Presenilin 1 transgene addition to amyloid precursor protein overexpressing transgenic rats increases amyloid beta 42 levels and results in loss of memory retention.

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 (Aß)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 Aß42. 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.

Disruption of adult expression of sexually selected traits by developmental exposure to bisphenol A.

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.

Voluntary wheel running access produces opposite effects in male and female rats on both palatable diet consumption and associated ventral striatal opioid- and dopamine-related gene expression.

The relationship between physical activity levels and feeding behaviors has been a focus of preclinical research for decades, yet this interaction has only recently been explored for potential sex differences. The aim of the present study was to isolate sex-dependent effects of voluntary wheel running (RUN) vs. sedentary locked wheel (SED) home cage conditions on palatability-driven feeding behavior using a 2-diet choice task between standard chow and a high-fat diet. The sex-dependent effects of physical activity on feeding behavior were examined following a within-subject novel reversal design of physical activity conditions (i.e., RUN > SED > RUN), to assess temporal sensitivity of the interaction. Following the final 2 weeks of reestablished and sustained RUN vs. SED conditions in separate groups of both males and females, reward-related opioid and dopamine gene expression within the nucleus accumbens (Acb) brain region were analyzed. Results demonstrated that the initial RUN > SED transition led to sex-dependent effects of SED condition, as males increased, and females decreased their high fat consumption, compared to their respective high fat consumption during previous RUN condition phase. Following reintroduction to the RUN condition, males decreased, and females increased their high fat consumption, compared to their separate SED control group. Last, sex-dependent shifts in ventral striatal opioid- and dopamine-related gene expression were observed to parallel the behavioral effects. The major findings of the study reveal that SED and RUN home cage conditions shift palatability-driven feeding in the opposite direction for males and females, these effects are sensitive to reversal, and these sex-dependent feeding behaviors track sex-dependent changes to critical reward-related gene expression patterns in the Acb. Considering the present high rates of sedentary behavior and obesity, furthering our understanding of the interaction between physical activity (or lack thereof) and feeding behavior should be a priority, especially in the context of these divergent sex-dependent outcomes.

Enhanced conditioned "liking" of novel visual cues paired with alcohol or non-alcohol beverage container images among individuals at higher risk for alcohol use disorder.

RATIONALE/OBJECTIVE: This study used an evaluative conditioning (EC) procedure to assess the affective properties of a CS for ingested drug reward in humans. Specifically, the study tested whether the evaluative response ("liking"/"disliking") to an arbitrary visual stimulus ("CS2," e.g., a purple hexagon) could be changed through pairings with an alcohol or non-alcohol beverage cue ("CS1," e.g., a full wine glass, a juice box), which is ostensibly a conditioned visual predictive stimulus for alcohol or non-alcohol liquid reward, respectively. METHODS: Participants (N = 369, 18-23 years, 66% female, 79% white, 21% reporting no alcohol use ever or in the past year) received 24 CS1 pairings with each CS2. CS2 and CS1 evaluations were assessed pre- and post-conditioning. RESULTS: Alcohol and non-alcohol CS2 "liking" correlated with alcohol use. "Liking" of the alcohol but not non-alcohol CS1 also correlated with alcohol use. Alcohol CS1 "liking" also correlated with alcohol and non-alcohol CS2 'liking," whereas non-alcohol CS1 'liking" correlated with non-alcohol but not alcohol CS2 "liking." CONCLUSIONS: Taken together, findings support the idea that drug-related visual stimuli acquire appetitive (hedonic and/or incentive) properties as a function of individual differences in drug use, which entail individual differences in exposure to the conditioning effects of addictive substances like alcohol. Findings also suggest a link between drug use and the propensity to attribute affective/motivational significance to reward-predictive cues in general.

Strategic behavior without awareness? Effects of implicit learning in the Eriksen flanker paradigm.

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.

Ovariectomy Influences Cognition and Markers of Alzheimer's Disease.

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-ß (Aß) deposition, levels of mRNAs involved in Aß 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 Aß42 and very low levels of Aß40 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 Aß42 than Aß40 at 17 months. Furthermore, levels of formic acid soluble Aß42 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 Aß degradation and AßPP cleavage (Neprilysin, Ide, Adam9, and Psenen) were found to be highly correlated with each other as well as hippocampal Aß deposition. Taken together, these results indicate that both ovariectomy and genotype influence AD markers in a complex manner.

Resistance-exercise training ameliorates LPS-induced cognitive impairment concurrent with molecular signaling changes in the rat dentate gyrus.

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-1ß (~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-3ß 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-3ß 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.

MGlu5 antagonism impairs exploration and memory of spatial and non-spatial stimuli in rats.

Metabotropic glutamate receptor subtype 5 (mGlu5) has been implicated in memory processing in some but not all learning tasks. The reason why this receptor is involved in some tasks but not in others remains to be determined. The present experiments using rats examined effects of the mGlu5-antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP)--applied systemically i.p. (1-10mg/kg) or bilaterally into the prelimbic cortex (1-10 microg)---on the ability of rats to explore and remember new stimuli. A cross-maze, open field, and object recognition task were used to evaluate exploration and memory and it was found that: (1) locomotion during exploration of spatial environments and exploration time at novel objects were reduced by i.p. but not by prelimbic administration of MPEP, (2) spatial short-term memory was impaired in cross-maze and object discrimination was reduced after both types of administration, (3) long-term retention of spatial conditioning in the cross-maze was inhibited after i.p. applications which (4) also inhibited spontaneous alternation performance during maze-exploration. Reduced exploratory locomotion and exploration time after i.p. injections may have contributed to the observed retention impairments. However, the fact that prelimbic administration of MPEP inhibited retention without reducing exploration shows that memory formation was also impacted directly by prelimbic mGlu5 in both spatial and non-spatial learning.

NMDA receptor blockade augmented nicotine-evoked dopamine release from rat prefrontal cortex slices.

Nicotine evokes dopamine release through activation of nicotinic acetylcholine receptors, and tobacco cigarette smoking is more prevalent among individuals diagnosed with schizophrenia. Blockade of ionotropic glutamate (NMDA) receptors can induce changes in central dopamine and glutamate circuits, which models the symptoms of schizophrenia. The effect of the NMDA receptor antagonist, ketamine, on the effect of nicotine in rat prefrontal cortex was examined using a slice superfusion assay in which cortical slices were preloaded with [(3)H] dopamine. A wide range of ketamine concentrations (0.1-300 microM) did not evoke [(3)H] overflow from slices, indicating that NMDA receptor blockade did not induce dopamine release. Ketamine, at concentrations that model the symptoms of schizophrenia (1-10 microM), augmented the effect of nicotine (1-100 microM) to evoke [(3)H] overflow from slices and decreased the threshold nicotine concentration to evoke [(3)H] overflow. This indicates that NMDA receptor blockade increased the potency and efficacy of nicotine to evoke dopamine release from prefrontal cortex slices, suggesting that ketamine induced hypersensitivity to nicotine. The present results support a role for nicotinic acetylcholine receptors in the pathophysiology and treatment of schizophrenia.

Effects of swim stress on latent inhibition using a conditioned taste aversion procedure.

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.

Ketamine induces hyperactivity in rats and hypersensitivity to nicotine in rat striatal slices.

The symptoms of schizophrenia can be modeled in rats through blockade of ionotropic glutamate receptors, which induces changes in central dopamine circuits. These circuits also contain nicotinic acetylcholine receptors that are activated by nicotine. A role for nicotine in the etiology of schizophrenia is supported by clinical observations of high tobacco use rates in individuals experiencing the psychopathology. The present study investigated the effect of the ionotropic glutamate receptor antagonist ketamine on the function of striatal nicotinic acetylcholine receptors to understand better the potential role of these receptors in schizophrenia. Ketamine (0.1-300 microM) was ineffective to evoke [3H] overflow from rat striatal slices preloaded with [3H]dopamine. Application of psychotomimetic ketamine concentrations (1-10 microM) to striatal slices augmented nicotine-evoked [3H] overflow. Finally, rats received ketamine (30-50 mg/kg) injections for 30 days, to model the development of the disorder, and hyperactivity was observed, although repeated ketamine treatment did not significantly alter nicotine-evoked [3H]dopamine overflow. These data indicate that the function of nicotinic acetylcholine receptors that mediate dopamine release are altered by ketamine, and support a role for nicotinic acetylcholine receptors in schizophrenia pathology.

Effects of extinction of a nontarget CS on performance to a target CS.

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.

Tone series and the nature of working memory capacity development.

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

Memory deficiency, cerebral amyloid angiopathy, and amyloid-ß plaques in APP+PS1 double transgenic rat model of Alzheimer's disease.

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-ß (Aß) showed extensive and mostly diffuse Aß 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 Aß deposits in cortical and leptomeningeal blood vessel walls and venous collagenosis. In addition to the Aß 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.

Modafinil evokes striatal [(3)H]dopamine release and alters the subjective properties of stimulants.

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.

Loss of Female Sex Hormones Exacerbates Cerebrovascular and Cognitive Dysfunction in Aortic Banded Miniswine Through a Neuropeptide Y-Ca2+-Activated Potassium Channel-Nitric Oxide Mediated Mechanism.

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<0.05), with significant impairments in the AB-OVX group (P<0.05). Resting carotid artery ß stiffness and vascular resistance during central hypovolemia were increased in the AB-OVX group (P<0.05), and blood flow recovery after central hypovolemia was reduced in both OVX groups (P<0.05). Isolated pial artery (pressure myography) vasoconstriction to neuropeptide Y was greatest in the AB-OVX group (P<0.05), and vasodilation to the Ca2+-activated potassium channel α-subunit agonist NS-1619 was impaired in both AB groups (P<0.05). The ratio of phosphorylated endothelial nitric oxide synthase:total endothelial nitric oxide synthase was depressed and Ca2+-activated potassium channel α-subunit protein was increased in AB groups (P<0.05). 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 Ca2+-activated potassium channel function and impaired nitric oxide signaling, the effects of which are exacerbated in the absence of female sex hormones.

Long-Term Visuo-Gustatory Appetitive and Aversive Conditioning Potentiate Human Visual Evoked Potentials.

Human recognition of foods and beverages are often based on visual cues associated with flavors. The dynamics of neurophysiological plasticity related to acquisition of such long-term associations has only recently become the target of investigation. In the present work, the effects of appetitive and aversive visuo-gustatory conditioning were studied with high density EEG-recordings focusing on late components in the visual evoked potentials (VEPs), specifically the N2-P3 waves. Unfamiliar images were paired with either a pleasant or an unpleasant juice and VEPs evoked by the images were compared before and 1 day after the pairings. In electrodes located over posterior visual cortex areas, the following changes were observed after conditioning: the amplitude from the N2-peak to the P3-peak increased and the N2 peak delay was reduced. The percentage increase of N2-to-P3 amplitudes was asymmetrically distributed over the posterior hemispheres despite the fact that the images were bilaterally symmetrical across the two visual hemifields. The percentage increases of N2-to-P3 amplitudes in each experimental subject correlated with the subject's evaluation of positive or negative hedonic valences of the two juices. The results from 118 scalp electrodes gave surface maps of theta power distributions showing increased power over posterior visual areas after the pairings. Source current distributions calculated from swLORETA revealed that visual evoked currents rose as a result of conditioning in five cortical regions-from primary visual areas and into the inferior temporal gyrus (ITG). These learning-induced changes were seen after both appetitive and aversive training while a sham trained control group showed no changes. It is concluded that long-term visuo-gustatory conditioning potentiated the N2-P3 complex, and it is suggested that the changes are regulated by the perceived hedonic valence of the US.

A chronic physical activity treatment in obese rats normalizes the contributions of ET-1 and NO to insulin-mediated posterior cerebral artery vasodilation.

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.

Effects of an extinguished CS on competition with another CS.

Three experiments were conducted using a conditioned taste aversion procedure with rats to examine the effect of nonreinforced presentations of a conditioned stimulus (CS) on its ability to compete with a target stimulus for manifest conditioned responding. Two CSs (A and B) were presented in a serial compound and then paired with the unconditioned stimulus. CS A was first paired with the US and then presented without the US (i.e., extinction) prior to reinforced presentation of the AB compound. Experiment 1 showed that A was poor at competing with B for conditioned responding when given conditioning and extinction prior to reinforcement of AB relative to a group that received both A and B for the first time during compound conditioning. That is, an extinguished A stimulus allowed greater manifest acquisition to B. Experiment 2 found that extinction treatment produced a poor CR to the pretrained and extinguished CS itself following compound conditioning. Experiment 3 found that interposing a retention interval after extinction of A and prior to compound conditioning enhanced A's ability to compete with B. The results of these experiments are discussed with regard to different theories of extinction and associative competition.

Electrophysiological CNS-processes related to associative learning in humans.

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.