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In a group of 83 normal adults, spatial memory performance in the Block-Tapping Test depended not only on path length but also on digit sequence, which, for a given path length, generates different spatial configurations. Sequences of homogeneous difficulty are proposed for defining the spatial span.
1. Neuronal activity was recorded from area 7a of monkeys performing a delayed match-to-sample task requiring release of a behavioral key when a visual stimulus appeared at a remembered spatial location. 2. Activity in the delay periods was significantly elevated in 28% of 405 neurons studied and could be classified as either sustained or anticipatory in nature. 3. Sustained activity was characterized by maintained or slowly decreasing discharge rates that were typically greater when the preceding stimulus was at a location that evoked a strong response. Sustained activity was terminated when a subsequent stimulus appeared at another location. 4. Anticipatory activity was characterized by accelerating discharge rates that were ordinarily greater after a stimulus at a location that evoked a weak response. Anticipatory activity was often associated with facilitated responses to the next stimulus. 5. These data demonstrate that a population of neurons in area 7a is active during the delay periods of a spatial memory task that does not require a behavioral response directed toward the location of the stimulus. This activity could represent a short-term memory trace for the spatial location of the preceding stimulus.
RATIONALE: Studies in humans of cognitive effects of dopaminergic drugs have largely focused on tasks of working memory, with a few studies also examining executive function. OBJECTIVES: This study was designed to investigate the effects of 1.25 mg of the dopamine D(2) agonist bromocriptine on spatial working memory, planning and discrimination reversal learning in young healthy volunteers. METHODS: Twenty volunteers were tested in a double-blind, placebo-controlled, cross-over design. The cognitive assessment included tests taken from the Cambridge Neuropsychological Test Automated Battery (CANTAB) designed to test visuo-spatial recognition memory and spatial working memory. In addition, tests of spatial planning and discrimination reversal learning were used to assess the more general effects of bromocriptine. Tests of subjective feelings and motivation were also incorporated into the battery. RESULTS: Bromocriptine enhanced the spatial memory span of subjects, whilst impairing their ability to reverse a learned probabilistic discrimination. Tests of recognition memory and planning were unaffected by the drug. The findings were not explained by changes in subjective mood or motivational measures. CONCLUSIONS: The pattern of findings observed here mirror medication-dependent observations seen in Parkinson's disease. The results are discussed with reference to the different anatomical networks known to subserve performance of the differentially affected tasks.
This paper studies the dynamics of attempting to access two spatial memories simultaneously and its implications for the accuracy of recall. Experiment 1 demonstrates in a range of conditions that two cues pointing to different experiences of the same object location produce little or no higher recall than that observed with a single cue. Experiment 2 confirms this finding in a within-subject design where both cues have previously elicited recall. Experiment 3 shows that these findings are only consistent with a model in which two representations of the same object location are mutually exclusive at both encoding and retrieval, and inconsistent with models that assume information from both representations is available. We propose that these representations quantify directionally specific judgments of location relative to specific anchor points in the stimulus; a format that precludes the parallel processing of like representations. Finally, we consider the apparent paradox of how such representations might contribute to the acquisition of spatial knowledge from multiple experiences of the same stimuli.
Aged Long-Evans rats were screened for spatial memory deficits using the Morris water maze task. Rats found to have impaired performance on the task (aged-impaired, AI) were then treated with a selective muscarinic M2 receptor antagonist, 5,11-dihydro-8-chloro-11-[[4-[3-[(2,2-dimethyl-1-oxopentyl)ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (BIBN-99; 0.5 mg/kg, s.c.), for 3 successive days while receiving additional water maze training. BIBN-99 significantly improved performance in the task during the 3 days of drug treatment. Treatment was then ceased for the remainder of the study and rats were tested again in the water maze on days 10, 17, and 24. Compared to vehicle-treated rats, enhanced performance was observed in the AI rats that had previously been treated with BIBN-99. These results indicate that BIBN-99 enhances spatial learning in AI animals and that enhanced (or long-term) memory persists in the absence of the drug. In a second experiment, a 2-month delay was imposed in between the original water maze screening and the drug treatment regime. Again, BIBN-99 significantly improved performance in AI rats. This latter study suggests that reference memory does not decay, even in an AI animal that had displayed poor learning following original water maze screening. Together, these studies help provide further insight into possible mechanism(s) of reference memory and its potential clinical usefulness.
Pentoxifylline, a phosphodiesterase inhibitor, produces a marked reversal of an age-dependent spatial memory deficit in Fischer 344 strain male rats. Performance of 26-month-old animals treated chronically with pentoxifylline approached that of 3-month-old controls. The effect was not dependent upon concurrent administration of the acetylcholine precursor choline chloride. It is concluded that the pentoxifylline-induced reversal of the age-dependent memory decline is not dependent on any presumed facilitation of acetylation and utilization of exogenously supplied transmitter substrate.
Young (10 month) and old (28 month) Fischer 344 rats were injected (IP) with 3,4-diaminopyridine (3,4-DAP) or saline 10 minutes before training on two tests of spatial memory (the Barnes circular platform and the radial 8-arm maze). This agent has been found to block potassium channels in neurons, thereby increasing calcium influx, prolonging the action potential, and leading to increased transmitter release. The circular platform task assessed the drug's effect on spatial reference memory over 24 hour intertrial intervals, and the radial maze assessed its effect on short-term working memory within a 5 minute test session. 3,4-DAP was found to selectively improve memory performance of the old animals, and, within that age group, only improved performance on the short-term memory task. 3,4-DAP may therefore be effective for only a restricted set of age-related memory problems.
In Experiment 1, rats were given a test to determine the order of preference among 3 types of food. Two groups of rats then were trained on a 12-arm radial maze in Experiment 2, with the 3 foods placed in fixed-arm locations for 1 group and in locations that varied randomly across sessions for the other group. The results replicated those of Dallal and Meck (1990) by showing faster learning and more clustering of arm choices by food type in the fixed-locations group than in the random-locations group. Two further experiments were performed to test the chunking hypothesis. Observations of working memory in Experiment 3 and the reorganization of reference memory in Experiment 4 both supported the chunking hypothesis by showing superior spatial memory and arm chunking by food type when chunk integrity was maintained than when it was compromised.
It has been suggested that maintenance in visuospatial immediate memory involves implicit motor processes that are analogous to the articulatory loop in verbal memory. An alternative account, which is explored here, is that maintenance is based on shifts of spatial attention. In four experiments, subjects recalled spatial memory span items after an interval, and in a fifth experiment, digit span was recalled after an interval. The tasks carried out during the interval included touching visual targets, repeating heard words, listening to tones from spatially separated locations, pointing to these tones, pointing to visual targets, and categorizing spatial targets as being from the left or right. Spatial span recall was impaired if subjects saw visual targets or heard tones, and this impairment was increased if either a motor response or a categorical response was made. Repeating words heard in different spatial locations did not impair recall, but reading visually presented words did interfere. For digit span only, the tasks involving a verbal response impaired recall. The results are interpreted within a framework in which active spatial attention is involved in maintaining spatial items in order in memory, and is interfered with by any task (visual, auditory, perceptual, motor) that also makes demands on spatial attention.
This work aims to clarify the role of histamine in learning and memory. This is done by studying the effect of administration of the histamine precursor, L-histidine (His), and the agonist of the H(3) receptor (R)-alpha-methylhistamine (RAMH), on acquisition and retention of spatial reference memory in rats. Treatment with RAMH (10 mg/kg i.p.) facilitates recovery of spatial memory. In contrast, administration of His (500 mg/kg i.p.) does not affect the performance of this task. Moreover, pharmacological modulation of the cerebral histaminergic system does not impair the animal's behavioral flexibility, i.e. their ability to adapt to a new learning task in the same stimular context. Improved retention of spatial memory after a reduction in cerebral histamine confirms the modulating role of this neurotransmitter in memory processes.
Protein kinase C (PKC) comprises a family of kinases consisting of nine subspecies that are differentially distributed in the central nervous system. This implies distinct functions. Its involvement is suggested in cellular and molecular mechanisms by which the hippocampus exerts influence on information processing. In this study, it was questioned whether abnormal activity in the neuronal substrate, particularly the hippocampal formation, induced by amygdala kindling indeed impairs spatial memory performance and correlated alpha, beta I/II, and gamma PKC subspecies expression. Rats were trained in a spatial discrimination task (SDT) and simultaneously kindled in the amygdala to induce abnormal, epileptiform activity. Control rats were only trained in the holeboard, a "free choice" maze, in which working (WM) and reference memory (RM) were simultaneously examined. Halfway through and at the end of the experiments the influence of kindling and SDT training on the immunoreactivity for PKC subspecies alpha, beta I/II, and gamma was evaluated in the hippocampal formation. Kindling resulted in a gradual increase in afterdischarge duration and motor seizure (MS) severity. Repeated SDT training ultimately resulted in an asymptotic level of WM and RM performance. As soon as generalized MSs developed, kindled rats failed to improve RM, whereas WM was not influenced. Compared to untrained rats, in trained controls PKC gamma but not PKC alpha beta I/II immunoreactivity was elevated in CA1 pyramidal and dentate gyrus granular cells. Generalized but not partial MSs abolished these alterations in PKC gamma immunoreactivity. The present data indicate that repeated training in a SDT affects the expression of PKC subspecies gamma but not of alpha or beta in the rat hippocampus. Generalized epileptiform activity impair both acquisition of new spatial RM information and PKC gamma expression. It is argued that PKC gamma plays a role in cellular mechanisms through which pathological brain activity impairs certain aspects of spatial memory.
The effects of cytotoxic lesions of nucleus medialis dorsalis on tests of spatial memory were examined in the rat. Extensive lesions of the nucleus did not impair either the acquisition or the subsequent performance of an automated test of working memory, delayed nonmatching-to-position. Detailed analysis of the animals' performance over varying retention delays failed to reveal any evidence of a deficit. The same animals performed normally in a spatial discrimination task and its subsequent reversals. The present results can be contrasted with those from animals with hippocampal system damage.
To explore memory impairments in temporal lobe epilepsy, we used two experimental models in the rats: (a) kainate-induced status epilepticus (SE) resulting in excitotoxic damage and in later spontaneous seizures; and (b) amygdala kindling, known to induce no lesions (or only minor) and neuronal reorganization. Long-term effects of these models on memory were investigated with a spatial learning task in a radial-arm maze, and a social interaction test that implies degree of short-term memory. An histological analysis was made to determine neuronal damage or loss caused by epileptic activity in brain regions that could be related to memory functions. Kainate-induced epilepsy produced large memory deficits in animals tested 5 months after the injection. The rats showed severe lesions in amygdala and hippocampus and piriform and entorhinal cortex. Spatial memory was strongly diminished. The social memory test was severely impaired, probably due to the extent of amygdala injury, which is known to disturb social behavior. On the contrary, kindled rats showed no evident lesion in any brain region and displayed performances as good as those of controls in both tests. These experiments demonstrated that memory deficits appear to be related to the severity of neuronal damage in limbic areas, and the ability to develop seizures (permanence) is not solely responsible for these memory disturbances.
Research with laboratory rats and humans demonstrating that the usual age-related deficits in spatial working memory can be attenuated or eliminated by prior training earlier in adult life is reviewed and possible mechanisms for this phenomenon are considered. A new technique for measuring remote memory for spatial information in humans is described and preliminary results with demented patients are discussed.
The behavioral effects of 6-hydroxydopamine, injected bilaterally into the lateral septum, were investigated in two tests of spatial memory (radial 8-arm and T-maze). Three different experiments were conducted in the radial maze. In experiment I, rats were permitted to learn the task with food reinforcement in all arms of the maze. In experiment II, retention of the spatial information (working memory) learned in experiment I was tested by interposing various time intervals between choice 4 and 5 of each trial. In experiment III, reference and working memory were simultaneously assessed by only reinforcing 4 choices in the radial maze. Performances were compared in spaced versus massed trials. In the T-maze, the rats were first tested for learning a spatial discrimination between the two arms of the maze, and subsequently for reversal of the previously learned response. The results showed that the rats with lesions were impaired in all experiments. This impairment was particularly marked in some aspects of the procedures used: (1) in the search for the last 4 pellets in experiment I, (2) in the first presentations of various intervals interposed between choices 4 and 5, (3) in the search for food in the baited arms when the trials were massed in experiment III and (4) in the reversal of previously learned spatial discrimination in the T-maze. These behavioral deficits in the rats with septal dopaminergic lesions were interpreted as an increased susceptibility to interference. The lesions were shown to have selectively depleted dopamine concentrations in the septum without damaging noradrenergic terminals or cholinergic cell bodies. It was concluded that dopaminergic neurons could have a modulatory influence on memory processes.
This study aimed to explore verbal and spatial memory spans in Alzheimer's (AD) and multi-infarct (MID) demented patients. For this purpose, we administered the forward and backward versions of the Digit Span and of the Corsi test to 18 AD, 18 MID and 26 controls. Results revealed a normal forward verbal span but reduced backward verbal and forward and backward spatial spans in both demented groups. These data are discussed in the light of the Working Memory model. It is argued that the normal verbal forward span is sustained by a normally functioning Articulatory Loop. The deficient processing resources of the Central Executive, on the other side, are responsible for the reduced extension of the other memory spans. The possible anatomical substrate of short-term memory impairment in dementia, as well as alternative interpretations of memory span performance in demented patients are discussed.
Object memory processes, evaluated in rhesus monkeys by delayed nonmatching-to-sample with trial-unique stimuli and object reversal learning, were more severely impaired by orbital frontal than by anterior cingulate lesions. Spatial memory processes, assessed by spatial delayed response and spatial reversal learning, showed a weak trend in the opposite direction, though on these tasks neither lesion produced a serious loss. Comparison of the present results with those of earlier studies on the effects of various limbic system lesions suggests that object memory processes, including object recognition and object-reward association, are served by a circuit consisting mainly of the rhinal cortex, orbitofrontal cortex, and the magnocellular division of the medial dorsal thalamic nucleus. Although both the rhinal and orbitofrontal components of this circuit appear to participate in both functions, evidence from the present and earlier studies suggests that the orbitofrontal component is the more important one for associative memory, i.e. the formation across trials of associations between particular objects or classes of objects and reward, whereas the rhinal component is the more critical one for recognition memory, i.e. the storage and retrieval within trials of the representations of particular objects.
Plasticity of the nervous system is dependent on mechanisms that regulate the strength of synaptic transmission. Excitatory synapses in the brain undergo long-term potentiation (LTP) and long-term depression (LTD), cellular models of learning and memory. Protein phosphorylation is required for the induction of many forms of synaptic plasticity, including LTP and LTD. However, the critical kinase substrates that mediate plasticity have not been identified. We previously reported that phosphorylation of the GluR1 subunit of AMPA receptors, which mediate rapid excitatory transmission in the brain, is modulated during LTP and LTD. To test if GluR1 phosphorylation is necessary for plasticity and learning and memory, we generated mice with knockin mutations in the GluR1 phosphorylation sites. The phosphomutant mice show deficits in LTD and LTP and have memory defects in spatial learning tasks. These results demonstrate that phosphorylation of GluR1 is critical for LTD and LTP expression and the retention of memories.