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Maternal hyperglycemia leads to gender-dependent deficits in learning and memory in offspring.

Pregnancy in the diabetic woman has long been associated with an increased risk of congenital malformation in the offspring. However, little is known about the effects of maternal diabetes on development of the central nervous system. To begin to gain an understanding of this problem, diabetes was induced in adult female Sprague-Dawley rats by injection with streptozotocin. Only animals with serum glucose levels greater than 200 mg/dl were used. Diabetic and control females were bred, and all newborn pups were cross-fostered to nondiabetic mothers. At 60 days of age, pups were tested in an elevated plus-maze to assess differences in emotionality and anxiety. There were no significant differences between offspring of diabetic dams and controls on this measure. All pups were then housed individually, put on food restriction, and maintained at 85% of their ad libitum weight. They were then trained in a Lashley III maze, which assesses learning and retention capability. The female offspring of diabetic dams performed poorer than controls, a finding that was supported by inhibitory avoidance data from a separate group of animals. All animals were then trained in a radial-arm maze. Results failed to find differences between experimental and control animals. It was concluded that the diabetic intrauterine environment has gender-specific effects on central nervous system development.

Animals↗

The effects of mesial temporal and cerebellar hypometabolism on learning and memory.

The effects of mesial temporal (MT) and cerebellar hypometabolism were studied using measures of verbal, visual and motor skill learning. Twelve patients with refractory temporal lobe epilepsy who showed asymmetrical mesial temporal lobe hypometabolism on [18F] fluoro-2-deoxy-glucose positron emission tomography (FDG-PET) were given tests involving 4 consecutive learning trials and a 30-min delayed recall trial. Delayed recognition was also assessed for the words and designs, and skill transfer was evaluated for mirror drawing. Compared to 9 normal control participants, patients with more marked MT hypometabolism on the left had impaired delayed recall of words and patients with more marked MT hypometabolism on the right showed impaired learning of novel designs, but normal retention over delay. Patients were not impaired in their mirror-drawing performance. The findings for MT hypometabolism correspond well to those obtained in other studies where patients have been classified on the basis of side of hippocampal atrophy or temporal lobe excision.

Adult↗

Inhibition of neprilysin by infusion of thiorphan into the hippocampus causes an accumulation of amyloid Beta and impairment of learning and memory.

An imbalance between anabolism and catabolism causes an accumulation of amyloid beta-peptide (Abeta), which is a proposed trigger of the onset of Alzheimer's disease. Neprilysin is a rate-limiting peptidase that participates in the catabolism of Abeta in the brain. We examined whether rats continuously infused with thiorphan, a specific neprilysin inhibitor, into the hippocampus develop cognitive impairments through accumulation of Abeta. Thiorphan infusion elevated hippocampal Abeta40 and Abeta42 levels in the insoluble but not the soluble fraction. Thiorphan-infused rats displayed cognitive impairments in the ability to discriminate in the object recognition test, associative learning in the conditioned fear learning test, and spatial memory in the water maze test, tasks that depend on the hippocampus. These cognitive abilities in the battery of behavioral tasks inversely correlated with insoluble Abeta contents in the hippocampus. The nicotine-stimulated release of acetylcholine in the hippocampus of thiorphan-infused rats was significantly lower than that in vehicle-infused rats. These results indicate that continuous infusion of thiorphan into the hippocampus causes cognitive dysfunction and reduces cholinergic activity by raising the level of Abeta in the hippocampus and suggest that a reduction of neprilysin activity contributes to the deposition of Abeta and development of Alzheimer's disease.

Acetylcholine↗

New perspectives on the mechanisms through which nitric oxide may affect learning and memory processes.

Nitric oxide (NO) has been well established as a molecule necessary for memory consolidation. Interestingly, the majority of research has focused on only a single mechanism through which NO acts, namely the up-regulation of guanylate cyclase (GC). However, since NO and NO-derived reactive nitrogen species are capable of interacting with a broad array of enzymes, ion channels and receptors, a singular focus on GC appears short-sighted. Although NO inhibits the action of a number of molecules there are four, in addition to GC, which are up-regulated by the direct presence of NO, or NO-derived radicals, and implicated in memory processing. They are: cyclic nucleotide-gated channels; large conductance calcium-activated potassium channels; ryanodine receptor calcium release (RyR) channels; and the enzyme mono(ADP-ribosyl) transferase. This review presents evidence that not only are these four molecules worthy of investigation as GC-independent mechanisms through which NO may act, but that behavioural evidence already exists suggesting a relationship between NO and the RyR channel.

Animals↗

The neurochemistry of learning and memory.

The neurochemical basis of memory has been approached experimentally in four different ways: the bioassay; the interventive approach; the interventive-correlative approach; and the correlative approach. These approaches are fundamentally similar to those used for the study of the chemistry of any behavior. Each of these approaches has serious limitations, and significant progress has only been made by combinations of more than one. I shall discuss each of these approaches in turn.

Adrenocorticotropic Hormone↗

Learning and memory in transgenic mice modeling Alzheimer's disease.

Recent advances in behavioral analyses of transgenic mouse models of Alzheimer's disease (AD) are discussed, and their impact on our understanding of the molecular basis of cognitive impairment in AD is considered. Studies of the relationship between memory and A Beta in transgenic mice expressing the amyloid precursor protein (APP) and its variants suggest that aging promotes the formation of soluble A Beta assemblies mediating negative effects on memory. A significant component of memory loss in APP transgenic mice is apparently caused by soluble A Beta assemblies, but whether and how much of the dementia within individuals afflicted with AD is caused by these A Beta species is unclear. Future studies in composite transgenic mice developing amyloid plaques, neurofibrillary tangles, and other AD pathology may allow for the determination of the relative contribution of A Beta and non-A Beta components to dementia.

Alzheimer Disease↗

Drug influences on learning and memory in aged animals and humans.

In this article the effects of neurotransmitter systems or specific drugs on cognitive functions of aged animals and humans are reviewed. While there have been used many different pharmacologic and behavioral approaches to treat and test cognitive deficits in aged animals and geriatric or demented patients, there is still the question of the validity of animal models of human disorders. Attempts are made to show that there are parallels and similarities. These similarities suggest that the neurological and neurochemical changes observed may play common roles in similar behavioral deficits observed in aged animals and humans.

Aging↗

Differentiating simple versus complex processing speed: influence on new learning and memory performance.

The current study was designed to examine how the construct of human information processing speed is conceptualized and measured, while also examining the influence of information processing speed on higher cognitive processes (i.e., learning). A mixed medical sample of 92 subjects participated in this study. Subjects underwent a broad-based neuropsychological evaluation, including measures of verbal and visuospatial new learning, spatial and verbal working memory, simple reaction time, choice reaction time, and information processing speed. Principal components factor analysis with varimax rotation resulted in a three-factor solution, comprised of: (1) simple speed/reaction time, (2) complex information processing and new learning, and (3) working memory. Notably, this factor solution identified 2 distinct forms of processing speed--simple and complex information processing speeds. In contrast to the abundance of literature grouping these two constructs together under one term (i.e., processing speed), these results indicate simple and complex speed to be distinct constructs assessed with different neuropsychological instruments. While the expected relationship between complex information processing capacities and working memory abilities was evident in this study, information processing speed also showed a significant relationship with new learning ability. The implications of this intriguing relationship are discussed.

Adult↗

Transgenic calmodulin-dependent protein kinase II activation: dose-dependent effects on synaptic plasticity, learning, and memory.

Genetic disruption of calmodulin-dependent protein kinase II (CaMKII) function alters hippocampal synaptic plasticity and memory in mice. We used transgenic mice carrying a tetracycline-regulated, calcium-independent form of CaMKII (CaMKII-Asp286) to investigate the role of CaMKII activation on synaptic plasticity and behavior. Mice expressing low levels of a CaMKII-Asp286 transgene have facilitated low-frequency (5 Hz)-induced long-term potentiation (LTP), whereas mice with high levels of transgene expression have a deficit in this form of plasticity. Behavioral impairments on fear-conditioned memory and visible water maze correlate with the level of CaMKII-Asp286 expression. Mice with high levels of CaMKII-Asp286 have reversible, compensatory changes in the expression of genes associated with inhibitory neurotransmission. These results demonstrate that in the hippocampus, CaMKII activation facilitates the induction of low-frequency LTP, but at high levels of expression, compensatory mechanisms act to inhibit the induction of this form of LTP. The most severe behavioral impairments are associated with activation of this compensatory mechanism.

Animals↗

Dose- and age-dependent alterations in choline acetyltransferase (ChAT) activity, learning and memory, and thyroid hormones in 15- and 30-day old rats exposed to 1.25 or 12.5 PPM polychlorinated biphenyl (PCB) beginning at conception.

1. Polychlorinated biphenyls (PCB) were released into the environment through improper disposal for decades, causing widespread contamination. Slow biodegradation and lipophilic properties of PCB caused its persistence and concentration through food webs. Exposure to these environmental contaminants through maternal transfer during early development has been associated with neurological and endocrinological alterations in several different organisms. 2. The present study extended a preliminary investigation which suggested low level exposure to PCB altered acetylcholine biosynthesis enzyme, choline acetyltransferase (ChAT), activity in the hippocampus and basal forebrain and caused aberrations in thyroid hormone and behavior. 3. Dietary exposure of 15-day-old animals to 1.25 ppm of Aroclor 1254 (LPCB) during gestation and lactation significantly elevated ChAT activity in both areas of the brain. Animals exposed to 12.5 ppm of Aroclor 1254 (HPCB) until 15 days of age demonstrated significant elevations of ChAT activity in the basal forebrain. Thyroxine (T4) concentrations were slightly elevated in 15-day-old LPCB animals and significantly depressed in HPCB exposed pups; triiodothyronine (T3) concentrations were not altered. 4. At 30 days both LPCB and HPCB treatment groups displayed significantly depressed ChAT activity in both areas of the brain. T3 and T4 concentrations were subnormal, although T4 was not significantly depressed in LPCB animals. 5. In the Morris water maze all animals, when tested between 25 and 29 days of age, improved their latency time to the platform over 10 spatial learning trials. However, when combined means of trials 8-10 were compared, HPCB exposed animals had significantly increased latency time to the podium compared to control and LPCB animals.

Aging↗

Refining learning and memory assessment in laboratory rodents. An ethological perspective.

In neuroscientific research, the importance of a multi-level approach in studying behaviour, ranging from the molecular to the behavioural level, has been increasingly recognised. In fact, behaviour represents the ultimate output of the brain, and behavioural phenotyping may provide functional information that may not be detectable using molecular, cellular, or histological evaluations. To correctly exploit the study of behaviour in the field of neuroscience, the principles and strategies of ethology must be carefully considered, so as to design appropriate experiments and accurately interpret data. In particular, ethological-type scoring, which entails both the close observation of the studied behaviour and the taking into account of its possible evolutionary history and adaptive significance, can contribute to standardising experimental protocols, so as to improve the quality of data and the welfare of the experimental animal.

Animals↗

Linopirdine (DuP 996) improves performance in several tests of learning and memory by modulation of cholinergic neurotransmission.

The actions of linopirdine (DuP 996; 3,3-bis[4-pyrindinylmethyl]-1-phenylindolin-2-one) were evaluated in rats and mice in several cognitive behavioral tests, and for its effects on hippocampal acetylcholine (ACh) overflow in rats. Using mice treated with the muscarinic receptor antagonist, scopolamine, we studied the effects of linopirdine on retention of a passive avoidance task. Linopirdine (0.1 and 1 mg/kg) ameliorated the scopolamine-induced deficit, but at doses ranging from 0.01-1 mg/kg, it did not affect passive avoidance retention in normal (untreated) mice. In a scopolamine-induced hyperactivity test, linopirdine (1 mg/kg) decreased the motoric stimulation associated with the cholinergic hypofunction, without affecting locomotor activity on its own. Using rats, we studied the effects of linopirdine on performance in the Morris water maze spatial memory task. Young rats treated with atropine (30 mg/kg), a muscarinic receptor antagonist, took significantly longer to locate the submerged platform across 12 trials. Linopirdine (0.01 and 0.1, but not 1 mg/kg) ameliorated the atropine deficit. In addition, linopirdine (0.1 mg/kg) ameliorated the deficit in cognition-impaired aged rats (23-24 mo), but did not affect unimpaired aged rats. In terms of neurochemical action, linopirdine (1, 10, and 100 microM) produced a concentration-dependent increase in K(+)-evoked ACh overflow from superfused rat hippocampal slices. Also, linopirdine (10 microM) similarly increased ACh release in young control rats and cognition-impaired and nonimpaired aged rats. Our results confirm and extend findings from other studies that demonstrate the cognition-enhancing action of linopirdine in rodent models.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

[The role of the prefrontal and parietal cortex in learning and memory in monkeys].

Removal of the 7th field of parietal cortex and sulcus principalis of prefrontal cortex did not affect learning processes for images with such properties as spatial frequency, orientation, geometrical form, but worsen learning characteristics in visual differentiation of spatial information making the learning processes unstable, longer and below the 85% level. Removal of sulcus principalis also affects learning of differentiation among various colour stimuli. The short-term memory in these monkeys are also much worse than in intact animals. A scheme of learning involving interacting sensory and cognitive processes controlled by motivation system, is proposed.

Animals↗

A simple and reliable test of olfactory learning and memory in mice.

The present paper describes a quick and efficient method for assessing olfactory discrimination learning in mice. In training mice received trials in which one odor (CS+) was paired with sugar and another odor (CS-) was paired with no sugar. When the mice were subsequently placed in a chamber with CS+ odor at one end and CS- odor at the other, they spent more time digging in CS+ than in CS- odor. In Experiment 2 mice trained with this procedure and tested after 60 days also spent more time digging in CS+ than CS- in the test phase, indicating that this olfactory discrimination task is effective for assessing long-term memory. In addition to the outbred strain of CD1 mice used in Experiments 1 and 2, C57Bl/6NCr/BR and DBA/2NCr/BR mice used in Experiment 3 also acquired this learned odor discrimination. Moreover, Experiment 4 showed that DBA animals were capable of acquiring this odor discrimination after receiving only two training trials (one exposure each to CS+ and CS-) per day for 4 days.

Animals↗