Performance more than working memory disrupted by acute systemic inflammation in rats in appetitive tasks.

Evidence from molecular biology, epidemiology, behavioral pharmacology, and clinical science support the conclusion that brain inflammation contributes to the pathogenesis of cognitive symptoms in Alzheimer's disease (AD) and other neuropsychological disorders. Three different tests were conducted to determine whether the acute inflammatory response induced by systemic lipopolysaccharide (LPS) treatment is accompanied by a selective disruption of working memory functioning in rats. Doses of LPS sufficient to induce a thermoregulatory response were administered intraperitoneally and their effects on behavioral measures of symbolic working memory, spatial learning, and spatial memory consolidation, were assessed. LPS-induced immune activation was found not to significantly affect memory processes in any of the behavioral tests used. However, LPS-induced immune activation caused performance deficits consistent with a disruptive effect of LPS on motivation and arousal. These results suggest that sickness behavior induced by immune stimulation is not necessarily accompanied by selective impairment in memory processes. The importance of distinguishing cognitive disruption from performance impairment in interpreting the behavioral effects of inflammatory mediators is discussed.

Ibuprofen effects on Alzheimer pathology and open field activity in APPsw transgenic mice.

We previously showed the non-steroidal anti-inflammatory drug (NSAID) ibuprofen suppresses inflammation and amyloid in the APPsw (Tg2576) Tg2576 transgenic mouse. The mechanism for these effects and the impact on behavior are unknown. We now show ibuprofen's effects were not mediated by alterations in amyloid precursor protein (APP) expression or oxidative damage (carbonyls). Six months ibuprofen treatment in Tg+ females caused a decrease in open field behavior (p < 0.05), restoring values similar to Tg- mice. Reduced caspase activation per plaque provided further evidence for a neuroprotective action of ibuprofen. The impact of a shorter 3 month duration ibuprofen trial, beginning at a later age (from 14 to 17 months), was also investigated. Repeated measures ANOVA of Abeta levels (soluble and insoluble) demonstrated a significant ibuprofen treatment effect (p < 0.05). Post-hoc analysis showed that ibuprofen-dependent reductions of both soluble Abeta and Abeta42 were most marked in entorhinal cortex (p < 0.05). Although interleukin-1beta and insoluble Abeta were more effectively reduced with longer treatment, the magnitude of the effect on soluble Abeta was not dependent on treatment duration.

Conditional choice-unique outcomes establish expectancies that mediate choice behavior.

Conditional discriminative choice tasks can be arranged such that all correct choices yield the same reinforcer or such that each type of correct choice has its own unique reinforcer. The former is the traditional "Common Outcomes" Procedure; the latter is the "Differential Outcomes" Procedure. Use of this Differential Outcomes Procedure facilitates the rate of learning, increases the asymptotic level of performance, and enhances working-memory based performances in both animals and humans. These facts have stimulated many questions and experiments about learning and memory mechanisms and fostered potential applications.

Inhibition of return in aging and Alzheimer's disease: performance as a function of task demands and stimulus timing.

Inhibition of return (IOR) is a phenomenon of spatial attention that biases attention toward novel events in the environment. Recent evidence suggests that the magnitude and timing of IOR varies as a function of task conditions (e.g., detection vs. discrimination tasks, short vs. long cue-target intervals, intrinsic vs. extrinsic cues). Although IOR appears relatively preserved with both normal aging and Alzheimer's disease (AD), it has been tested under relatively simple task conditions. To test whether IOR is resistant to age and / or AD when cognitive demands are increased, we employed a double-cue IOR paradigm that required categorization as well as detection responses. The stimulus onset asynchrony (SOA) between the cue and target events was varied to determine whether group differences existed in IOR effects over time. Younger normal adults and older normal adults exhibited significant IOR effects on both the detection task and the categorization task at a short cue-target SOA (950 ms). In contrast, AD patients exhibited significant IOR effects at the short SOA on the detection task but not on the categorization task. From the short to the long SOA (3500 ms), IOR effects exhibited by younger normal adults declined significantly during both the detection and the categorization tasks, suggesting that inhibition resolved over time. In contrast, neither older normal adults nor AD patients exhibited SOA-related IOR reductions on the detection task. These results suggest that IOR may show differential age- and AD-related vulnerabilities depending on task conditions and timing characteristics.

Anxiety and helplessness in the face of stress predisposes, precipitates, and sustains gastric ulceration.

When an organism is subjected to stress, gastric ulcers or ulcerations commonly develop but the vulnerability to and amount of pathology induced varies considerably between individuals. The role of psychological factors in determining the occurrence and severity of these ulcerations is amply demonstrated in the studies reviewed here. The present paper (a) gives a brief history of the search for the causes of gastric ulcer, (b) provides a review of our own research which reveals that vulnerability to gastric ulceration is modulated by psychologically meaningful experiences, and (c) offers a multifactorial perspective on the causes of gastric ulceration and the future of research on it.

Inflammatory pathogenesis in Alzheimer's disease: biological mechanisms and cognitive sequeli.

Experimental evidence from molecular biology, biochemistry, epidemiology and behavioral research support the conclusion that brain inflammation contributes to the pathogenesis of Alzheimer's disease and other types of human dementias. Aspects of neuroimmunology relating to the pathogenesis of Alzheimer's disease are briefly reviewed. The effects of brain inflammation, mediated through cytokines and other secretory products of activated glial cells, on neurotransmission (specifically, nitric oxide, glutamate, and acetylcholine), amyloidogenesis, proteolysis, and oxidative stress are discussed within the context of the pathogenesis of learning and memory dysfunction in Alzheimer's disease. Alzheimer's disease is proposed to be an etiologically heterogeneous syndrome with the common elements of amyloid deposition and inflammatory neuronal damage.

Comparison of different animal models of stress reveals a non-monotonic effect.

A handling-only control and two footshocked stressed groups for which the numbers of footshocks, 10 or 100, were determined by different proposed clinically relevant models were compared after a 15-day delay on the alerting-immobility response to a sudden reduction in noise. Only the 10-shocks group showed a significantly increased level of alert-immobility. The implications of this non-monotonicity of effects of increasing stress for modelling and scientific practice are considered.

Inhibition and habituation: preserved mechanisms of attentional selection in aging and Alzheimer's disease.

Are inhibition and habituation, processes that contribute to selective attention, impaired by aging or Alzheimer's disease (AD)? Younger adults, older adults, and adults with AD read lists of letters presented either alone or paired with distractor letters. Slower reading times for lists containing distractors relative to lists without distractors indexed concurrent interference (distraction). Slower reading times for lists in which distractors subsequently became targets relative to lists in which distractors and targets were unrelated indexed negative priming (inhibition). Faster reading times when distractors were constant in identity or location rather than random indexed repeated distractor effects (habituation). Distraction increased with aging and AD, whereas inhibition and habituation showed no age- or AD-related decline, suggesting that inhibition and habituation still function to aid attentional selection in older adults and adults with AD.

Present imperfect: a critical review of animal models of the mnemonic impairments in Alzheimer's disease.

This paper reviews the current literature on animal models of the memory impairments of Alzheimer's disease (AD). The authors suggest that modeling of the mnemonic deficits in AD be limited to the amnesia observed early in the course of the disease, to eliminate the influence of impairments in non-mnemonic processes. Tasks should be chosen for their specificity and selectivity to the behavioral phenomena observed in early-stage AD and not for their relevance to hypothetical mnemonic processes. Tasks that manipulate the delay between learning and remembering are better able to differentiate Alzheimer patients from persons with other disorders, and better able to differentiate effects of manipulations in animals. The most commonly used manipulations that attempt to model the amnesia of AD are reviewed within these constraints. The authors conclude that of the models examined, lesions of the medial septal nucleus produce behavioral deficits that are most similar to the mnemonic impairments in the earliest stage of AD. However, the parallel is not definitive and more work is needed to clarify the relationship between neurobiology and behavior in AD.

Intrahippocampal injections of exogenous beta-amyloid induce postdelay errors in an eight-arm radial maze.

Alzheimer's disease is characterized by the progressive loss of short-term memory and the accumulation of large amyloid plaques, the primary core of which is the beta-amyloid 1-40 (beta A4) peptide. It has been suggested that beta A4 plays a causative role in the memory degeneration seen in Alzheimer's patients. The current study was designed to test the effects of bilateral intrahippocampal injections of beta A4 on performance in a radial arm maze foraging task with a delay imposed following the fourth choice. Eight Sprague-Dawley rats were injected with either beta A4 (10(-3) M) or vehicle (HPLC buffer) immediately prior to testing in the maze. Although beta A4 did not impair performance on the predelay choices, it did significantly increase errors immediately postdelay. These results suggest that contrary to previous findings, beta A4 does have acute effects when challenged with a short-term memory load and may play a significant role in some memory deficits seen in Alzheimer's disease.

Prediction of individual vulnerability to stress-induced gastric ulcerations in rats: a factor analysis of selected behavioral and biological indices.

Fifty rats were subjected seriatim to 6 different test tasks (open-field, startle, drug-induced sterotypy, oral finickiness, defensive burying, and memory for aversive event). This yielded 12 test-specific plus 2 general biobehavioral measures (growth and defecation). These 14 measures were subjected to factor analysis to determine if these measured tapped a common construct of "emotionality." The data yielded a 4-factor structure of Finickiness, Defensiveness, Startle-Sensitivity, and Dopaminergic-Sensitivity that accounted for 62% of the variance. Then, all rats were subjected to restraint-in-water stress to induce gastric ulcerations. Multivariate techniques tested if there was a factor or factor-structure that could predict individual differences in vulnerability to the stress-induced gastric ulcerations. Only the Dopaminergic-Sensitivity factor predicted ulcerogenic vulnerability, and its predictive power resided substantially in the latency to initiate stereotypic gnawing induced by apomorphine. This single test score correlated with amount of ulcer (r = +0.52), accounting for 25% of the variance in ulcer, suggesting that 1. prescreening rats on this variable could be a tool for reducing intrastrain experimental variance in future studies of treatments that modulate ulcerogenicity, and 2. the dopaminergic system may be intimately involved in the causal path of ulcerogenicity.

Food- and nonfood-related differential outcomes in equivalence learning by adults with Prader-Willi syndrome.

Adults with Prader-Willi syndrome learned the conditional relations necessary for the formation of two equivalence classes under four conditions: (a) nondifferential, nonedible outcomes; (b) nondifferential, edible outcomes; (c) differential, nonedible outcomes; and (d) differential, edible outcomes. Tests for transitive relations revealed superior performance when the two differential outcomes procedures, in which a distinct reinforcer was associated with each stimulus set, were used during teaching. Performance on test trials following nondifferential outcomes training was better when edible outcomes were used during teaching for 4 of the 5 participants. An enhancement of performance on the derived relations separated by two or three nodal stimuli was seen when a differential outcomes procedure was used to teach the baseline conditional relations.

Richard L. Solomon and learned helplessness.

This article reviews the course of development of research on a currently popular explanatory approach to dysfunctional behavior, the learned helplessness analysis. The early history is prominent in this review as it reflects the inspirations of Richard L. Solomon, a scholar who fostered the resurgence of psychologists' interests in Pavlovian conditioning in the 1950s and 1960s. Current research is characterized as having four separate themes: elaboration of "symptoms," elucidating the role of fear, explicit modeling, and extensions involving attributional constructs.

Reversal of beta-amyloid-induced retention deficit after exposure to training and state cues.

We explored amnesia induced by posttraining injection of beta-amyloid protein (beta A4) in four experiments. Previous reports showed that beta A4 impaired retention of learning maintained either by food reward or by shock relief. The experiments in this paper attempted to determine (1) if the amnesia is specific to the 1-40 beta A4 amino-acid sequence; and (2) if the amnesia can be attributed to a consolidation process. Subjects were 190 male Sprague-Dawley rats, 3 to 6 months old. Subjects were given five training trials on a left-right discrimination in a Y-maze with a food reward and injected immediately afterward with beta A4(1-40) or vehicle. One week later they were trained to criterion. Experiment 1 used a control group that was injected with the reverse-sequence peptide (40-1). The performance of the beta A4(40-1) group was unimpaired. Experiments 2 and 3 attempted to reverse the amnestic effects of beta A4 using noncontingent presentation of aspects of the training context during the retention interval. Experimental subjects in Experiment 2 were exposed to the Y-maze in the absence of reinforcers, 24, 22, and 2 h before retention testing. In Experiment 3, subjects were given a 1-min exposure to the reinforcers, outside the Y-maze, 24 h before retention testing. Both manipulations reversed beta A4-induced amnesia. In Experiment 4, beta A4-induced impairments were reversed by reinjecting beta A4 immediately before retention testing. Results indicate that beta A4 injected after partial training does not interfere with a consolidation process.

Differing mechanisms for proactive effects of intermittent and single shock on gastric ulceration.

Rats exposed to either 80 5-s shocks on a VT 60-s or to a single 400-s shock plus 80-min rest in the shock apparatus show dramatically increased degree of ulceration induced 72 h later by exposure to 75-min restraint-in-water stress (at 19 degrees C). However, the proactive effect of the 80 shocks on later gastric ulceration was blocked by SC injection of 7 mg/kg naltrexone 20 min prior to the shock session; naltrexone treatment prior to the single shock session had no ameliorating effect. A second experiment confirmed opioid involvement in the proactive augmentation of vulnerability by showing that when a 20 mg/kg injection of morphine replaced the shocks, rats showed a comparable increase in vulnerability. A third experiment replicated the basic findings from the first experiments that 80 intermittent shocks increase vulnerability to the ulcerogenicity of restraint-in-water and that this effect can be mimicked by replacing the shock stress with a 20 mg/kg injection of morphine; however, other groups showed that injection of 40 mg/kg produced a similar effect whereas 10 mg/kg was ineffective as a mimic. This suggests that there are at least two types of proactive effects from shock experiences that can increase later vulnerability to shock-induced gastric ulceration; one is opioid mediated and the other is not. This finding parallels reports made about mediation of prior shock-induced hypoalgesias and expands the spectrum to psychosomatic phenomenon.

Effects of an exogenous beta-amyloid peptide on retention for spatial learning.

Three experiments assessed the effects of beta-amyloid 1-40 (beta A4) on spatial learning in Sprague-Dawley rats. In Experiment 1, rats were trained on a signaled footshock avoidance in a Y-maze. Rats received a single injection of beta A4 or vehicle in both sides of the hippocampus immediately after the fifth trial. The beta A4 group took significantly longer than the vehicle group to learn to avoid the shock when trained to criterion 1 week later, suggesting a detrimental effect of beta A4 on memory consolidation. Experiment 2 used a food reinforcer rather than shock relief under procedures similar to Experiment 1. Again, the beta A4 group took longer to learn the maze to criterion. This shocks that the effect in Experiment 1 was not specific to shock-maintained learning. In Experiment 3, rats were trained to retrieve a food pellet from each arm of an eight-arm radial maze. After training to criterion, beta A4 or vehicle was administered intrahippocampally 30 min before the daily session for 26 sessions. There were no acute or chronic effects of beta A4 injection on radial maze performance, and no aggregation of beta A4 or significant necrosis was observed upon postmortem histological analysis. These experiments suggest that single injections of beta A4 impair memory consolidation, but repeated injections of beta A4 over an extended period do not affect well-learned behavior.

The effects of scopolamine, diazepam, and lorazepam on working memory in pigeons: an analysis of reinforcement procedures and sample problem type.

Two groups of pigeons were trained on a delayed-matching-to-sample (DMTS) task with both identity and symbolic problems, that had either a) specific outcomes correlated (differential group) or b) outcomes uncorrelated (nondifferential group), for each correct sample-choice sequence. After reaching a criterion of 90% correct at the 0 s delay, subjects were tested under saline, methylscopolamine (0.03 mg/kg), scopolamine (0.007, 0.015, 0.03 mg/kg), diazepam (0.0, 1.0, 1.75, 2.5 mg/kg), and lorazepam (0.0, 0.5, 0.75, 1.0 mg/kg) at delays of 0 to 8 s. Scopolamine, diazepam, and lorazepam at all doses impaired performance in the nondifferential group; however, in the differential group, the medium and high doses of both scopolamine and lorazepam, and only the high dose of diazepam impaired performance. The differential outcomes procedure, relative to the nondifferential procedure, enhanced retention in the non-drug state and under these amnestic drugs. Impairments observed in the differential group were a result of decreased performance only on samples correlated with a secondary reinforcer (flashing hopper light); there was no decreased performance on samples correlated with a primary reinforcer (grain). Neither group showed any differences in performance as a function of identity versus symbolic problems in a nondrug or drug state.

Behavioral and neurochemical mechanisms of opioid-antidepressant interactions.

Twelve pigeons key-pecked under a multiple variable interval 15-s, 150-s schedule of food reinforcement. The effects of methadone were studied alone and in combination with chronic daily administration of either imipramine (IMI) or desipramine (DMI). Chronic IMI was also given following reductions in response rates by unsignaled delay-to-reinforcement (UDR). Acute administration of methadone produced dose-dependent reductions in response rates under both schedules of reinforcement. Chronic daily administration of IMI or DMI alone did not result in lasting changes in baseline responding. When administered in combination, chronic daily IMI significantly attenuated the rate-reducing effects of methadone, whereas neither a low nor a high dose of chronic daily DMI was effective. The same dose of chronic daily IMI failed to ameliorate response rate reductions under delayed reinforcement. The behavioral and neurochemical specificity of the antidepressant effect is discussed.