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PubMed1999

Citicoline protects hippocampal neurons against apoptosis induced by brain beta-amyloid deposits plus cerebral hypoperfusion in rats.

Citicoline is an endogenous intermediate involved in the biosynthesis of brain phospholipids and acetylcholine which has been extensively used for the treatment of several neurodegenerative conditions. The effects of citicoline on neurodegeneration, apoptosis and learning were investigated in male Sprague Dawley rats subjected to implants of the beta-amyloid fragment 1-40 (A beta 4: 3 Mmol) into the right hippocampus and to permanent unilateral occlusion of the carotid artery. Citicoline (CDP; 0, 62.5, 125 and 250 mg/kg/day i.p.) was given during 2 days before and for 5 days after surgery, and the extension of the degeneration and the number of apoptotic figures (TUNEL technique) were evaluated in the dentate gyrus (DG) and the CA1 area of the hippocampus. Citicoline, at 125 and 250 mg/kg, reduced the number of apoptotic neurons in the hippocampus of rats with A beta 4/hypoperfusion-induced neurodegeneration (CDP0 = 105.3 +/- 32.8 apoptotic figures; CDP125 = 39.2 +/- 7.4** apoptotic figures; CDP250 = 34.5 +/- 14.4** apoptotic figures; **p < 0.01 vs. CDP0). CDP also reduced neuronal degeneration in the CA1 area in a dose-dependent manner (CDP0 = 450.5 +/- 130.1 microns; CDP62.5 = 280.6 +/- 76.3 microns; CDP125 = 86.6 +/- 37.3* microns; CDP250 = 121.7 +/- 85.3* microns; p < 0.05 vs. CDP0). Variability of results was very high in the DG, where a significant reduction in the extent of neurodegeneration was only observed in the group of rats receiving 62.5 mg/kg of citicoline. Finally, citicoline improved retention of a passive avoidance learning task, increasing the number of avoidances (Av) (CDP0 = 4.2 +/- 0.7 Av; CDP62.5 = 6.9 +/- 1.0 Av; CDP125 = 7.9 +/- 0.7** Av; CDP250 = 8.5 +/- 0.6** Av; **p < 0.01 vs. CDP0) in a dose-related manner. Based on these results, it was concluded that citicoline exerts antiapoptotic, neuroprotective and antiamnesic effects in conditions of neurodegeneration induced by A beta 4 plus hypoperfusion.

Amyloid beta-Peptides↗

PubMed1982

Brain cyclic AMP and memory in mice.

A phosphodiesterase inhibitor 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (Rolipram, 10 mg/kg IP) administered immediately, but not 3 hr post-training, reversed an amnesia for an inhibitory avoidance response induced by the protein synthesis inhibitor anisomycin. Immediate post-training administration of Rolipram also enhanced retention for a weakly learned avoidance response. Unshocked animals did not show increased test latencies thus ruling out conditioned aversion as an explanation for the enhanced avoidance. Mice treated with Rolipram (10 mg/kg after training showed elevated cyclic AMP but not cyclic GMP in frontal cortex, thalamus, and hypothalamus. These results support the suggestion that cyclic AMP may play a role in memory processes.

Animals↗

PubMed2000

The effects of predator learning, forgetting, and recognition errors on the evolution of warning coloration.

This paper demonstrates that the specifics of predator avoidance learning, information loss, and recognition errors may heavily influence the evolution of aposematism. I establish a mathematical model of the change in frequency over time of bright individuals of a distasteful prey species. Warning color spreads through green beard selection as reformulated by Guilford (1990); bright colored forms gain an advantage due to their phenotypic resemblance to other bright forms, which have been sampled by the predator. I use a general classical conditioning model to examine gradual predator learning and forgetting, and then consider the extreme of one-trial learning and no forgetting over time that may occur with very toxic prey. The advantage of conspicuous coloration under these latter conditions depends upon its role in lowering a constant probability of the prey being misidentified and thus mistakenly attacked by a predator, a rarely emphasized factor in the evolution of warning coloration. This constant probability of mistaken attacks can also be interpreted as a constant probability that forgetting has occurred (forgetting does not increase with time) or a periodic decision by the predator to resample avoided prey. I show that when predators learn and forget gradually, as under the general classical conditioning model, it is very difficult for aposematic coloration to become established unless bright individuals cross an often high threshold frequency through chance factors. In contrast, the conditions expected with highly toxic prey promote the evolution of warning coloration more easily, by means from the fixation of very bright mutations to the fixation of successive mutations each of which causes a small increase in a prey's conspicuousness. The results therefore predict that aposematic coloration may have evolved in a different manner in different predator and prey systems. They also suggest that it may be extremely difficult for warning coloration to evolve in more mildly toxic or distasteful prey outside of a mimicry system.

Animals↗

PubMed1990

Behavioral changes in rats fed a diet containing 2,4-dichlorophenoxyacetic butyl ester.

Oral administration of 2,4-dichlorophenoxyacetic butyl ester (2,4-Dbe) at a dose of 69 mg/kg/day to nulliparous females had no deleterious effects on either open field (OF) and rotarod performance. By contrast, dams treated with 2,4-Dbe during pregnancy exhibited impairments of OF activity, rotarod performance and improved active avoidance learning (AAL) retention. Administration of 2,4-Dbe to 90-day-old intact male rats depressed spontaneous OF activity, acquisition of conditioned avoidance responses (CARs) and rotarod endurance, but improved AAL performance. Castration itself impaired performance in the rotarod test, and improved AAL, but did not alter OF activity significantly. The effects of castration were reversed by exogenous testosterone. In gonadectomized rats, 2,4-Dbe prevented the reversal of the effect of testosterone on the influence of castration on behavior if given concomitantly with the testosterone. However, when the 2,4-Dbe treatment started seven days after testosterone, the 2,4-Dbe effects on OF, rotarod and AAL behaviors were reinstated. Thus, testosterone appears to be important for causing the toxic effects of 2,4-Dbe in rats.

2,4-Dichlorophenoxyacetic Acid↗

PubMed2006

The impact of tryptophan depletion and 5-HTTLPR genotype on passive avoidance and response reversal instrumental learning tasks.

Transient reductions in serotonin levels during tryptophan depletion (TD) are thought to impair reward processing in healthy volunteers, while another facet of the serotonergic system, the serotonin transporter (5-HTTLPR) short allele polymorphism, is implicated in augmented processing of aversive stimuli. We examined the impact and interactions of TD and the serotonin promoter polymorphism genotype on reward and punishment via two forms of instrumental learning: passive avoidance and response reversal. In this study, healthy volunteers (n=35) underwent rapid TD or control procedures and genotyping (n=26) of the 5-HTTLPR for long and short allele variants. In the passive avoidance task, tryptophan-depleted volunteers failed to respond sufficiently to rewarded stimuli compared to the control group. Additionally, long allele homozygous individuals (n=11) were slower to learn to avoid punished stimuli compared to short allele carriers (n=15). TD alone did not produce measurable deficits in probabilistic response reversal errors. However, a significant drug group by genotype interaction was found indicating that in comparison to short allele carriers, tryptophan-depleted individuals homozygous for the long allele failed to appropriately use punishment information to guide responding. These findings extend prior reports of impaired reward processing in TD to include instrumental learning. Furthermore, they demonstrate behavioral differences in responses to punishing stimuli between long allele homozygotes and short allele carriers when serotonin levels are acutely reduced.

Adult↗

PubMed1985

Residual effects of chronic cannabis treatment on behavior in mature rats.

Mature rats (starting weight at least 270 g) were treated daily with cannabis extract (daily THC dose 20 mg/kg) for 3 months. After a 1- to 4-month drug-free period, residual effects on a variety of behaviors were studied. No residual effects were found in learning of an eight-arm radial maze task, nor on a differential reinforcement of low-rate responding (DRL-20) task, nor on open field activity. On the other hand, two-way shuttle box avoidance learning was facilitated by previous cannabis treatment, since cannabis-treated rats exhibited shorter mean latencies to avoid footshock than vehicle controls. The findings indicate greater vulnerability of immature organisms (previous studies) than mature organisms (the present study) to long-term effects of chronic cannabis administration.

Animals↗

PubMed1992

Local norepinephrine depletion and learning-related neuronal activity in cingulate cortex and anterior thalamus of rabbits.

Multi-unit neuronal activity was recorded in posterior cingulate cortex (area 29) and the anterior ventral (AV) thalamic nucleus during discriminative instrumental avoidance learning wherein a response (stepping in an activity wheel) to a 0.5-s tone (CS+) prevented a foot-shock 5 s after CS+ onset. Presentations of a different tone (CS-) on 50% of the conditioning trials in an irregular sequence with the CS+ did not predict shock and thus required no response. Two groups of rabbits received intracranial micro-injections of 6-hydroxydopamine (6-OHDA) to locally deplete the NE in area 29 or the AV nucleus. Vehicle was injected in the non-depleted area in each group and a third group received vehicle injections in both areas. Dopamine neurons in subjects that received 6-OHDA were protected by pre-treatment with GBR-12909. Neuronal data were collected during two pre-training sessions in response to the tones only and when the tones and shock were presented unpaired. Thalamically depleted rabbits made more, and cortically depleted rabbits made fewer, avoidance responses than controls during the early stages of behavioral acquisition, and cortically depleted rabbits made fewer responses than controls and thalamically depleted rabbits during extinction testing administered after the completion of acquisition. One effect of NE depletion on neuronal activity was entirely local: elimination of neuronal sensitization effects (enhanced discharges elicited by tones during the unpaired tone-shock pre-training treatment relative to pre-training with tones only). Other neuronal effects of NE depletion were system-wide, i.e., they occurred whether the depletion was cortical or thalamic.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

PubMed1963

The role of temporal discriminations in the reinforcement of Sidman avoidance behavior.

Animals learn to avoid with the Sidman procedure even though the avoidance response is not followed by the termination of any warning stimulus in the environment. What reinforces this response? The accepted explanation has been that the avoidance response is reinforced when it terminates other behavior that has become aversive by pairing with shock. However, the reinforcement may also be derived from the temporal discriminations that develop with Sidman avoidance. These and other temporal discriminations show that the animal has available some events that vary with the postresponse time. The shock will closely follow the temporal stimuli at long postresponse times and would be expected to make them aversive. The stimuli at short postresponse times would have a relatively low aversiveness due to their more remote relation to shock. Since the avoidance response changes a long postresponse time to a short one, that response would be followed by a decrease in aversiveness which would reinforce it. When sharp temporal discriminations are present, reinforcement from the decrease in aversiveness of temporal stimuli probably plays a dominant role in maintaining the avoidance response. This formulation fits the available data and has adequate answers for the objections that have been raised to earlier conceptions of the role temporal discriminations might play in Sidman avoidance. Although under some conditions the reinforcement in Sidman avoidance seems to be primarily due to the decrease in aversiveness of temporal stimuli, under other conditions there probably is reinforcement from the termination of conditioned aversive responses.

Animals↗

PubMed2000

Decision time and prey gregariousness influence attack probability in naïve and experienced predators.

Aposematic coloration often has an element of conspicuousness. One suggested benefit of conspicuousness is that it enables the prey to be detected at a greater distance, allowing a predator more time to make a correct decision about attacking it and thus reducing possible recognition errors made by predators. I conducted an experiment, with chicks, Gallus gallus domesticus, as predators on live aposematic and nonaposematic prey, to investigate the effects of decision time and signal size on predator sampling behaviour. The chicks were subjected to different degrees of competition to influence how quickly decisions had to be made. Chicks in four treatment groups, either in the presence or absence of a competing chick, were presented with either solitary prey or prey in groups. In the presence of a competitor, chicks attacked the prey more often and more quickly and needed more attacks before they started to avoid the prey. With prey in groups, chicks took longer to attack, attacked less often, learnt to avoid prey more quickly and killed fewer aposematic prey. This experiment provides evidence for the importance of time and signal size for predators' attack decisions. More time to view prey prior to attack could produce a stronger image and thus encourage avoidance learning and produce a stronger neophobic avoidance effect. Copyright 2000 The Association for the Study of Animal Behaviour.

Journal Article↗

PubMed1989

Using genetically-defined rodent strains for the identification of hippocampal traits relevant for two-way avoidance behavior: a non-invasive approach.

Genetically-defined rodent strains permit the identification of hippocampal traits which are of functional relevance for the performance of two-way avoidance behavior. This is exemplified here by analyzing the relationship between infrapyramidal mossy fibers (a tiny projection terminating upon the basal dendrites of hippocampal pyramidal neurons) and two-way avoidance learning in about 800 animals. The necessary steps include 1) identification of structural traits sensitive to selective breeding for extremes in two-way avoidance, 2) testing the robustness of the associations found by studying individual and genetical correlations between hippocampal traits and behavior, 3) establishing causal relationships by Mendelian crossing of strains with extreme structural traits and studying the behavioral consequences of such structural 'randomization', 4) confirming causal relationships by manipulating the structural variable in inbred (isogenic) strains, thereby eliminating the possibility of genetic linkage, and 5) ruling out the possibility of spurious associations by studying the correlations between the hippocampal trait and other behaviors known to depend on hippocampal functioning. In comparison with the classical lesion approach for identifying relationships between brain and behavior, the present procedure appears to be superior in two aspects: it is non-invasive, and it focuses automatically on those brain traits which are used by natural selection to shape behaviorally-defined animal populations, i.e., it reveals the natural regulators of behavior.

Animals↗

PubMed1979

Endogenous brain angiotensin II disrupts passive avoidance behavior in rats.

The presence of angiotensinogen, the precursor of angiotensin II (ANG II), in brain tissue and in cerebrospinal fluid (CSF) allows stimulation of endogenous brain ANG II by renin. Passive avoidance tests were performed in female Wistar rats. The animals received an electrical shock after entering a black box on the first experimental day. Avoidance was tested every 24 h for 5 consecutive days. Renin in doses of 0.01 and 0.1 units was injected once into the lateral brain ventricles 2 min before the first test. CSF ANG II increased from 40 to 4547 and 5152 fmol per ml (means), respectively. A dose-dependent disruption of avoidance learning was observed, the frequency to enter the black box increasing from 11% (control) to 29% and 46%, and the latency decreasing from 165 (control) to 143 and 116 sec, respectively. These effects were statistically significant (P less than 0.001) for more than 24 h and returned to control levels after 48 to 120 h. Administration of the converting-enzyme inhibitor SQ 14225 i.v.t. prior to renin injections abolished the renin effects. Injections of renin given 22 h after learning were without effect.

Angiotensin II↗

PubMed2000

Potassium signalling in the brain: its role in behaviour.

This paper examines evidence that glial cells respond to changes in extracellular potassium ([K+]e) in ways that contribute to modulation of neuronal activity and thereby behaviour. Glial cells spatially (and probably directionally) redistribute potassium from regions of increasing concentration to those with a lesser concentration. This redistribution is largely responsible for slow potential shifts associated with behavioural responses of animals. These slow shifts are related in amplitude to the level of 'arousal' of an animal, and its motivational state. In addition, glia, especially astrocytes, respond to changes in [K+]e, the presence of transmitters like nor-adrenaline and glutamate and at least some hormones with changes in their metabolism and/or the morphological characteristics of the cell. The ionic, metabolic and morphological responses of glia to changes in extracellular potassium after neuronal activity have been associated with at least some forms of learning, including habituation, one trial passive avoidance learning and changes associated with enriched environments. The implication of these effects of potassium signalling in the brain is that there is considerable involvement of glia in a number of processes crucial to neuronal activity. Glia may also form another route for information distribution in the brain that is at least bi-directional, though less specific than its neuronal counterparts. It is evident that the Neuroscience of the future will have to incorporate much more study of neuron-glial interactions than hitherto.

Animals↗

PubMedDate not supplied

Active learning with support vector machine applied to gene expression data for cancer classification.

There is growing interest in the application of machine learning techniques in bioinformatics. The supervised machine learning approach has been widely applied to bioinformatics and gained a lot of success in this research area. With this learning approach researchers first develop a large training set, which is a time-consuming and costly process. Moreover, the proportion of the positive examples and negative examples in the training set may not represent the real-world data distribution, which causes concept drift. Active learning avoids these problems. Unlike most conventional learning methods where the training set used to derive the model remains static, the classifier can actively choose the training data and the size of training set increases. We introduced an algorithm for performing active learning with support vector machine and applied the algorithm to gene expression profiles of colon cancer, lung cancer, and prostate cancer samples. We compared the classification performance of active learning with that of passive learning. The results showed that employing the active learning method can achieve high accuracy and significantly reduce the need for labeled training instances. For lung cancer classification, to achieve 96% of the total positives, only 31 labeled examples were needed in active learning whereas in passive learning 174 labeled examples were required. That meant over 82% reduction was realized by active learning. In active learning the areas under the receiver operating characteristic (ROC) curves were over 0.81, while in passive learning the areas under the ROC curves were below 0.50.

Artificial Intelligence↗

PubMed1987

Difference in learning and retention by Albino-Swiss mice. Part IV. Effect of some nutrients.

According to the preceding papers, the possible difference in activity of some nutrients on memory retrieval of "good" and "poor" learning mice was studied. Among the substances used, only phenylalanine significantly improved memory recall of poor learning mice. On the contrary, tryptophan, tyrosine, phosphatidylserine and choline did not influence memory retention of previously learned avoidance of both poor and good learning mice.

Amino Acids↗

PubMed1986

Difference in learning and retention by Albino Swiss mice. Part III. Effect of some brain stimulants.

According to the two preceding papers, the possible difference in activity of brain stimulants on memory retrieval of "good" and "poor" learning mice was studied. Among the drugs studied, caffeine, oxiracetam and nicotine significantly improved memory recall of poor learning mice. On the contrary, methylphenidate, fipexide and piracetam did not significantly modify memory retention of previously learned avoidance of both poor and good learning mice.

Animals↗

PubMed1992

Enhanced learning produced by injection of neurokinin substance P into the region of the nucleus basalis magnocellularis: mediation by the N-terminal sequence.

The effect of unilateral injection of the neurokinin substance P (SP) and of certain N- or C-terminal SP-fragments into the region of the nucleus basalis magnocellularis (NBM) on inhibitory avoidance learning was investigated. Rats with chronically implanted cannulae were tested on a one-trial uphill avoidance task. Immediately after the training trial, rats were injected with 0.74 pmol SP or equimolar dosed SP(1-7), DIME-C7, or SP(7-11). Control groups included vehicle-injected rats and a group given an injection of SP(1-7) 5-h after the trial. When tested 24 h later, rats treated with SP or SP(1-7), but not with DIME-C7 or SP(7-11), exhibited longer step-up latencies than vehicle-treated controls. The retention latencies for rats in the SP(1-7) 5-h delay group did not differ from those of vehicle-injected animals, ruling out proactive effects of SP(1-7) on performance. The results show that SP facilitates retention of an inhibitory avoidance response when injected into the NBM. Furthermore, the amino acid sequence that encodes this effect may be located in the N-terminal part of the SP-molecule.

Animals↗

PubMedDate not supplied

Fetal alcohol effects in long- and short-sleep mice: activity, passive avoidance, and in utero ethanol levels.

Genetic differences in susceptibility to fetal alcohol effects (FAE) have been suggested by both human and animal studies. The Long-Sleep (LS) and Short-Sleep (SS) mouse lines, selectively bred for differences in ethanol-induced narcosis, provide a model for studying differential alcohol sensitivity in the etiology of FAE. LS and SS mice were intubated with either 2.9 g/kg (20% w/v) ethanol (E) or an isocaloric amount of sucrose (S) twice per day (6 hr apart) on Days 7 through 15 of pregnancy. An untreated control group (C) was maintained for each line. Offspring were fostered to lactating Rockland-Swiss mice at birth. LS offspring prenatally exposed to ethanol exhibited increased open-field activity relative to LS controls, but this effect was due to the overactivity of one litter. Activity for SS mice prenatally exposed to ethanol did not differ from control levels. Ethanol content in blood (280 mg/dl), amniotic fluid (258 mg/dl), and fetal tissue (230 mg/dl) did not differ in similarly treated LS and SS dams. In a second experiment, females were treated from Days 7 through 18 of gestation, and their offspring were tested for either open-field activity or passive avoidance learning. There were no group differences in open-field activity, but LS mice prenatally exposed to alcohol took more trials to reach a passive avoidance criterion than their controls, whereas similarly treated SS mice did not differ from controls. These results suggest that genetically-mediated sensitivity to ethanol influences susceptibility to FAE and that this may be task specific.

Animals↗

PubMed1999

Role of aversively motivated behavior in the olfactory bulbectomy syndrome.

The aim of the present studies was to determine the extent to which changes in defensive behaviors could account for some of the behavioral effects of bilateral olfactory bulbectomy (OBX) in rats. Four tests of aversively-motivated behavior were conducted in bulbectomized and sham-operated rats: activity in a dimly lit or brightly lit open field, passive avoidance, foot shock-induced freezing, and defensive withdrawal. OBX reduced the duration of immobility in the open field. Bulbectomized rats exhibited less freezing in response to foot shock than sham-operated rats. In the defensive-withdrawal test, bulbectomized rats made more transitions into and spent less time inside the covered enclosure than sham-operated rats. The experiments thus reveal two novel paradigms for assessing the behavioral effects of OBX. The results also suggest that deficits in aversively-motivated behavior, specifically defensive freezing, may comprehensively explain the putative "hyperactivity" and "passive-avoidance learning deficits" widely associated with the OBX behavioral syndrome.

Animals↗