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Effects of triazolam and diazepam on learning and memory as assessed using a water maze.

One of the reported adverse side effects of the frequently prescribed benzodiazepines diazepam (Valium) and triazolam (Halcion) is an impairment of anterograde memory in humans. The experiments described in this article compared the effects of triazolam and diazepam on performance in a water maze task that is sensitive to drugs that affect learning and memory. The water maze utilized is a traditional type of maze with alleyways and door choices, unlike the Morris open water maze. Time required to find an out-of-the-water platform and errors committed during the swim are used as performance measures. Rats were tested on a previously learned maze configuration and on the acquisition of new maze configurations. Neither diazepam (0.25, 1.0, or 2.0 mg/kg) nor triazolam (0.05, 0.2, or 0.3 mg/kg) injected 30 min prior to testing on the previously learned maze affected swim time or errors committed. Administration of diazepam (0.5, 1.0, or 2.0 mg/kg, IP) prior to daily training on three different new maze configurations did not affect swim time, but did increase swim errors. Triazolam administered at 0.1, 0.2, or 0.3 mg/kg markedly impaired performance as assessed by either swim time or errors. There were no differences in performance of rats previously treated with triazolam, diazepam, or vehicle in learning another new maze after drug treatment was terminated. These data demonstrate that both diazepam and triazolam affect acquisition but not recall of maze configurations and support similar conclusions reached using other types of tasks in humans and animals.

Animals↗

Important associations among EEG-dynamics, event-related potentials, short-term memory and learning.

Averaged and single sweep auditory event-related potentials (ERPs) were analysed in the time and frequency domain to demonstrate a dynamic, functional relationship between prestimulus EEG activity and poststimulus ERP changes. Evidence is presented of prestimulus "preparation changes" which were elicited by the presentation of regular, frequent target tones. The development of preparation changes was associated with prestimulus EEG synchronisation, frequency selective phase alignment at the point of stimulation and a greater predictability of the poststimulus response to target and nontarget tones. Time varying responses to target and nontarget tones are described for different experimental conditions and related to preparation rhythms. The mechanisms and possible neural correlates of the endogenous P300 change are discussed. The findings from this study and other relevant investigations have been used to formulate hypotheses about the relationships among preparation changes, ERPs and short-term memory, habituation and learning.

Adult↗

Reversal of learning and memory impairments following lesion of the nucleus basalis magnocellularis (NBM) by concurrent noradrenergic depletion using DSP4 in the rat.

In the following study the behavioural effects of simultaneous lesion of the nucleus basalis magnocellularis (NBM) using ibotenic acid and noradrenergic depletion following a single i.p. administration of DSP4 (50 mg/kg) were examined in the rat. NBM lesion induced a deficit in acquisition of a reinforced T-maze alternation task, a working memory adaptation of a spatial navigation task in a water maze and 24 h retention in a passive avoidance task compared to sham controls. No effect of the lesion on a reference memory version of spatial navigation in a water maze task was found. Animals that received a combination of NBM lesion and DSP4 treatment showed no impairment on any of the tasks that were impaired by NBM lesion alone. This indicates a reversal of the learning and memory deficits consequent to NBM lesion by simultaneous noradrenergic depletion. NBM lesion induced a significant reduction in choline-acetyltransferase activity in the frontal cortex, and DSP4 induced a significant decrease in noradrenaline concentration in occipital cortex and hippocampus, confirming the effects of these treatments. These results suggest an interaction between central noradrenergic and cholinergic systems in learning and memory processes.

Adrenergic Agents↗

Predictive accuracy of the wide range assessment of memory and learning in children with attention deficit hyperactivity disorder and reading difficulties.

The predictive accuracy of the Wide Range Assessment of Memory and Learning (WRAML; Sheslow & Adams, 1990) over and above more standardized diagnostic tools in children with attention deficit hyperactivity disorder (ADHD) and reading disabilities (RD) was examined. Fifty-three children with ADHD, 63 with RD, 63 with ADHD-RD, and 112 normal comparison children were administered the WRAML, the Wechsler Intelligence Scale for Children-Third Edition (WISC-III; Wechsler, 1991), the Achenbach (1991) Child Behavior Checklist (CBCL), and the Woodcock-Johnson Psycho-Educational Battery-Revised (WJ-R; Woodcock & Johnson, 1989). Results of a series of discriminant function analyses revealed that the academic, intellectual, and behavioral measures could correctly classify 73.1% of children, but the WRAML subtests alone were able to correctly classify only 58.5% of participants. Combining all of the memory, academic, intellectual, and behavioral measures resulted in 77.5% of cases being correctly classified. These results suggest that the use of a measure of memory functioning such as the WRAML did not significantly improve the predictive accuracy of a diagnosis of ADHD, RD, or both over and above more standard diagnostic academic, intellectual, and behavioral measures.

Attention Deficit Disorder with Hyperactivity↗

Effects of alpha-MSH, TRH and AVP on learning and memory, pain threshold, and motor activity: preliminary results.

The effect of daily peripheral administration of various peptides on learning and memory performance was studied in male albino rats. Groups of rats were treated with either TRH (1.0 mg/kg) alpha-MSH (1.0 mg/kg), or saline for three days. Other groups were treated either with vasopressin (1.0 microgram/kg) or saline. All treatments were 30 min before testing in a Morris Water Task apparatus. This type of learning is spatial learning which requires integration of environmental cues. Only alpha-MSH treated rats exhibited improved learning on Day 1 and Day 3 of the training period. One month later all rats were retested with no difference between the experimental groups. Single doses of these peptides caused a nonsignificant increase in pain threshold. The body weight gain of vasopressin-treated rats was significantly reduced as well as their motoric behavior. Therefore, the alpha-MSH effect on learning cannot be explained by nonspecific effects on body weight, pain threshold, or motor activity level.

Animals↗

Long short-term memory.

Learning to store information over extended time intervals by recurrent backpropagation takes a very long time, mostly because of insufficient, decaying error backflow. We briefly review Hochreiter's (1991) analysis of this problem, then address it by introducing a novel, efficient, gradient-based method called long short-term memory (LSTM). Truncating the gradient where this does not do harm, LSTM can learn to bridge minimal time lags in excess of 1000 discrete-time steps by enforcing constant error flow through constant error carousels within special units. Multiplicative gate units learn to open and close access to the constant error flow. LSTM is local in space and time; its computational complexity per time step and weight is O(1). Our experiments with artificial data involve local, distributed, real-valued, and noisy pattern representations. In comparisons with real-time recurrent learning, back propagation through time, recurrent cascade correlation, Elman nets, and neural sequence chunking, LSTM leads to many more successful runs, and learns much faster. LSTM also solves complex, artificial long-time-lag tasks that have never been solved by previous recurrent network algorithms.

Algorithms↗

Memory and learning disturbances in multiple sclerosis. MRI lesions and neuropsychological correlation.

Thirty-five patients with definite multiple sclerosis (MS) were studied. They underwent neuropsychological testing and magnetic resonance imaging (MRI). The MRI findings at different brain areas levels were compared with the neuropsychological findings. A quantitative system was used to measure MRI-MS lesions. In this series, a positive correlation was established between memory and learning disturbances measured by Battery 144, and the lesions measured by MRI (total, hemispheric and, particularly, periventricular lesions). MRI can detect MS lesions, and this study shows that a correlation between MRI and neuropsychological findings is possible if quantitative methods are used to distinguish different MS involvement areas in relation to neuropsychological tasks. These findings suggest that hemispheric lesions in MS produce cognitive disturbances and MRI could be a useful tool in predicting memory and learning impairment.

Adolescent↗

Environmental enrichment enhances neurogranin expression and hippocampal learning and memory but fails to rescue the impairments of neurogranin null mutant mice.

Environmental enrichment is known to enhance hippocampal neurogenesis and cognitive functions. Neurogranin (Ng), a specific substrate of protein kinase C (PKC), is abundantly expressed in brain regions important for cognitive functions. Deletion of Ng in mice causes severe deficits in spatial learning and long-term potentiation (LTP) in the hippocampal CA1 region. These Ng-/- mice, as compared with Ng+/+, respond poorly after treatment of their hippocampal slices with agents that activate signaling molecules important for learning and memory, including Ca2+/calmodulin-dependent protein kinase II (alphaCaMKII), PKC, protein kinase A (PKA), extracellular signal-regulated kinase (ERK), and cAMP response element-binding protein (CREB). In the present study, adult mice were housed in either regular home cages (control group) or more spacious cages with an exercise wheel and change of toys twice per week (enriched group) for at least 3 weeks. Enriched Ng+/+ and Ng+/- mice showed enhanced LTP in the hippocampal CA1 after high-frequency stimulation, but Ng-/- mice were affected only minimally. Behaviorally, the enriched Ng+/+ and Ng+/-, but not Ng-/- mice, performed significantly better than their respective control cohorts in Morris water maze and in step-down fear conditioning. Enriched Ng+/- mice also showed improvement in the radial arm maze. Quantitative immunoblot analyses showed that the enriched groups of all three genotypes exhibited elevated hippocampal levels of alphaCaMKII and CREB, but not ERK. Interestingly, enrichment caused a significant increase in hippocampal Ng levels both in Ng+/+ and Ng+/- mice that seemed to contribute to their improved LTP and behavioral performances. These results suggest that Ng gates the neuronal signaling reactions involved in learning and memory. During environmental enrichment, these Ng-regulated reactions are also critical for the enhancement of synaptic plasticity and cognitive functions.

Animals↗

[Effect an ACTH analog on the processes of learning and memory in rats].

On the basis of the idea of the important role of neurotransmitter systems in realization of neuropeptide effects, the participation was studied of the monoaminergic systems in the mechanisms of the ACTH analogue influence on the processes of learning and memory in control animals and animals with a changed functional state of the monoaminergic systems. In parallel the influence was studied of the ACTH analogue on the content of the endogenic monoamines in various brain structures of rats. It has been shown that administration of the ACTH analogue in a dose of 10 mcg affects the elaboration and preservation of conditioned reflexes (CRs) of passive avoidance, CRs of two-side avoidance and labyrinth CRs only in conditions of changed functional state of the monoaminergic systems. Amnesia, usually elicited by 5-oxytryptophane and disulfiram is prevented by administration of the ACTH analogue. Administration of the ACTH analogue is accompanied by the intensification of serotonine metabolism in the midbrain and medulla and by an increase of noradrenaline content in the hypothlamus.

5-Hydroxytryptophan↗

Fimbria-fornix vs selective hippocampal lesions in rats: effects on locomotor activity and spatial learning and memory.

The behavioral effects of interrupting the axons that pass in the fimbria and dorsal fornix were compared with the effects of selective removal of the cells that comprise the hippocampus with ibotenic acid. Starting 4.5 months after surgery, lesioned and control rats were (i) trained in both the Morris water maze and the eight-arm radial maze using protocols that placed an emphasis on either working memory (WM) or reference memory (RM) and (ii) tested for locomotor activity in the home cage. In comparison to sham-operated rats, the rats from both lesion groups were impaired in most learning/memory tasks, but there were some interesting differences between the two lesioned groups. When compared to rats with fimbria-fornix lesions (FIFX rats), hippocampal rats (HIPP rats) were slower in learning to swim to a visible platform and showed a greater impairment than FIFX rats in the radial-maze task when the testing procedure required the utilization of RM and WM in a more demanding WM task. In the test of locomotor activity, FIFX and control rats did not differ, but HIPP rats were more active than the rats in both other groups. The pattern of results obtained after a 4.5-month recovery period support the following general conclusions. (1) While there are some similarities in the effects on behavior of interrupting the axons in the fimbria-fornix compared to removing the hippocampus, there are some important differences. (2) From the findings that are available, a possible explanation to account for the difference between FIFX and HIPP rats is that the 4.5-month survival time permitted some recovery in the group of rats with FIFX lesions. (3) While it is well known that the Morris water maze and the radial-arm maze tasks provide useful measures of spatial learning and memory processes, our results suggest that the information provided by the two spatial learning tasks may differ in important respects.

Analysis of Variance↗

Spacing of repetitions improves learning and memory after moderate and severe TBI.

Extensive research has determined that new learning in healthy individuals is significantly improved when trials are distributed over time (spaced presentation) compared to consecutive learning trials (massed presentation). This phenomenon known as the "spacing effect" (SE) has been shown to enhance verbal and nonverbal learning in healthy adults of different ages and in different memory paradigms (e.g., recognition, recall, etc.). The purpose of this study was to examine whether learning in adults with moderate and severe traumatic brain injury (TBI) is improved using a spacing-of-repetitions procedure. Using a within-groups design, participants with TBI (n = 20) were presented a list of 115 words that were presented either once (single condition), twice consecutively (massed condition), or twice with 11 words between presentations (spaced condition). Participants were required to rank each word from 1 to 10 according to their familiarity with the word; they were not asked to "memorize" words for a later test. Word list learning was measured with a free recall test immediately following list presentation and with free recall and recognition tests after a 30-min delay. Participants recalled and recognized significantly more spaced words than massed words during this word list learning task. These results strongly indicate that the spacing of repetitions improves learning and memory in individuals who have sustained moderate to severe TBI. Implications for rehabilitation are discussed.

Adolescent↗