deficits can result in a reduction in scopolamine-evoked release of acetylcholine within the hippocampus. The data further suggest that presynaptic mechanisms mediating release of acetylcholine could play a significant role in cholinergic neurotransmission deficits following TBI.

Acetylcholine↗
PubMed1993

Spatial working memory in humans as revealed by PET.

The concept of working memory is central to theories of human cognition because working memory is essential to such human skills as language comprehension and deductive reasoning. Working memory is thought to be composed of two parts, a set of buffers that temporarily store information in either a phonological or visuospatial form, and a central executive responsible for various computations such as mental arithmetic. Although most data on working memory come from behavioural studies of normal and brain-injured humans, there is evidence about its physiological basis from invasive studies of monkeys. Here we report positron emission tomography (PET) studies of regional cerebral blood flow in normal humans that reveal activation in right-hemisphere prefrontal, occipital, parietal and premotor cortices accompanying spatial working memory processes. These results begin to uncover the circuitry of a working memory system in humans.

Brain↗
PubMed2003

The relationship between dominance, corticosterone, memory, and food caching in mountain chickadees (Poecile gambeli).

It has been hypothesized that in avian social groups subordinate individuals should maintain more energy reserves than dominants, as an insurance against increased perceived risk of starvation. Subordinates might also have elevated baseline corticosterone levels because corticosterone is known to facilitate fattening in birds. Recent experiments showed that moderately elevated corticosterone levels resulting from unpredictable food supply are correlated with enhanced cache retrieval efficiency and more accurate performance on a spatial memory task. Given the correlation between corticosterone and memory, a further prediction is that subordinates might be more efficient at cache retrieval and show more accurate performance on spatial memory tasks. We tested these predictions in dominant-subordinate pairs of mountain chickadees (Poecile gambeli). Each pair was housed in the same cage but caching behavior was tested individually in an adjacent aviary to avoid the confounding effects of small spaces in which birds could unnaturally and directly influence each other's behavior. In sharp contrast to our hypothesis, we found that subordinate chickadees cached less food, showed less efficient cache retrieval, and performed significantly worse on the spatial memory task than dominants. Although the behavioral differences could have resulted from social stress of subordination, and dominant birds reached significantly higher levels of corticosterone during their response to acute stress compared to subordinates, there were no significant differences between dominants and subordinates in baseline levels or in the pattern of adrenocortical stress response. We find no evidence, therefore, to support the hypothesis that subordinate mountain chickadees maintain elevated baseline corticosterone levels whereas lower caching rates and inferior cache retrieval efficiency might contribute to reduced survival of subordinates commonly found in food-caching parids.

Analysis of Variance↗
PubMed2002

High-density microarray analysis of hippocampal gene expression following experimental brain injury.

Behavioral, biophysical, and pharmacological studies have implicated the hippocampus in the formation and storage of spatial memory. Traumatic brain injury (TBI) often causes spatial memory deficits, which are thought to arise from the death as well as the dysfunction of hippocampal neurons. Cell death and dysfunction are commonly associated with and often caused by altered expression of specific genes. The identification of the genes involved in these processes, as well as those participating in postinjury cellular repair and plasticity, is important for the development of mechanism-based therapies. To monitor the expression levels of a large number of genes and to identify genes not previously implicated in TBI pathophysiology, a high-density oligonucleotide array containing 8,800 genes was interrogated. RNA samples were prepared from ipsilateral hippocampi 3 hr and 24 hr following lateral cortical impact injury and compared to samples from sham-operated controls. Cluster analysis was employed using statistical algorithms to arrange the genes according to similarity in patterns of expression. The study indicates that the genomic response to TBI is complex, affecting approximately 6% (at the time points examined) of the total number of genes examined. The identity of the genes revealed that TBI affects many aspects of cell physiology, including oxidative stress, metabolism, inflammation, structural changes, and cellular signaling. The analysis revealed genes whose expression levels have been reported to be altered in response to injury as well as several genes not previously implicated in TBI pathophysiology.

Animals↗
PubMed1998

Effect of the subchronic treatment with the acetylcholinesterase inhibitor heptastigmine on central cholinergic transmission and memory impairment in aged rats.

The effect of subchronic administration of the acetylcholinesterase (AChE) inhibitor heptastigmine (HEP 0.6 mg/kg s.c. daily for 15 days) was investigated on cortical extracellular acetylcholine (ACh) levels and on memory function in aged male rats (26 months old at the beginning of the experiments) using microdialysis and behavioural techniques. Twenty-four hours after the last treatment, cortical ACh levels were significantly higher in rats subchronically treated with HEP than in rats treated with saline and AChE activity was still inhibited in cortex, hippocampus and striatum. The injection of a challenge dose of HEP (0.6 mg/kg s.c.) 24 h after the last treatment produced a faster and a more sustained increase of ACh in the cortex of subchronically treated rats compared to those repeatedly injected with saline. However, the maximum increase of ACh levels after injection of the challenge was comparable in both groups. In an object recognition test in which the pretest and test phase were spaced by 45 days, HEP prevented the deterioration of spatial memory occurring during this period, but had no effect on non-spatial memory. The present results suggest that moderate inhibition of brain AChE is able to maintain high levels of cortical extracellular ACh in aged rats and that this increase matches facilitatory effect of HEP on spatial memory.

Acetylcholinesterase↗
PubMed1980

Immediate memory for spatial location.

Performance characteristics in a spatial-location task were examined nonmetrically. In Experiment 1, subjects reproduced the location of a dot either from immediate memory or while actually looking at the dot. Independent analyses of accuracy and the direction of incorrect reproductions yielded evidence for a fast-acting locational-memory process that may be distinct both from locational-perception processes and from response-bias processes. In Experiment 2, three different borders were used to vary the distance between the dot location and the border. Locational-memory accuracy increased as this distance decreased. Incorrect reproductions tended to occur toward rather than away from the border, and the robustness of this effect decreased for dot locations nearer to the border. Due to our nonmetric approach, the above conclusions are generalizable to all psychological conceptions whose spatial distances are monotonically related to the external spatial distances investigated here. A weighted-distortion theory of memory for spatial location is proposed to account for these and other findings.

Distance Perception↗
PubMed2001

Chronic administration of docosahexaenoic acid improves the performance of radial arm maze task in aged rats.

1. In the present study, we investigated the effect of docosahexaenoic acid (DHA) on spatial memory related learning ability in aged (100 weeks) male Wistar rats. 2. Rats were fed a fish oil-deficient diet through three generations and were then randomly divided into two groups. Over 10 weeks, one group was per orally administered 300 mg/kg per day DHA dissolved in 5% gum Arabic solution and the other group was administered the vehicle alone. Five weeks after the start of the administration, rats were tested with the partially baited eight-arm radial maze to estimate two types of spatial memory related learning ability displayed by reference memory error and working memory error. 3. Chronic administration of DHA significantly decreased the number of reference memory errors and working memory errors. 4. The level of lipid peroxide (LPO) in the hippocampus tended to decrease with chronic DHA administration and demonstrated a positive correlation with the number of reference memory errors. 5. These results suggest that the accumulation of hippocampal LPO reduces spatial memory related learning ability in aged rats. Moreover, chronic administration of DHA was effective in decreasing the level of hippocampal LPO, then improving learning ability.

Aging↗
PubMed2005

Haploinsufficiency of the arginine-vasopressin gene is associated with poor spatial working memory performance in rats.

Behavioral pharmacological studies have implicated a role for the neurophysin arginine-vasopressin in learning and memory. Vasopressin, and its analogues, can produce either improvements or impairments in mnemonic functions, effects that depend upon the agent administered, the memory process measured and the task employed. As recent data have implicated vasopressin in regulating the cognitive functions of the prefrontal cortex, we sought to determine whether changes in vasopressinergic tone would affect a form of memory that is dependent upon this brain region. To that end, we used a genetic approach to examine how haploinsufficiency of the vasopressin gene affects working memory performance. Specifically, we tested a naturally occurring null-mutant rat on an operant delayed-non-match-to-position task. Male and female heterozygous and wild-type rats were trained to perform this working memory task, and the effects of varying the delay across which they had to maintain task information were systematically varied. Although vasopressin-deficient rats omitted fewer trials and completed trials more quickly, they exhibited delay-dependent deficits of choice accuracy. The genotype effects were not modified by sex. Collectively, these data indicate that even partial vasopressin deficiency can trigger deficits of spatial working memory performance and add to the growing body of results supporting a regulatory control of neocortical-dependent cognitive functions by this neurohormone.

Analysis of Variance↗
PubMed1989

Intracerebral drug delivery in rats with lesion-induced memory deficits.

Pharmacological treatments directed at increasing cortical acetylcholine activity in patients with Alzheimer's disease have largely been disappointing, perhaps because denervated areas of brain may not be exposed to adequate amounts of drug. A new method has been developed to enable localized intracerebral delivery of neurotransmitter substances using a polymeric drug delivery system. Microspheres of a polyanhydride sebacic acid copolymer were impregnated with bethanechol, an acetylcholinesterase-resistant cholinomimetic. Twenty rats received bilateral fimbria-fornix lesions, producing cholinergic denervation of the hippocampus and marked impairment in spatial memory. The animals were trained for 2 weeks to run after which they received bilateral intrahippocampal implants of saline (five rats), blank polymer (five rats), or bethanechol-impregnated polymer (10 rats). Following implantation, spatial memory was assessed by radial-maze performance testing for 40 days. Untreated lesioned rats showed persistently poor spatial memory, entering maze arms with near random frequency. Similarly, animals treated with saline and blank polymer did not improve after implantation. Rats treated with bethanechol-impregnated microspheres, however displayed significant improvement within 10 days after implantation; this improvement persisted for the duration of the experiment (p less than 0.05, Student's t-test). Histological analysis of regional acetylcholinesterase staining showed widespread loss of activity throughout the hippocampus bilaterally in all animals. The microsphere implants were visible within the hippocampus, with minimal reactive changes in surrounding brain. It is concluded that intracerebral polymeric drug delivery successfully reversed lesion-induced memory deficits, and has potential as a neurosurgical treatment method for Alzheimer's disease and other neurodegenerative disorders.

Anhydrides↗
PubMed1977

The function of septo-hippocampal connections in spatially organized behaviour.

The role of septo-hippocampal connections in spatial behaviour is examined in lesion and stimulation experiments in rats. Destruction of septo-hippocampal connections produces a severe and enduring deficit in the ability to perform a spatial memory task. Furthermore, crossed unilateral lesions of the entorhinal area and fimbria-fornix produce the same deficit as bilateral lesions in either the entorhinal area or the fimbria-fornix, as predicted from a disconnection analysis of hippocampal lesions. Evidence also suggests that septo-hippocampal damage produces a greater deficit in spatial behaviours when a flexible response is required than when a consistent response is required, although this difference is a relative one rather than an absolute one. Finally, disruptive stimulation of the hippocampus while rats are performing a spatial memory task produces retrograde amnesia but not proactive interference. Taken together, these data indicate an important role of the septo-hippocampal system in spatial behaviour, and in the maintenance of spatial memories.

Animals↗
PubMed1998

Effects of S-8510, a novel benzodiazepine receptor partial inverse agonist, on basal forebrain lesioning-induced dysfunction in rats.

We investigated the effects of a novel benzodiazepine partial inverse agonist, S-8510 (2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo [4,5-d] pyrano [4,3-b] pyridine monophosphate monohydrate), on the impairment of spatial memory, decreased high-affinity choline uptake and acetylcholine release in basal forebrain-lesioned rats. S-8510 (3 and 5 mg/kg, p.o. 30 min before each training session) significantly ameliorated the basal forebrain-lesion-induced impairment of spatial memory in water maze task. In vivo brain microdialysis studies showed that systemic administration of S-8510 at 3 and 10 mg/kg significantly increased the release of acetylcholine in the front-parietal cortex in basal forebrain-lesioned rats. Further, repeated administration of S-8510 (3 and 10 mg kg(-1) day(-1) for 5 days) reversed the decrease in cortical high-affinity choline uptake induced by basal forebrain lesion. Thus, S-8510 improved the spatial memory impairment induced by lesion of the basal forebrain in rats. In addition, it increased acetylcholine release and high-affinity choline uptake from the cortex, a region closely associated with memory, in basal forebrain-lesioned rats. These results indicate that S-8510 has cognition enhancing and cholinergic-activating effects in the basal forebrain-lesioned rats, suggesting that this agent may be useful for the treatment of mild to moderate senile dementia including Alzheimer's disease.

Acetylcholine↗