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Alzheimer's disease (AD) is one of the most devastating and costly diseases, and prevalence of AD increases with age. Furthermore, females are twice as likely to suffer from AD compared to males. The cessation of reproductive steroid hormone production during menopause is hypothesized to cause this difference. Two rodent AD models, APP21 and APP+PS1, and wild type (WT) rats underwent an ovariectomy or sham surgery. Changes in learning and memory, brain histology, amyloid-β (Aβ) deposition, levels of mRNAs involved in Aβ production and clearance, and synaptic and cognitive function were determined. Barnes maze results showed that regardless of ovariectomy status, APP+PS1 rats learned slower and had poor memory retention. Ovariectomy caused learning impairment only in the APP21 rats. High levels of Aβ42 and very low levels of Aβ40 were observed in the brain cortices of APP+PS1 rats indicating limited endogenous PS1. The APP+PS1 rats had 43-fold greater formic acid soluble Aβ42 than Aβ40 at 17 months. Furthermore, levels of formic acid soluble Aβ42 increased 57-fold in ovariectomized APP+PS1 rats between 12 and 17 months of age. The mRNA encoding Grin1 significantly decreased due to ovariectomy whereas levels of Bace1, Chat, and Prkcb all decreased with age. The expression levels of mRNAs involved in Aβ degradation and AβPP cleavage (Neprilysin, Ide, Adam9, and Psenen) were found to be highly correlated with each other as well as hippocampal Aβ deposition. Taken together, these results indicate that both ovariectomy and genotype influence AD markers in a complex manner.

Effective treatments preventing brain neuroinflammatory diseases are lacking. Resistance-exercise training (RT) ameliorates mild cognitive impairment (MCI), a forerunner to neuroinflammatory diseases. However, few studies have addressed the molecular basis by which RT abates MCI. Thus experiments were performed to identify some molecular changes occurring in response to RT in young, female Wistar rats. To induce MCI, intraventricular lipopolysaccharide (LPS) injections were used to increase dentate gyrus inflammation, reflected by significantly increased TNF-α (~400%) and IL-1β (~1,500%) mRNA ( P < 0.0001) after 6 wk. Five days after LPS injections, half of LPS-injected rats performed RT by ladder climbing for 6 wk, 3 days/wk, whereas half remained without ladders. RT for 6 wk increased lean body mass percentage ( P < 0.05), individual muscle masses (gastrocnemius and tibialis anterior) ( P < 0.05), and maximum lifting capacity ( P < 0.001). The RT group, compared with sedentary controls, had 1) ameliorated spatial learning deficits ( P < 0.05), 2) increased dentate gyrus phosphorylation of IGF-1R, protein kinase B, and GSK-3β proteins ( P < 0.05), components of downstream IGF-1 signaling, and 3) increased dentate gyrus synaptic plasticity marker synapsin protein ( P < 0.05). Two follow-up experiments (without LPS) characterized dentate gyrus signaling during short-term RT. Twenty-four hours following the third workout in a 1-wk training duration, phosphorylation of ERK1/2 and GSK-3β proteins, as well as proliferation marker protein, PCNA, were significantly increased ( P < 0.05). Similar changes did not occur in a separate group of rats following a single RT workout. Taken together, these data indicate that RT ameliorates LPS-induced MCI after RT, possibly mediated by increased IGF-1 signaling pathway components within the dentate gyrus.NEW & NOTEWORTHY The data suggest that resistance-exercise training restores cognitive deficits induced by lipopolysaccharides and can activate associated IGF-1 signaling in the dentate gyrus. Our data show, for the first time, that as few as three resistance-exercise workouts (spread over 1 wk) can activate IGF-1 downstream signaling and increase proliferation marker PCNA in the dentate gyrus.

When a target conditioned stimulus (CS A) is paired with an unconditioned stimulus in the presence of a second, conditioned stimulus (CS B) during compound conditioning trials, the associative strength of CS B can influence the magnitude of the conditioned response (CR) to CS A. For example, extinction of the competing, nontarget CS B can influence the CR to CS A. An enhancement of the CR to the target CS A due to extinction of the nontarget CS B after compound conditioning is sometimes referred to as “recovery from overshadowing” – a type of retrospective revaluation. The present experiments examined retrospective revaluation effects using a conditioned taste aversion procedure. The experiments obtained an effect on the CR to CS A following extinction of CS B. The results are discussed with respect to the comparator hypothesis, within-compound associations, and retrieval as well as other relationships between the target CS and nontarget CS.

Earlier studies have shown that a latent inhibitor is poor at competing for learning with another conditioned stimulus on a compound conditioning trial. Previous research also has shown that the poor conditioned response produced to a latent inhibitor can be reversed by a retention interval placed after conditioning and prior to testing the conditioned response. In the present conditioned taste aversion experiments, a CS flavor (“A”) was given CS-alone preexposures prior to a pairing of the CS with the US. A serial compound conditioning phase then occurred in which this CS was able to compete with an added novel CS (“B”) when the two CSs were paired with the US. However, prior to the compound conditioning phase, a retention interval occurred lasting either one day or many days (15 days in one experiment and 21 days in another experiment). It was found that the lengthy retention interval enhanced the competitive potential of the pretrained CS. These results show that treatments that enhance the expression of a CS-US association can also enhance the competitive ability of the CS.

Recent advances in understanding visual working memory, the limited information held in mind for use in ongoing processing, are extended here to examine auditory working memory development. Research with arrays of visual objects has shown how to distinguish the capacity, in terms of the number of objects retained, from the precision of the object representations. We adapt the technique to sequences of nonmusical tones, in an investigation including children (6-13 years, N = 84) and adults (26-50 years, N = 31). For each series of 1 to 4 tones, the participant responded by using an 80-choice scale to try to reproduce the tone at a queried serial position. Despite the much longer-lasting usefulness of sensory memory for tones compared with visual objects, the observed tone capacity was similar to previous findings for visual capacity. The results also constrain theories of childhood working memory development, indicating increases with age in both the capacity and the precision of the tone representations, similar to the visual studies, rather than age differences in time-based memory decay. The findings, including patterns of correlations between capacity, precision, and some auxiliary tasks and questionnaires, establish capacity and precision as dissociable processes and place important constraints on various hypotheses of working memory development. (PsycINFO Database Record

This study tested the hypotheses that obesity-induced decrements in insulin-stimulated cerebrovascular vasodilation would be normalized with acute endothelin-1a receptor antagonism and that treatment with a physical activity intervention restores vasoreactivity to insulin through augmented nitric oxide synthase (NOS)-dependent dilation. Otsuka Long-Evans Tokushima Fatty rats were divided into the following groups: 20 wk old food controlled (CON-20); 20 wk old free food access (model of obesity, OB-20); 40 wk old food controlled (CON-40); 40 wk old free food access (OB-40); and 40 wk old free food access+RUN (RUN-40; wheel-running access from 20 to 40 wk). Rats underwent Barnes maze testing and a euglycemic hyperinsulinemic clamp (EHC). In the 40-wk cohort, cerebellum and hippocampus blood flow (BF) were examined (microsphere infusion). Vasomotor responses (pressurized myography) to insulin were assessed in untreated, endothelin-1a receptor antagonism, and NOS inhibition conditions in posterior cerebral arteries. Insulin-stimulated vasodilation was attenuated in the OB vs. CON and RUN groups ( P ≤ 0.04). Dilation to insulin was normalized with endothelin-1a receptor antagonism in the OB groups (between groups, P ≥ 0.56), and insulin-stimulated NOS-mediated dilation was greater in the RUN-40 vs. OB-40 group ( P < 0.01). At 40 wk of age, cerebellum BF decreased during EHC in the OB-40 group ( P = 0.02) but not CON or RUN groups ( P ≥ 0.36). Barnes maze testing revealed increased entry errors and latencies in the RUN-40 vs. CON and OB groups ( P < 0.01). These findings indicate that obesity-induced impairments in vasoreactivity to insulin involve increased endothelin-1 and decreased nitric oxide signaling. Chronic spontaneous physical activity, initiated after disease onset, reversed impaired vasodilation to insulin and decreased Barnes maze performance, possibly because of increased exploratory behavior. NEW & NOTEWORTHY The new and noteworthy findings are that 1) in rodents, obesity-related deficits in insulin-mediated vasodilation are associated with increased influence of insulin-stimulated ET-1 and depressed influence of insulin-stimulated NOS and 2) a physical activity intervention, initiated after the onset of disease, restores insulin-mediated vasodilation, likely by normalizing insulin-stimulated ET-1 and NOS balance. These data demonstrate that the treatment effects of chronic exercise on insulin-mediated vasodilation extend beyond active skeletal muscle vasculature and include the cerebrovasculature.

This experiment examined the effects of a redundant cue that predicted the target response to a target stimulus in a response conflict procedure using a flanker task. Participants received trials with five-character arrays with a central target character and distractor flanker characters that matched (compatible) or did not match (incompatible) the central target. Participants’ expectancies for compatible and incompatible trials were manipulated by presenting pre-trial cues that signaled the occurrence of compatible or incompatible trials. Some groups received a single cue predicting the target stimulus and the required target response. Other groups received this cue along with a second redundant, predictive cue. The presence of a second, redundant cue during training in which incompatible trials were predicted facilitated performance (errors were reduced) compared to when only a single cue was present. This finding is consistent with the potentiation effect in conditioning and learning. Extinction of the nontarget cue prior to testing on the target (a retrospective revaluation manipulation) had no effect on performance. The finding of potentiation between pre-trial cues that predict incompatible trials, but not cues that predict compatible trials, suggests that different strategic processes may occur during adaptation to conflict when different kinds of trials are expected.

The neurophysiology of human associative memory has been studied with electroencephalographic techniques since the 1930s. This research has revealed that different types of electrophysiological processes in the human brain can be modified by conditioning: sensory evoked potentials, sensory induced gamma-band activity, periods of frequency-specific waves (alpha and beta waves, the sensorimotor rhythm and the mu-rhythm) and slow cortical potentials. Conditioning of these processes has been studied in experiments that either use operant conditioning or repeated contingent pairings of conditioned and unconditioned stimuli (classical conditioning). In operant conditioning, the appearance of a specific brain process is paired with an external stimulus (neurofeedback) and the feedback enables subjects to obtain varying degrees of control of the CNS-process. Such acquired self-regulation of brain activity has found practical uses for instance in the amelioration of epileptic seizures, Autism Spectrum Disorders (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). It has also provided communicative means of assistance for tetraplegic patients through the use of brain computer interfaces. Both extra and intracortically recorded signals have been coupled with contingent external feedback. It is the aim for this review to summarize essential results on all types of electromagnetic brain processes that have been modified by classical or operant conditioning. The results are organized according to type of conditioned EEG-process, type of conditioning, and sensory modalities of the conditioning stimuli.

There is evidence that both Pavlovian conditioned inhibition training and CS-alone extinction trials result in a CS that passes a summation and retardation test. The present experiments compared the extent that these two procedures produced a CS that could pass these tests. Such a comparison could provide insight into the kind of inhibitory learning that results, specifically whether two CSs on the nonreinforced trials compete for the acquisition of inhibitory learning. Very little evidence of competition for inhibitory learning has been obtained in previously published studies. Evidence consistent with more inhibition occurring using the Pavlovian CI procedure than extinction was obtained.

Transgenic rat models of Alzheimer's disease were used to examine differences in memory and brain histology. Double transgenic female rats (APP+PS1) over-expressing human amyloid precursor protein (APP) and presenilin 1 (PS1) and single transgenic rats (APP21) over-expressing human APP were compared with wild type Fischer rats (WT). The Barnes maze assessed learning and memory and showed that both APP21 and APP+PS1 rats made significantly more errors than the WT rats during the acquisition phase, signifying slower learning. Additionally, the APP+PS1 rats made significantly more errors following a retention interval, indicating impaired memory compared to both the APP21 and WT rats. Immunohistochemistry using an antibody against amyloid-β (Aβ) showed extensive and mostly diffuse Aβ plaques in the hippocampus and dense plaques that contained tau in the cortex of the brains of the APP+PS1 rats. Furthermore, the APP+PS1 rats also showed vascular changes, including cerebral amyloid angiopathy with extensive Aβ deposits in cortical and leptomeningeal blood vessel walls and venous collagenosis. In addition to the Aβ accumulation observed in arterial, venous, and capillary walls, APP+PS1 rats also displayed enlarged blood vessels and perivascular space. Overall, the brain histopathology and behavioral assessment showed that the APP+PS1 rats demonstrated behavioral characteristics and vascular changes similar to those commonly observed in patients with Alzheimer's disease.

Findings and theoretical views regarding the effects of nontarget stimulus presentations on the habituation of neophobia to a target stimulus are discussed. These findings include the effects of a distractor stimulus on the habituation of neophobia, the role of similarity and dissimilarity of the two stimuli on habituation, the role of associations or conditioning involving the two stimuli and the influence of retention intervals on such effects. The discussion illustrates potentially valuable ways that events can influence each other during preexposure, especially those that can occur during exposure to a novel flavor. The discussion also points out various processes that may occur during the habituation of neophobia.

Culture can impact cognitive processes, including effects on causal attributions. This study examined cultural differences in revaluative attributions when two potential causes of an outcome are initially present, but new relevant causal information is later available, suggesting potential adjustments could be made with respect to the original judgment. Study 1 ( N = 206) found that both Chinese and American participants showed revaluative attributions regarding the target cause when a nontarget cause was decreased in its validity during a subsequent phase. That is, the target cause was later judged as more valid when a nontarget cause was decreased in validity (the deflation effect). However, only American participants exhibited a significant decrease in the perceived validity of a target cause when the nontarget cause was increased in its validity (the inflation effect). Study 2 ( N = 189) replicated these findings and also showed that dialectical thinking was a mediator of this cultural difference in revaluative attributions. The present study shows that culturally shaped cognitive processing can influence multicausal inferences.

Background Postmenopausal women represent the largest cohort of patients with heart failure with preserved ejection fraction, and vascular dementia represents the most common form of dementia in patients with heart failure with preserved ejection fraction. Therefore, we tested the hypotheses that the combination of cardiac pressure overload (aortic banding [ AB ]) and the loss of female sex hormones (ovariectomy [ OVX ]) impairs cerebrovascular control and spatial memory. Methods and Results Female Yucatan miniswine were separated into 4 groups (n=7 per group): (1) control, (2) AB , (3) OVX , and (4) AB ‐ OVX . Pigs underwent OVX and AB at 7 and 8 months of age, respectively. At 14 months, cerebral blood flow velocity and spatial memory (spatial hole‐board task) were lower in the OVX groups ( P AB ‐ OVX group ( P AB ‐ OVX group ( P OVX groups ( P AB ‐ OVX group ( P 2+ ‐activated potassium channel α‐subunit agonist NS ‐1619 was impaired in both AB groups ( P 2+ ‐activated potassium channel α‐subunit protein was increased in AB groups ( P Conclusions Mechanistically, impaired cerebral blood flow control in experimental heart failure may be the result of heightened neuropeptide Y–induced vasoconstriction along with reduced vasodilation associated with decreased Ca 2+ ‐activated potassium channel function and impaired nitric oxide signaling, the effects of which are exacerbated in the absence of female sex hormones.

Previous work examining animal models of cognitive flexibility have focused on tasks where animals are required to shift between cues in order to reach a food reward from among a limited set of choices. Performance by nonhuman animals on these tasks, including reversal learning, intradimensional set-shifting, and extradimensional set-shifting, are affected by pharmacological action on serotonergic, dopaminergic, and alpha-adrenergic, but not beta-adrenergic receptors. However, beta-adrenergic antagonists, such as propranolol, are widely utilized for conditions such as test anxiety. Propranolol improves performance in humans during cognitive flexibility tasks where there is a broad set of potential solutions. The current investigation utilized a digging task where the rodent must develop a novel solution in order to obtain a reward. Similar to the effects observed in humans, propranolol improved performance on this task, while not affecting performance on set-shifting tasks, as with previous animal studies. This may allow future investigation of the neurobiological mechanism by which propranolol affects context-specific anxiety, and could provide insight into the neurobiology of creativity.

Metabotropic glutamate (mGlu) receptors impact learning and memory. Although some evidence indicates the importance of these receptors in conditioned taste aversion (CTA), the subtype-specific involvement of mGlu receptors in this associative learning task remains to be determined. These experiments examined the effects of (1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268), a selective group II mGlu receptor agonist, cis-2-[[(3,5-dichlorophenyl)amino]carbonyl]cyclohexanecarboxylic acid (VU0155041), a mGlu4 positive allosteric modulator, N,N'-dibenzhydrylethane-1,2-diamine (AMN082), a mGlu7 allosteric agonist, and 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP), a mGlu7 negative allosteric modulator, on the acquisition of CTA using male Sprague-Dawley rats. Systemic injections of LY379268, AMN082, and MMPIP prior to conditioning decreased the acquisition of CTA, revealing that mGlu2/3 and mGlu7 are involved in CTA learning.

Metabotropic glutamate receptor 5 (mGlu5) has been implicated in a variety of learning and memory processes and is important for avoidance learning. The present studies used an mGlu5 receptor positive allosteric modulator, 3-cyano-N-(1,3 diphenyl-1H-hyrazol-5-yl)benzamide (CDPPB), to characterize the importance of mGlu5 receptors in aversively- and appetitively-motivated spatial learning tasks (tasks in which the instrumental contingency involves discriminative cues that differ in spatial location). C57Bl/6 male mice were initially trained in the Barnes maze in the absence of drug. Subsequently, CDPPB (30 mg/kg, i.p.), administered 20 min prior to each of 3 daily reversal learning training sessions in the Barnes maze, significantly enhanced performance compared to vehicle-treated controls and had a significant effect on search strategy. Mice treated with CDPPB also displayed significantly less perseverative behavior than control-treated animals. In a second experiment, male Sprague–Dawley rats were trained in an appetitively-motivated, delayed alternation version of a T-maze. 30 mg/kg CDPPB (s.c.), delivered 20 min prior to each of 5 daily training sessions, enhanced the delay rats were able to withstand between the sample and choice portions of each T-maze trial. The present results emphasize the role of mGlu5 receptors in spatial learning tasks and support previous studies which report mGlu5 positive allosteric modulators can enhance learning in some tasks and may have potential as nootropic drugs.

Abstract. Many studies have examined competition between cues for learning. Research examining cue competition has used cues that predict the occurrence of an outcome, or, in some rare cases, competition between cues that predict the absence of an outcome (predicting that an outcome explicitly will not occur). Alternatively, learned irrelevance occurs when a cue lacks the ability to predict the occurrence or absence of an outcome. Using an Eriksen flanker task, the present study evaluated competition among cues that do not have predictive value, that is, competition for learning that an outcome is unpredictable. Subjects’ inability to predict the occurrence of compatible and incompatible trials was manipulated by presenting cues that were uncorrelated with these trial types. Accuracy results showed competition between cues possessing a lack of predictive ability. The results are discussed in terms of propositional and associative theories of learning.

Background We previously reported the production of transgenic rats (APP21 line) that over-express human amyloid precursor protein (APP) containing Swedish and Indiana mutations. In order to generate a better model for Alzheimer’s disease (AD), the APP21 rat line was used to generate double transgenic line that over-expressed Presenilin 1 (PS1) with L166P mutation in addition to APP transgene (APP + PS1 line). Results Thirty-two double transgenic founders were generated and the ultimate transgenic founder was selected based on PS1 transgene copy number and level of amyloid-beta (Aβ)42 peptide. The APP + PS1 double transgenic rats had 38 times more PS1 in brains compared to APP rats. Behavioral assessment using Barnes maze showed that APP + PS1 rats exhibited a larger learning and memory deficit than APP21 rats. Double transgenic rats also produced more Aβ42. Histological examination of the brains showed that the APP21 rat line displayed neurofibrillary tangles and in contrast, the APP + PS1 line showed chromatolysis in hippocampal neurons and neuronal loss in CA3 region of hippocampus. Conclusions Due to the separate segregation of APP and PS1 transgenes in APP + PS1 double transgenic rats, this transgenic line may be a valuable model for studying the effects of various levels of APP and PS1 transgenes on various aspects of brain pathologies associated with the AD phenotype. Electronic supplementary material The online version of this article (doi:10.1186/s12868-016-0281-8) contains supplementary material, which is available to authorized users.

Background Cognitive impairment in the setting of heart failure with preserved ejection fraction remains poorly understood. Using aortic‐banded miniature swine displaying pathological features of human heart failure with preserved ejection fraction, we tested the hypothesis that increased carotid artery stiffness and altered carotid blood flow control are associated with impaired memory independent of decreased cardiac output. Furthermore, we hypothesized that chronic exercise prevents carotid artery vascular restructuring and preserves normal blood flow control and cognition in heart failure with preserved ejection fraction. Methods and Results Yucatan pigs aged 8 months were divided into 3 groups: control (n=7), aortic‐banded sedentary (n=7), and aortic‐banded exercise trained (n=7). At 6 months following aortic‐banded or control conditions, memory was evaluated using a spatial hole‐board task. Carotid artery vascular mechanics and blood flow were assessed at rest, and blood flow control was examined during transient vena cava occlusion. Independent of decreased cardiac output, the aortic‐banded group exhibited impaired memory that was associated with carotid artery vascular stiffening, elevated carotid artery vascular resistance, and exaggerated reductions in carotid artery blood flow during vena cava occlusion. Chronic exercise augmented memory scores, normalized blood flow control, and improved indices of carotid artery vascular stiffening. Indices of vascular stiffening were significantly correlated with average memory score. Conclusions Carotid artery stiffness and altered vasomotor control correlate with impaired cognition independent of cardiac systolic dysfunction. Carotid artery vascular mechanics may serve as a biomarker for vascular cognitive impairment in heart failure with preserved ejection fraction. Chronic low‐intensity exercise reduces vascular stiffening and improves cognition, highlighting the utility of exercise therapy for treating vascular cognitive impairment in heart failure with preserved ejection fraction.

Two experiments investigated competition between cues that predicted the correct target response to a target stimulus in a response conflict procedure using a flanker task. Subjects received trials with five-character arrays with a central target character and distractor flanker characters that matched (compatible) or did not match (incompatible) the central target. Subjects’ expectancies for compatible and incompatible trials were manipulated by presenting pre-trial cues that signaled the occurrence of compatible or incompatible trials. On some trials, a single cue predicted the target stimulus and the required target response. On other trials, a second redundant, predictive cue was also present on such trials. The results showed an effect of competition between cues for control over strategic responding to the target stimuli, a finding that is predicted by associative learning theories. The finding of competition between pre-trial cues that predict incompatible trials, but not cues that predict compatible trials, suggests that different strategic processes may occur during adaptation to conflict when different kinds of trials are expected.

Previous research has found that swim stress during a classical conditioning trial attenuates conditioned taste aversion (CTA). In the current study, rats were used to examine the effects of inescapable swim stress on the habituation of neophobia to a flavored solution and reacquisition of an extinguished conditioned taste aversion. In Experiment 1, subjects were initially exposed to a taste, with some subjects receiving a swim experience to assess the level of neophobia on a subsequent taste-exposure test. Rats in Experiment 2 were given a taste-LiCl trial followed by extensive CS-alone extinction trials. Subjects then received the taste-LiCl pairing again, followed for some by a swim experience to examine its effect on subsequent reconditioning. Swim stress influenced CS processing on the final extinction trial. Thus, reacquisition was attenuated by swim, but there was no effect of swim stress on the attenuation of neophobia. These results are discussed in terms of the effects of stress on CS processing.

D1-receptor antagonism is known to impair rodent memory but also inhibits spontaneous exploration of stimuli to be remembered. Hypo-exploration could contribute to impaired memory by influencing event processing. In order to explore this effect, the D1 receptor antagonist, SCH23390, was administered to rats via routes that either did or did not affect spontaneous exploration: systemic or prelimbic administration, respectively. Effects were tested in spatial and non-spatial memory tasks selected for their requirements for self-initiated exploration of stimuli to be remembered in order to examine the effects on memory: cross-maze and object recognition task. Systemic administration reduced spatial exploration in cross-maze as well as in an open field test, and also reduced object exploration. Spatial (hippocampus-dependent) short-term memory was inhibited in the cross-maze and non-spatial short-term object retention was also impaired. In contrast to these systemic effects, bilateral injections of SCH23390 into the prelimbic cortices altered neither spatial nor object exploration, but did inhibit short-term memory in both cross-maze and object recognition task. Therefore, the inhibiting effects of SCH23390 on both spatial and non-spatial memory were not mediated indirectly via reduced exploration of stimuli to be remembered, but through antagonism of a prelimbic D1-R function that is directly involved in memory formation. Finally, a cooperative regulation of spatial exploration between D1-R and mGlu5 was indicated by a synergistic effect of the antagonists SCH23390 and MPEP.

This study provides an examination of spatial learning and a behavioral assessment of irritability and locomotion in TgCRND8 mice, an amyloid precursor protein transgenic model of Alzheimer's disease. Performance was assessed using the Barnes maze, the touch escape test, and an open-field test. While past research focused primarily on 2-5-month-old TgCRND8 mice, the present study used an older age cohort (9-month-old female mice), in addition to a 4-month-old cohort of both transgenic (Tg) and wildtype female mice. Both younger and older Tg mice displayed poor spatial learning in the Barnes maze task compared to their wildtype littermates, as demonstrated by significantly longer latencies and more errors both during acquisition and at a 2-week retest. No differences in irritability were found between Tg and control mice in the younger cohort; however, older Tg mice displayed significantly higher irritability compared with wildtype littermates, as measured by the touch escape test. Additionally, Tg mice of both age cohorts showed increased locomotion and slowed habituation during a 60-min open-field test over 3 days of testing. These results demonstrate that TgCRND8 mice show significant deficits in spatial and nonspatial behavioral tasks at advanced stages of amyloid pathology.

Exposure to endocrine disrupting compounds (EDCs), such as bisphenol A (BPA), may cause adverse health effects in wildlife and humans, but controversy remains as to what traits are most sensitive to EDCs and might serve as barometers of exposure. Expression of sexually selected traits that have evolved through intrasexual competition for mates and intersexual choice of mating partner are more dependent on developmental and physical condition of an animal than naturally selected traits and thus might be particularly vulnerable to disruption by developmental exposure to EDCs. We have used the deer mouse ( Peromyscus maniculatus ) as a model to test this hypothesis. Adult male–male competition for mates in this species is supported by enhanced spatial navigational and exploratory abilities, which enable males to search for prospective, widely dispersed females. Male deer mice exposed to BPA or ethinyl estradiol (EE) through maternal diet showed no changes in external phenotype, sensory development, or adult circulating concentrations of testosterone and corticosterone, but spatial learning abilities and exploratory behaviors were severely compromised compared with control males. Because these traits are not sexually selected in females, BPA exposure predictably had no effect, although EE-exposed females demonstrated enhanced spatial navigational abilities. Both BPA-exposed and control females preferred control males to BPA-exposed males. Our demonstration that developmental exposure to BPA compromises cognitive abilities and behaviors essential for males to reproduce successfully has broad implications for other species, including our own. Thus, sexually selected traits might provide useful biomarkers to assess risk of environmental contamination in animal and human populations.

Metabotropic glutamate receptor 5 (mGlu5) has been implicated in a variety of learning processes and is important for inhibitory avoidance and conditioned taste aversion learning. MGlu5 receptors are physically connected with NMDA receptors and they interact with, and modulate, the function of one another in several brain regions. The present studies used systemic co-administration of an mGlu5 receptor positive allosteric modulator, 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and an NMDA receptor antagonist dizocilpine maleate (MK-801) to characterize the interactions of these receptors in two aversive learning tasks. Male Sprague–Dawley rats were trained in a single-trial step-down inhibitory avoidance or conditioned taste aversion task. CDPPB (3 or 10 mg/kg, s.c.), delivered by itself prior to the conditioning trial, did not have any effect on performance in either task 48 h after training. However, CDPPB (at 3 mg/kg) attenuated the MK-801 (0.2 mg/kg, i.p.) induced learning deficit in both tasks. CDPPB also reduced MK-801-induced hyperactivity. These results underlie the importance of mGlu5 and NMDA receptor interactions in modulating memory processing, and are consistent with findings showing the efficacy of positive allosteric modulators of mGlu5 receptors in reversing the negative effects of NMDA receptor antagonists on other behaviors such as stereotypy, sensorimotor gating, or working, spatial and recognition memory.

The role of the metabotropic glutamate receptor 5 (mGlu(5) receptor) in learning and memory and other behaviors are reviewed by examining the influence of selective antagonists and genetic knockout on performance. This receptor is involved in spatial learning, contextual fear conditioning, inhibitory avoidance, fear potentiated startle, and conditioned taste aversion. However, mGlu(5) receptor antagonists have proven to be ineffective in other learning tasks, such as the delayed-match-to-position test and a three-hole spatial learning task. Locomotion is often decreased by mGlu(5) receptor antagonists; and other behaviors such as social interaction and consummatory responses can also be affected. In mGlu(5) receptor knockout mice, performance in contextual fear conditioning and spatial water maze tasks is impaired. Although the available evidence is suggestive of an important contribution of mGlu(5) receptors to cognitive functions, further studies are needed, particularly those with in vivo evaluation of the role of mGlu(5) receptors in selective brain regions in different stages of memory formation.

This experiment investigated whether subjects' selection and use of strategies in detecting a target letter in a flanker task requires intention. Subjects' expectancies for compatible and incompatible trials (trials on which the response to the flanker stimulus was consistent or inconsistent with the target response) were manipulated by presenting cues that signaled the occurrence of these types of trials. Three groups of subjects received explicit, partially explicit, or implicit instructions about the meaning of the cues. By the end of the experiment, all the groups were able to select and use strategies based on the cues to improve their performance. However, this strategy selection developed slowly with practice in the latter two groups, whereas it was present from the outset in the first group. In addition, forced choice tests performed after the experiment showed that the subjects in the implicit condition could not intentionally indicate which stimuli were most likely to follow a given cue. Thus, the data suggest that the selection of strategies occurred outside the subjects' awareness, and without their intention.

In conditioned taste aversion (CTA), animals learn to avoid a flavored solution (conditioned stimulus, CS) previously paired with internal malaise (unconditioned stimulus, US). Metabotropic glutamate receptor 5 (mGlu5) has been implicated in learning and memory processes and is necessary for CTA. In the present study, local microinjections of a mGlu5-selective antagonist, 3-[2-methyl-1,3-thiazol-4yl)ethynyl]pyridine (MTEP, 0, 1 or 5 μg) into the insular cortex and basolateral amygdala were used in male, Sprague-Dawley rats to examine the role of mGlu5 receptors in the encoding of taste memory. MTEP was infused 20 min before saccharin intake during CTA conditioning. MTEP injection into the basolateral amygdala resulted in robust CTA, similar to the vehicle-treated animals but slowed extinction; that is, MTEP enhanced CTA. MTEP injection into the insular cortex resulted in an increased saccharin intake on the conditioning trial, which potentially influenced the performance on the test trials; MTEP had no effect on CTA learning when controlled access to saccharin was used on the conditioning trial. These results indicate that mGlu5 receptors are involved in taste memories in a region-specific manner.

We explored the adage that “at the end of life nobody wishes they’d made more money”, by inducing a limited-time perspective (LTP) in some participants. In Study 1, participants in the LTP condition who were high in extrinsic value orientation (EVO) became less greedy in a raffle-ticket-taking task, making them as generous as intrinsic participants. Study 2 replicated this effect and demonstrated the effect was robust to alternative explanations. Study 3 examined value reports directly, finding that LTP participants evidenced reduced EVO and were less proself in a decomposed prisoner’s dilemma. Results are considered via an integration of multiple lines of research including humanistic, life-span, social-cognitive, and existential perspectives, with the conclusion that a LTP can facilitate in certain individuals a reassessment and realignment of their value systems and behaviors.

Modafinil is a mild psychostimulant used for the treatment of sleep and arousal-related disorders, and has been considered a pharmacotherapy for cocaine and amphetamine dependence; however, modafinil's mechanism of action is largely unclear. The present study investigated modafinil using drug discrimination and slice superfusion techniques. Rats were trained to discriminate cocaine (1.6 or 5 mg/kg) or amphetamine (0.3 mg/kg) from saline injection for food reinforcement. Modafinil (64-128 mg/kg) substituted partially for both cocaine doses and amphetamine. Pretreatment with a lower modafinil dose (32 mg/kg) augmented the discriminative stimulus properties of cocaine (1.6 mg/kg dose group) and amphetamine. In neurochemical experiments, modafinil (100-300 microM) evoked [(3)H]overflow from rat striatal slices preloaded with [(3)H]dopamine in a concentration-dependent manner; however, modafinil was less potent and efficacious than amphetamine and nicotine. The dopamine transporter inhibitor nomifensine (10 microM) blocked modafinil-evoked [(3)H]overflow, and concentrations of modafinil (100 microM) that did not have intrinsic activity attenuated amphetamine (1 and 3 microM)-evoked [(3)H]overflow. Modafinil-evoked [(3)H]overflow was not altered by the nicotinic acetylcholine receptor antagonist mecamylamine, and modafinil did not alter nicotine-evoked [(3)H]overflow, indicating that nicotinic acetylcholine receptors likely are not important for modafinil's mechanism of action. The present results indicate that modafinil evokes dopamine release from striatal neurons and is a psychostimulant that is pharmacologically similar to, but much less potent and efficacious than, amphetamine.

Two conditioned taste aversion experiments with rats were conducted to establish if a target taste that had received a prior pairing with illness could be subject to second-order conditioning during extinction treatment in compound with a flavor that also received prior conditioning. In these experiments, the occurrence of second-order conditioning was indicated by protection from extinction of the aversion elicited by the target taste. This possibility, although intuitive, deserves attention because current associative models [e.g., Rescorla, R. A., & Wagner, A. R. (1972). A theory of Pavlovian conditioning: variations in the effectiveness of reinforcement and nonreinforcement. In A. H. Black & W. F. Prokasy (Eds.), Classical conditioning II: Current research and theory (pp. 64–99). New York: Appleton-Century-Crofts.] predict exactly the opposite outcome, namely, that compound extinction of two CSs should result in enhanced extinction.

Schlenker's triangle model (Schlenker, Britt, Pennington, Murphy, & Doherty, 1994, Schlenker, Pontari, & Christopher, 2001) identifies three excuses people use to avoid taking responsibility after failure: that one had no control in the situation, that the obligation was unclear, and that it was not really one's obligation. Three retrospective studies tested the presumed negative association between excuse making and responsibility taking. The studies also examined the effects of self-determination theory's concept of motivational internalization (Deci & Ryan, 2000) upon these variables. A complex but replicable pattern emerged, such that responsibility taking and motivational internalization correlated with adaptive outcomes such as future commitment and positive expectancy and excuse making did not. Of particular interest, perceiving that the person levying the obligation internalized motivation predicted responsibility taking, in all three studies. Implications for the triangle model, as well as for theories of maturity and personality development, are considered.

Learning impairment is a common feature of the neuronal ceroid lipofuscinoses (NCL), a family of lysosomal storage disorders associated with progressive neurodegeneration. Murine models for the neuronal ceroid lipofuscinoses include the well-characterized motor neuron degeneration ( mnd / mnd ) model for one variant of late infantile NCL (CLN8), and the more recently generated models for the infantile (CLN1) and juvenile (CLN3) forms of NCL. To determine whether these mouse models exhibit behavioral deficits analogous to the learning impairment characteristic of the human disorders, the performance of these animals on an associative learning task was assessed. The abilities of affected and normal control mice to associate a light stimulus with a food reward were evaluated in 14–16-week-old animals using a T-maze. Normal mice were able to reach a criterion for having learned to make the association within a mean of 9.4 trials. The CLN8 and CLN3 mice, on the other hand, required means of 26.2 and 27.5 trials, respectively, to reach the same performance criterion ( p

Metabotropic glutamate receptors (mGluRs) have been implicated in several types of cognitive and associative learning. Although recent evidence indicates an influence of mGluRs in conditioned taste aversion (CTA), the subtype-specific involvement of mGluRs in this learning paradigm remained to be determined. The aim of this study was to examine the role of Group I mGluR subtypes in CTA using a selective mGluR5 antagonist (2-methyl-6-(phenylethynyl)-pyridine, MPEP) and a selective mGluR1 antagonist (1-aminoindan-1,5-dicarboxylic acid, AIDA). Male, water-deprived, Sprague–Dawley rats were injected i.p. with 6 or 12 mg/kg MPEP or saline. Twenty-five minutes later, all rats received 15-min access to a 0.1% saccharin solution (Sac) immediately followed by an injection of 0.15 M LiCl at 1.33% body weight. The animals were tested with 15-min access to Sac on each of four test days. MPEP-treated animals consumed more Sac on the test trials than saline-treated rats. In another experiment, controlled access to Sac was used by infusing the solution on the conditioning trial. Consistent with the above results, MPEP attenuated the degree of CTA. Similar experiments using the mGluR1 antagonist AIDA, have found no effect on CTA learning. These results suggest that the two subtypes of Group I mGluRs are differentially involved in taste aversion learning.

Alzheimer's disease (AD) is a progressive, age-dependent neurodegenerative disorder affecting specific brain regions that control memory and cognitive functions. Epidemiological studies suggest that exercise and dietary antioxidants are beneficial in reducing AD risk. To date, botanical flavonoids are consistently associated with the prevention of age-related diseases. The present study investigated the effects of 4 months of wheel-running exercise, initiated at 2-months of age, in conjunction with the effects of the green tea catechin (-)-epigallocatechin-3-gallate (EGCG) administered orally in the drinking water (50 mg/kg daily) on: (1) behavioral measures: learning and memory performance in the Barnes maze, nest building, open-field, anxiety in the light-dark box; and (2) soluble amyloid-β (Aβ) levels in the cortex and hippocampus in TgCRND8 (Tg) mice. Untreated Tg mice showed hyperactivity, relatively poor nest building behaviors, and deficits in spatial learning in the Barnes maze. Both EGCG and voluntary exercise, separately and in combination, were able to attenuate nest building and Barnes maze performance deficits. Additionally, these interventions lowered soluble Aβ1-42 levels in the cortex and hippocampus. These results, together with epidemiological and clinical studies in humans, suggest that dietary polyphenols and exercise may have beneficial effects on brain health and slow the progression of AD.

Rats in a flavor aversion procedure were used to examine the extent to which an extinguished CS can pass a retardation and summation test for conditioned inhibition after either a short or a long retention interval. Rats were given a single pairing of a flavored solution with LiCl, and then received a large number of CS-alone extinction trials. Following extinction, some subjects received a 3-week retention interval following extinction while others did not. Extinction produced evidence of conditioned inhibition on both tests when a short retention interval occurred following extinction. However, conditioned inhibition was attenuated by the long retention interval when assessed with a retardation test, but no effect of the long retention interval was observed when inhibition was evaluated with a summation test.

In two experiments, water-deprived rats were given a single pairing of a sucrose solution with LiCl in one context (Context 1). Some subjects then received three nonreinforced exposures to sucrose, that is, extinction, in Context 1. Other subjects received these three sucrose extinction trials in a different context (e.g., Context 2). A third group of subjects was included that received one extinction trial in each of three different contexts (Contexts 2, 3, and 4). Following this treatment, the rats were returned to Context 1 and were tested for their aversion to sucrose. Subjects given extinction trials only in one context other than the conditioning context (e.g., Context 2) yielded a greater aversion sucrose at test than subjects given extinction in Context 1, that is, a renewal effect occurred. Moreover, the groups given extinction in three different contexts exhibited attenuated renewal relative to subjects that received extinction trials only in Context 2. The discussion focuses on the possible mechanism underlying the renewal effect.

Rats were used to examine the effects of inescapable swim stress on latent inhibition using a conditioned taste aversion procedure. Subjects were subjected to inescapable swim after each of three saccharin taste preexposures and saccharin was later paired with LiCl. The ability of swim to influence latent inhibition was assessed on subsequent saccharin test trials. Swim stress significantly attenuated latent inhibition. The implications of these results regarding the effects of swim stress on conditioned taste aversion are discussed.

Research in our laboratory required a sensitive, reliable, inexpensive touch detector for use with rats to test the reinforcement of inhibition (e.g., Anger, 1983). A small touch detector was also desirable so that the detector could be mounted on the rat's cage close to the object being touched by the rat, whose touches in turn were being detected by current passing through the animal, thereby reducing the influence of other signals. The commercial units available required 50 MΩ or less to trigger them. Such sensitivity often would not detect a rat touching a metal object with its paws. Moreover, commercial products such as Coulbourn's Contact Circuit (Product #H24-05) and Columbus's Lick Counter (DM-8) cost $195 and $182.50, respectively, per unit. A detector was desired that would detect several hundred MΩ, and directly operate a multipole relay. Earlier attempts to develop such a detector used seven transistors, but those units became unreliable due to transistor failure. It seemed desirable to minimize the number of components. Operational amplifier chips are extremely sensitive, but produce low outputs. The Darlington amplifier chip has tremendous amplifying power. The combination of just those two chips was ideal for this problem (see Figure 1). The common operational amplifier LM741 (LM741CN, Newark InOne, Catalog #07B6949) feeding into a Darlington TIP120 (Radio Shack, Catalog #276-2068) could operate a 200-Ω mercury-wetted 6-pole relay. The transistors and other components were soldered on small circuit boards, some as small as 5.7 cm by 4.4 cm, and then covered with silicon embedding material to protect them from moisture, dust, and materials from the rat (see Figure 2). A small hole covered with thin transparent plastic can be made in the embedding material above the 741 operational amplifier so that the chip (which was in a socket) could be changed. Alternatively, the circuit could be housed in a casing rather than being embedded in silicon. The unit operated on the usual 24 volts DC. A 200-Ω relay is sketched in the diagram in Figure 1, but a variety of relays could be used. Fig 1 Circuit diagram of touch detector. Fig 2 Two touch detectors. The sensitivity of different units varied widely. This was largely due to variation in the 741 operational amplifiers. The 741s were purchased from Radio Shack. Twenty- five of the 741s were purchased and tested in one detector unit. The measure of sensitivity was the highest MΩ at which the relay stayed operational 100% of the time. The sensitivity with the 25 chips varied from 150 to 730 MΩ. Chips were packaged in clear bubble wrap attached to a card. The card listed the names of several countries of possible origin. Many chips were labeled with three letters such as “CHN”, “MAL”, etc. These abbreviations referred to country of origin. Currently, the chips have the entire country name on the chip and/or card. The sensitivity was highly correlated with these symbols. Those marked CHN ranged from 540 to 730 MΩ; those marked MAL ranged from 400 to 640 MΩ. Most of the other chips ranged from 150 to 280 MΩ. For some purposes maximum sensitivity was desirable, but for other applications less sensitivity was preferable. Variability in the chips requires fine tuning by changing resistance values to improve or ensure operation. The detector has capacitance limitations just like any detector, but merely needs adjustment in the amount of resistance to suit one's particular needs for detection purposes. The circuit must be electrically isolated. If a battery is used for the power supply then the circuit will be isolated. If a source of direct current is used by a transformer, then an isolating transformer should be used and the -24 V should be at zero volts rather than “building ground”. The manipulandum must also be electrically isolated. An experienced electronic engineer today probably could design a much better detector than this amateur design, but to our knowledge that has not occurred. A circuit such as this one is very universal and is a basic building block of electronic amplification. It can be used to detect touch, licking, photocell detection, and other contact-related measures in rats as well as humans and other animals. Of course, sensitivity depends on many factors including the amount of moisture and how much animal tissue makes contact with the manipulandum. Six of these units operated for several years without failure. The estimated cost per unit is $7.50.

Long-term effects of learned associations between an image and a taste have not been studied with electromagnetic brain scanning techniques. The possibility that taste conditioning may change sensory image processing was investigated in young adult subjects. EEG-responses evoked by images were recorded before and after a training session using an image as conditioned stimulus and a pleasant taste as unconditioned stimulus. The results showed that in posterior electrodes placed over visual cortex areas, the following changes occurred after conditioning: (1) the amplitude and duration of the N2-P3 waves in the visual evoked potentials were enhanced; (2) the N2 and P3 peak delays were shortened; (3) power induced by image presentation was enhanced in the delta and theta frequency bands; (4) cross-hemispheric delta and theta coherences among the posterior electrodes were enhanced; (5) calculations of the underlying whole brain distribution of currents using swLORETA showed elevated current densities in posterior voxels. None of the above changes occurred in a sham-trained control group. In electrodes placed over the prefrontal cortex, delta and theta power also rose significantly. It is suggested that the appetitive taste conditioning potentiated synaptic activity in visual cortex networks and that this led to an increased speed of image processing.

Two experiments examined the influence of postconditioning treatments of contextual cues on instrumental responding acquired with a signaled delay of reinforcement schedule. In Experiment 1, mere exposure to the conditioning context after instrumental training resulted in an attenuated response rate during an extinction test. In the second experiment, responding was decreased by exposure to the contextual cues or sessions in which signaled noncontingent reinforcements occurred. The greatest response decrement, however, occurred following unsignaled noncontingent food presentations. The results are discussed with respect to the different roles of contextual cues on operant responding.