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PubMed2006

A double dissociation of dorsal and ventral hippocampal function on a learning and memory task mediated by the dorso-lateral striatum.

The objectives of this research were to further delineate the neural circuits subserving proposed memory-based behavioural subsystems in the hippocampal formation. These studies were guided by anatomical evidence showing a topographical organization of the hippocampal formation. Briefly, perpendicular to the medial/lateral entorhinal cortex division there is a second system of parallel circuits that separates the dorsal and ventral hippocampus. Recent work from this laboratory has provided evidence that the hippocampus incidentally encodes a context-specific inhibitory association during acquisition of a visual discrimination task. One question that emerges from this dataset is whether the dorsal or ventral hippocampus makes a unique contribution to this newly described function. Rats with neurotoxic lesions of the dorsal or ventral hippocampus were assessed on the acquisition of the visual discrimination task. Following asymptotic performance they were given reversal training in either the same or a different context from the original training. The results showed that the context-specific inhibition effect is mediated by a circuit that includes the ventral but not the dorsal hippocampus. Results from a control procedure showed that rats with either dorso-lateral striatum damage or dorsal hippocampal lesions were impaired on a tactile/spatial discrimination. Taken together, the results represent a double dissociation of learning and memory function between the ventral and dorsal hippocampus. The formation of an incidental inhibitory association was dependent on ventral but not dorsal hippocampal circuitry, and the opposite dependence was found for the spatial component of a tactile/spatial discrimination.

Animals↗
PubMed1998

[Role of nitric oxide in learning and memory processes].

Nitric oxide (NO) is a free radical gas that is synthesized from L-arginine by NO synthase (NOS). Activation of NMDA, non-NMDA or metabotropic glutamate receptors causes NO formation through NOS activation. From data obtained in experiments performed by microdialysis together with nitrate assay, we have proposed that NO production in the cerebellum following non-NMDA and metabotropic glutamate receptor activation may be independent of NOS activity, while NMDA receptor-mediated NO production depends on its activity. Glial cells appear to play a role in modulating NO production by regulating L-arginine availability. Activation of NMDA receptors and the increase in intracellular calcium concentration is a trigger for the long-term potentiation (LTP). NO acts as a retrograde messenger in the hippocampal LTP to enhance glutamate release from presynaptic nerve terminal, in which cyclic GMP may be involved. Behavioral studies demonstrate that NO is involved in some forms of learning and memory. Our studies suggest that NMDA/NO/cyclic GMP signaling plays a role in spatial working memory. Further, it is suggested that NO production in the brain is altered by aging. These results support the hypothesis that NO plays a role in mechanism of synaptic plasticity.

Aging↗
PubMed2000

Targeting genes and proteins in the analysis of learning and memory: caveats and future directions.

Gene targeting using homologous recombination in embryonic stem (ES) cells and transgenic approaches in general allow one to precisely manipulate single genes and investigate their in vivo function in the mouse. Geneticists argue that these techniques are superior to pharmacological approaches as they obviate the lack of highly specific pharmacological agents in the study of brain function and behavior. However, by now it has become clear that transgenic approaches also have some limitations. One problem is spatial and temporal specificity of the genetic manipulation. The other is the possibility that the introduced genetic alteration gives rise to complex, secondary phenotypic changes. This may be a disadvantage in the functional analysis of genes associated with learning and memory especially if the gene of interest plays roles in embryonic development of the brain as well as in adult neural function. Examples of such genes include, but are not limited to, those encoding neurotrophins, cell adhesion molecules, and protein kinases. Second generation gene targeting with inducible and cell type restricted knock-out, or transgenic approaches with inducible gene expression systems, will solve some problems. However, at present these strategies also suffer from difficulties inherent to the traditional knock-out. Several strategies alternative to transgenic approaches are also available. Antisense oligonucleotides, antibodies, or pharmacological agents may be used to manipulate molecular events at the transcription, translation, or protein function levels. I review these strategies briefly and suggest yet another approach: protein targeting with the use of recombinant immunoadhesins. I suggest that this latter approach has the specificity of gene targeting but lacks some of its disadvantages.

Animals↗
PubMed1987

Effects of meclofenoxate and citicholine on learning and memory in aged rats.

The maze method for active avoidance with punishment reinforcement and the step-through method for passive avoidance with negative reinforcement were used to study the processes of learning and memory in 22-month-old rats, as well as the effects of meclofenoxate (Mf) and citicholine (CCh) on these processes. Meclofenoxate, administered in a dose of 50 mg/kg twice daily for 7 days using the maze-training method, increased the number of responses to the conditioned stimulus, when retention tests were made 24 hours and 7 days after training, whereas citicholine, applied in the same way in a dose of 10 mg/kg, shortened the latency of the responses with reinforcement during the training and increased the number of correct responses to the conditioned stimulus in retention tests 7 days after the training. With the same pattern of administration, both Mf and CCh strongly prolonged the time spent by the animals in the light chamber (i.e., improved retention) in tests using the step-through method 24 hours and 7 days after the training. Both drugs prevented the occurrence of scopolamine-induced (2 mg/kg i.p.) amnesia. A comparison of the results obtained for 22-month-old rats with the results obtained in earlier experiments on 5-month-old rats under fully identical experimental conditions showed that the age-dependent differences in the memory process and in the effects on it of the psychotropic agents meclofenoxate and citicholine were not unidirectional in character.

Aging↗
PubMed2002

Brevican-deficient mice display impaired hippocampal CA1 long-term potentiation but show no obvious deficits in learning and memory.

Brevican is a brain-specific proteoglycan which is found in specialized extracellular matrix structures called perineuronal nets. Brevican increases the invasiveness of glioma cells in vivo and has been suggested to play a role in central nervous system fiber tract development. To study the role of brevican in the development and function of the brain, we generated mice lacking a functional brevican gene. These mice are viable and fertile and have a normal life span. Brain anatomy was normal, although alterations in the expression of neurocan were detected. Perineuronal nets formed but appeared to be less prominent in mutant than in wild-type mice. Brevican-deficient mice showed significant deficits in the maintenance of hippocampal long-term potentiation (LTP). However, no obvious impairment of excitatory and inhibitory synaptic transmission was found, suggesting a complex cause for the LTP defect. Detailed behavioral analysis revealed no statistically significant deficits in learning and memory. These data indicate that brevican is not crucial for brain development but has restricted structural and functional roles.

Animals↗
PubMed2006

Learning and memory associated with aggression in Drosophila melanogaster.

Male Drosophila melanogaster (Canton-S strain) exhibit aggression in competition for resources, to defend territory, and for access to mates. In the study reported here, we asked: (i) how long flies fight; (ii) whether flies adopt distinct winning and losing strategies as hierarchical relationships are established; (iii) whether flies exhibit experience-dependent changes in fighting strategies in later fights; and (iv) whether flies fight differently in second fights against familiar or unfamiliar opponents. The results showed that flies fought for up to 5 h. As hierarchical relationships were established, behavioral strategies changed: winners progressively lunged more and retreated less, whereas losers progressively lunged less and retreated more. Encounters between flies were frequent during the first 10 min of pairing and then dropped significantly. To ask whether flies remembered previous fights, they were re-paired with familiar or unfamiliar opponents after 30 min of separation. In familiar pairings, there were fewer encounters during the first 10 min of fighting than in unfamiliar pairings, and former losers fought differently against familiar winners than unfamiliar winners. Former losers lost or no decision was reached in all second fights in pairings with familiar or unfamiliar winners or with naive flies. Winner/winner, loser/loser, and naive/naive pairings revealed that losers used low-intensity strategies in later fights and were unlikely to form new hierarchical relationships, compared with winners or socially naive flies. These results strongly support the idea that learning and memory accompany the changes in social status that result from fruit fly fights.

Aggression↗
PubMed2005

Differential effects of two blockers of small conductance Ca2+-activated K+ channels, apamin and lei-Dab7, on learning and memory in rats.

SK channels are responsible for long-lasting hyperpolarization following action potential and contribute to the neuronal integration signal. This study evaluates the involvement of SK channels on learning and memory in rats, by comparing the effects of two SK channel blockers, i.e., apamin which recognizes SK2 and SK3 channels, and lei-Dab7 which binds SK2 channels only. lei-Dab7 totally competes and contests apamin binding on whole brain sections (IC(50): 11.4 nM). Using an olfactory associative task, intracerebroventricular blocker injections were tested on reference memory. Once the task was mastered with one odor pair, it was then tested with a new odor pair. Apamin (0.3 ng), injected before or after the acquisition session, improved new odor pair learning in a retention session 24 hours later, whereas lei-Dab7 (3 ng) did not significantly affect the mnesic processes. These results indicated that the blockage of SK channels by apamin facilitates consolidation on new odor associations; lei-Dab7, containing only SK2 subunits, remains without effect suggesting an involvement of SK3 channels in the modulation of the mnesic processes.

Analysis of Variance↗
PubMed2004

Search for cognitive trait components of schizophrenia reveals a locus for verbal learning and memory on 4q and for visual working memory on 2q.

Research to identify predisposing genes for complex diseases relying solely on clinical diagnosis is probably not ideal. Here, we analyzed genome-wide data for 168 schizophrenia families using neuropsychological variables associated with disease susceptibility, with the aid of SOLAR, a program for variance-component analysis. The linkage signal was greatly accentuated by application of the quantitative traits compared with diagnosis. We found evidence for a locus for verbal learning and memory on 4q21 (Z=3.01, Z(mp)=3.84 and empiric P=0.031 for delayed memory; Z=2.96, Z(mp)=3.4 and P=0.026 for verbal learning) and suggestive evidence for visual working memory on 2q36 (Z=2.80, Z(mp)=2.08 and P=0.093). In addition, some evidence emerged for a locus for recognition memory on 10p13, visual attention on 15q22 and executive function on 9p22 in the complete sample, as well as for delayed memory on 8q12, semantic clustering and intrusions on 1q42 and visual attention on 3p25 in the genealogically distinctive sample subsets. Of the loci linked to schizophrenia in diverse populations, in addition to the earlier mentioned regions, some evidence of linkage was observed for 2q, 6q, 7q, 11q, 13q, 14q, 18q and 22q. Our results reveal initial information on the effect of the loci associated with schizophrenia in multiple studies, and emphasize the value of trait components in the search for susceptibility loci for complex diseases.

Analysis of Variance↗
PubMed2002

Chronic inhibition of glutamine synthetase is not associated with impairment of learning and memory in mice.

The convulsant methionine sulfoximine (MSO) is a byproduct of the agenized flour commonly used for feeding domestic animals decades ago. MSO is a powerful glycogenic and epileptogenic agent, and it is an irreversible inhibitor of glutamine synthetase. This latter effect was hypothesized to be responsible for the increase in the incidence of some neuropathologies in humans, such as Alzheimer's disease or Parkinson's disease. In order to test this hypothesis, we chronically administered MSO to two inbred strains of mice, C57BL/6J and BALB/cJ, and analyzed possible alterations in learning and memory features of these mice. Mice were given 20 mg/kg of MSO three times a week for 10 weeks. Spatial learning capabilities assessed with a radial maze were not affected by the long-term MSO treatment, although activity was significantly decreased in BALB/cJ mice. Thus, our data suggest that long-term administration of non-convulsive and non-glycogenic doses of MSO do not alter the spatial memory of mice. Our results do not support the hypothesis that chronic treatment with MSO influences hippocampus-dependent learning abilities in mice.

Animals↗
PubMed1998

Spatial learning and memory deficits induced by dopamine administration with decreased glutathione.

Administration of buthionine sulfoximine (BSO) selectively inhibits glutathione (GSH) biosynthesis and induces a GSH deficiency. Decreased GSH levels in the brain may result in less oxidative stress (OS) protection, because GSH contributes substantially to intracellular antioxidant defense. Under these conditions, administration of the pro-oxidant, dopamine (DA), which rapidly oxidizes to form reactive oxygen species, may increase OS. To test the cognitive behavioral consequences of decreased GSH, BSO (3.2 mg in 30 microliters, intracerebroventricularly) was administered to male Fischer 344 rats every other day for 4 days. In addition, DA (15 microliters of 500 microM) was administered every day [either 1 h after BSO (BSO + DA group) or 1 h before BSO (DA + BSO group), when given on the same day as BSO] and spatial learning and memory assessed (Morris water maze, six trials/day). BSO + DA rats, but not DA + BSO rats, demonstrated cognitive impairment compared to a vehicle group, as evidenced by increased latencies to find the hidden platform, particularly on the first trial each day. Also, the BSO + DA group utilized non-spatial strategies during the probe trials (swim with no platform): i.e., less time spent in the platform quadrant, fewer crossings and longer latencies to the previous platform location, and more time spent in the platform quadrant, fewer crossings and longer latencies to the previous platform location, and more time spent around the edge of the pool rather than in the platform zone. Therefore, the cognitive behavioral consequences of decreasing GSH brain levels with BSO in conjunction with DA administration depends on the order of administration. These findings are similar to those seen previously on rod and plank walking performance, as well as to those seen in aged rats, suggesting that the oxidation of DA coupled with a reduced capacity to respond to oxidative stress may be responsible for the induction of age-related cognitive deficits.

Aging↗
PubMed2000

Chroman amide 12P inhibition of lipid peroxidation and protection against learning and memory impairment.

Structure modification of the cerebroprotective chroman amide 12 to improve the drug delivery to the target organ by protecting the active hydroxy functional group was carried out in this study. Chroman amide 12P, which the O-acetyl group was served to protect the active group to be delivered to the target organ, was synthesized. Ex vivo antilipid peroxidation activity of 12P was significantly greater than the activity of 12 while the in vitro inhibition of 12P was found to be lower. These indicated that 12P with protected active group effectively reached the brain, the target site, but in vitro, 12P was unable to release its parent or released slowly. Neuropharmacological effect of 12P was investigated in mice. 12 and 12P (50-100 mg/kg, i.p.) showed significant suppression on the hypermotility induced by methamphetamine. 12P (100 mg/kg, i.p.) was more potent than 12, 54.36% and 38.73% suppression, respectively. The result suggested the enhancement of brain delivery and the antagonism against aberrant dopamine release. In the water maze test, 12P (200 mg/kg) as well as tacrine (3 mg/kg) significantly reduced the learning and memory impairment induced by scopolamine (0.5 mg/kg). The results support the enhanced brain delivery and the additional role of radical scavengers in the modulation of brain neurotransmitters in the aberrant condition.

Amnesia↗
PubMed1991

Effect of apamin, a toxin that inhibits Ca(2+)-dependent K+ channels, on learning and memory processes.

Apamin, a neurotoxin extracted from bee venom, specifically binds to a particular class of Ca(2+)-activated K+ channels which are involved in the slow afterhyperpolarization (S-AHP) that follows action potentials in many excitable cells. We tested in mice the effects of apamin on learning and memory processes. The results showed that pre-training injection of apamin accelerated the acquisition of a bar-pressing response but also increased the bar-pressing rates of the animals. This latter result suggests that apamin accelerated acquisition because it increased behavioral activity in general and the number of bar-presses in particular. Post-training apamin injection retroactively and non-contingently facilitated memory processes taking place shortly after training in a bar-pressing task. The lack of an effect of the delayed apamin injection showed that apamin did not act proactively on memory retrieval processes. These results suggest that apamin-sensitive KCa channels may contribute to memory processes.

Animals↗
PubMed1984

The effect of sleep before or after learning on memory.

Early studies in which it was found that learning followed by sleep was better remembered than learning followed by wakefulness were interpreted as giving support for the Interference Theory of Forgetting. More recent studies have shown better retention over the first half of the night's sleep (slow-wave sleep) than over the second half (REM sleep), and conclusions have been drawn that a Decay Theory of Forgetting is more strongly supported. Those studies, however, confounded the type of sleep following learning with sleep prior to learning. When prior sleep was controlled in the present study, there was no support for a first half-night sleep benefit, and, contrary to Decay Theory, there was a second half-night benefit for high imagery material. The strong detrimental effect of sleep prior to learning was inconsistent with the Interference Theory of Forgetting and suggested, instead, the importance of the consolidation process for long-term memory.

Adult↗
PubMed2001

Retrospective revaluation in humans: learning or memory?

The phenomenon of retrospective revaluation has posed considerable problems for many associative learning theories as it involves a change in the associative strength of a cue on trials on which that cue is absent. The present series of experiments pursues this idea of changes in associative strength between evoked representations of cues, in an effort to establish, de novo, an excitatory connection between two cues simultaneously activated in memory. Given the finding of Dwyer, Mackintosh, and Boakes (1998) that simultaneous activation of absent cues in the memory of rats resulted in learning comparable to that seen in retrospective revaluation, we expected that if retrospective revaluation was found in humans, then excitatory learning due to simultaneous activation would also be seen. This was not the case. The implications of our results are discussed in terms of Dickinson and Burke's (1996) modified SOP model and a version of McLaren's (1993) APECS network. We conclude that many of the effects attributed to learning in retrospective revaluation studies are better thought of as due to changes in the retrievability of items in memory.

Adult↗
PubMed2004

Beta-amyloid (1-42)-induced learning and memory deficits in mice: involvement of oxidative burdens in the hippocampus and cerebral cortex.

We have demonstrated that oxidative stress is involved, at least in part, in beta-amyloid protein (Abeta)-induced neurotoxicity in vivo [Eur. J. Neurosci. 1999;11:83-90; Neuroscience 2003;119:399-419]. However, mechanistic links between oxidative stress and memory loss in response to Abeta remain elusive. In the present study, we examined whether oxidative stress contributes to the memory deficits induced by intracerebroventricular injection of Abeta (1-42) in mice. Abeta (1-42)-induced memory impairments were observed, as measured by the water maze and passive avoidance tests, although these impairments were not found in Abeta (40-1)-treated mice. Treatment with antioxidant alpha-tocopherol significantly prevented memory impairment induced by Abeta (1-42). Increased activities of the cytosolic Cu,Zn-superoxide dismutase (Cu,Zn-SOD) and mitochondrial Mn-superoxide dismutase (Mn-SOD) were observed in the hippocampus and cerebral cortex of Abeta (1-42)-treated animals, as compared with Abeta (40-1)-treated mice. The induction of Cu,Zn-SOD was more pronounced than that of Mn-SOD after Abeta (1-42) insult. However, the concomitant induction of glutathione peroxidase (GPX) in response to significant increases in SOD activity was not seen in animals treated with Abeta (1-42). Furthermore, glutathione reductase (GRX) activity was only increased at 2h after Abeta (1-42) injection. Production of malondialdehyde (lipid peroxidation) and protein carbonyl (protein oxidation) remained elevated at 10 days post-Abeta (1-42), but the antioxidant alpha-tocopherol significantly prevented these oxidative stresses. Therefore, our results suggest that the oxidative stress contributes to the Abeta (1-42)-induced learning and memory deficits in mice.

Amyloid beta-Peptides↗
PubMed1983

The development of inhibitory learning and memory in hooded and albino rats.

A special kind of passive avoidance was elaborated which made it possible to study inhibitory conditioning in hooded (Long-Evans) and albino (Wistar) rat strains from day of birth to 10 or 11 days of age. Remaining on the safe platform for 60 sec, thus avoiding an electrified grid, for the 1st and 2nd time were the criteria. Passive avoidance was established from the first postnatal hours in both strains. A general developmental trend was demonstrated by a decreasing number of trials to both criteria and increase of average latencies. A temporary inversion of this trend in hooded rats took place at the age of 2 days, and in albinos at the age of 3 days. Habituation or fatigue were excluded by control experiments without noxious stimulation, and the associative character of the reaction was further proved by sensitization experiments. Evidence of memory retention was obtained as early as between the day of birth and the next day. The animals which served on the day of birth as controls needed, on the following day, significantly more trials than naive animals or pups which had been taught, one day before, to avoid the electrified grid. This phenomenon was called 'learned safety' for the previously control animals behaved as if they had learned that descent to the grid was safe. The 24-h memory of the learned inhibitory reaction--withholding movements towards the grid--was first observed in hooded rats between 1 and 2 days of age. Thus the capability to learn an inhibitory reaction has been proved in the neonatal rat which is born less mature than many other altricious mammals. Though learning and memory in both rat strains improved with age, there were small differences in favor of their earlier development in pigmented animals.

Aging↗
PubMed2001

Learning and memory in streptozotocin-induced diabetic rats in a novel spatial/object discrimination task.

Diabetes mellitus is associated with disturbances of cognitive functioning. The aim of this study was to examine cognitive functioning in diabetic rats using the 'Can test', a novel spatial/object learning and memory task, without the use of aversive stimuli. Rats were trained to select a single rewarded can from seven cans. Mild water deprivation provided the motivation to obtain the reward (0.3 ml of water). After 5 days of baseline training, in which the rewarded can was marked by its surface and position in an open field, the animals were divided into two groups. Diabetes was induced in one group, by an intravenous injection of streptozotocin. Retention of baseline training was tested at 2-weekly intervals for 10 weeks. Next, two adapted versions of the task were used, with 4 days of training in each version. The rewarded can was a soft-drink can with coloured print. In a 'simple visual task' the soft-drink can was placed among six white cans, whereas in a 'complex visual task' it was placed among six soft-drink cans from different brands with distinct prints. In diabetic rats the number of correct responses was lower and number of reference and working memory errors higher than in controls in the various versions of the test. Switches between tasks and increases in task complexity accentuated the performance deficits, which may reflect an inability of diabetic rats to adapt behavioural strategies to the demands of the tasks.

Animals↗
PubMed1997

Long-term effects of developmental exposure to 2,2',3,5',6-pentachlorobiphenyl (PCB 95) on locomotor activity, spatial learning and memory and brain ryanodine binding.

There is mounting evidence that perinatal exposure to ortho-substituted PCB congeners causes neurobehavioral and neurochemical alterations. The molecular mechanism for these effects is not understood, but certain ortho-substituted PCBs have been found to interact specifically with ryanodine-sensitive Ca2+ channels in vitro. These channels are widely expressed in brain and are thought to be responsible for Ca(2+)-induced Ca2+ release. Thus, the ryanodine receptor may represent a selective molecular target through which ortho-substituted PCBs disrupt calcium signaling in neurons, and produce neurochemical and neurobehavioral alterations. Of the PCBs evaluated, 2,2',3,5',6-pentachlorobiphenyl (PCB 95) exhibits the highest potency and efficacy towards the ryanodine receptor in vitro. Therefore, we conducted an in vivo study to investigate the effects of developmental exposure to PCB 95 on neurobehavioral functional and regional brain ryanodine binding. Time-mated Sprague-Dawley rats were dosed with PCB 95 (8 or 32 mg/kg/day) or corn oil vehicle via gavage on gestation days 10-16. One male and one female from each litter were evaluated for neurobehavioral effects. Locomotor activity was evaluated in an automated open field at 35 and 100 days of age. Spatial learning and memory was assessed using an eight arm radial maze working memory task at 60 days of age and a T-maze delayed spatial alternation task at 140 days of age. The animals were then euthanized and [3H] ryanodine binding was assayed in homogenates of cerebral cortex, hippocampus and cerebellum. Rats exposed to PCB 95 showed normal levels of activity as juveniles, but were hypoactive in adulthood. They also showed a faster acquisition of the working memory task on the radial arm maze, but did not differ from controls on the T-maze delayed spatial alteration task. Region-specific changes in ryanodine binding to Ca2+ channels were also observed, with decreased binding in the hippocampus, increased binding in the cerebral cortex and a biphasic effect in the cerebellum. How these changes in ryanodine receptor function are related to the alterations in behavior will be a challenging problem to elucidate.

Animals↗