Inhibitory control in BALB/c mice sub-strains during extinction learning.

Dysregulation of executive function (EF) involves alterations in cognitive flexibility / control and is underscored by learning impairments in neurodevelopmental disorders. Here, we examine cognitive inflexibility in BALB/cJ mice (a mouse model showing diminished sociability, increased anxiety and inattentive behaviour) and closely related "reference" BALB/cByJ mice. We used an appetitive extinction paradigm to investigate if cognitive flexibility measures are different between learning acquisition and extinction. The two BALB/c sub-strains learned to respond to a stimulus in a touchscreen operant chamber, after which the reward was removed and responses should be inhibited. Both mice sub-strains showed a different rate of learning while acquiring the task, in which the BALB/cJ mice were faster learners compared to the BALB/cByJ mice. This was not observed during the extinction phase, in which the BALB/cJ mice were able to extinguish responding to unrewarded stimuli equally. Within the BALB/cJ sub-strain, variation in the ability to inhibit a learnt response was observed when comparing them to similar grouped BALB/cByJ mice: BALB/cJ animals that reached the criterion were more reward driven, while BALB/cJ mice failing to reach the set criterion during extinction processing make more mistakes. Additionally, the changes observed during acquisition, were driven by animals not reaching the extinction criterion. Our results suggest that the BALB/c mice sub-strains may use different strategies to learn during appetitive extinction. This may be useful in the phenotypic dissection of cognitive flexibility in BALB/c sub-strains and their mapping on genetic variance revealed by next-generation sequencing in future studies.

Facilitation of spatial working memory performance following intra-prefrontal cortical administration of the adrenergic alpha1 agonist phenylephrine.

RATIONALE: Spatial working memory is dependent on the appropriate functioning of the prefrontal cortex (PFC). PFC activity can be modulated by noradrenaline (NA) released by afferent projections from the locus coeruleus. The coreuleo-cortical NA system could therefore be a target for cognitive enhancers of spatial working memory. Of the three classes of NA receptor potentially involved, the α2 and α1 classes seem most significant, though agents targeting these receptors have yielded mixed results. This may be partially due to the use of behavioural assays that do not translate effectively from the laboratory to the clinical setting. Use of a paradigm with improved translational potential may be essential to resolve these discrepancies. OBJECTIVES: The objective of this study was to assess the effects of PFC-infused α2 and α1 adrenergic receptor agonists on spatial working memory performance in the touchscreen continuous trial-unique non-matching to location (cTUNL) task in rats. METHODS: Young male rats were trained in the cTUNL paradigm. Cannulation of the mPFC allowed direct administration of GABA agonists for task validation, and phenylephrine and guanfacine to determine the effects of adrenergic agonists on task performance. RESULTS: Infusion of muscimol and baclofen resulted in a delay-dependent impairment. Administration of the α2 agonist guanfacine had no effect, whilst infusion of the α1 agonist phenylephrine significantly improved working memory performance. CONCLUSIONS: Spatial working memory as measured in the rat cTUNL task is dependent on the mPFC. Enhancement of noradrenergic signalling enhanced performance in this paradigm, suggesting a significant role for the α1 receptor in this facilitation.

A novel 2- and 3-choice touchscreen-based continuous trial-unique nonmatching-to-location task (cTUNL) sensitive to functional differences between dentate gyrus and CA3 subregions of the hippocampus.

RATIONALE: The touchscreen continuous trial-unique non-matching-to-location task (cTUNL) has been developed to optimise a battery of tasks under NEWMEDS (Novel Methods leading to New Medication in Depression and Schizophrenia, http://www.newmeds-europe.com ). It offers novel task features of both a practical and a theoretical nature compared to existing touchscreen tasks for spatial working memory. OBJECTIVES: The objective of this study was to determine whether the cTUNL task is sufficiently sensitive to differentiate between dentate gyrus (DG) and CA3 hippocampal subregion contributions to performance. METHODS: The effect of DG and CA3 dysfunction on memory for locations in the cTUNL task was tested. Rats were assessed on versions of the task-two-choice and three-choice-that differed in memory load. Performance was challenged using manipulations of delay and the spatial separation between target and sample locations. RESULTS: Dysfunction of the DG disrupts performance across both delay and spatial separations in two-choice cTUNL when the delay is variable and unpredictable. Increasing the working memory load (three stimuli) increases sensitivity to DG dysfunction, with deficits apparent at fixed, short delays. In contrast, CA3 dysfunction did not disrupt performance. CONCLUSION: Acquisition of cTUNL was rapid, and the task was sensitive to manipulations of delays and separations. A three-choice version of the task was found to be viable. Finally, both the two- and three-choice versions of the task were able to differentiate between limited dysfunction to different areas within the hippocampus. DG dysfunction affected performance when using unpredictable task parameters. CA3 dysfunction did not result in impairment, even at the longest delays tested.

New translational assays for preclinical modelling of cognition in schizophrenia: the touchscreen testing method for mice and rats.

We describe a touchscreen method that satisfies a proposed 'wish-list' of desirables for a cognitive testing method for assessing rodent models of schizophrenia. A number of tests relevant to schizophrenia research are described which are currently being developed and validated using this method. These tests can be used to study reward learning, memory, perceptual discrimination, object-place associative learning, attention, impulsivity, compulsivity, extinction, simple Pavlovian conditioning, and other constructs. The tests can be deployed using a 'flexible battery' approach to establish a cognitive profile for a particular mouse or rat model. We have found these tests to be capable of detecting not just impairments in function, but enhancements as well, which is essential for testing putative cognitive therapies. New tests are being continuously developed, many of which may prove particularly valuable for schizophrenia research.

Early-life stress mediated modulation of adult neurogenesis and behavior.

Early life is a period of unique sensitivity during which experience can confer enduring effects on brain structure and function. During early perinatal life the quality of the surrounding environment and experiences, in particular the parent-child relationship, is associated with emotional and cognitive development later in life. For instance, adverse early-life experience is correlated with an increased vulnerability to develop psychopathologies and aging-related cognitive decline. These are thought to be mediated by acute and long-lasting effects on the, at that time still developing, stress-neuroendocrine and cognitive systems. Adult hippocampal neurogenesis is involved in learning and memory while both regulation of the stress response as well as early-life stress is known to permanently reduce neurogenesis, and to be implicated in these functional deficits. In order to increase our understanding of the influence of the perinatal environment on the long-lasting programming of neurogenesis, we here discuss immediate and lasting effects of various adverse early-life experiences on hippocampal neurogenesis and the associated behavioral alterations. Considering the persistence of these effects, the underlying molecular mechanisms, with focus on the potential epigenetic mechanisms will be discussed as well. Finally, special attention will be paid to the prominent sex differences in early-life stress-induced alterations in neurogenesis.

Reduction in hippocampal neurogenesis after social defeat is long-lasting and responsive to late antidepressant treatment.

Major depressive disorder is a chronic disabling disease, often triggered and exacerbated by stressors of a social nature. Hippocampal volume reductions have been reported in depressed patients. In support of the neurogenesis theory of depression, in several stress-based animal models of depression, adult hippocampal neurogenesis was reduced and subsequently rescued by parallel antidepressant treatment. Here, we investigated whether repeated social defeat and subsequent individual housing for 3 months induces long-lasting changes in adult hippocampal neurogenesis in rats, and whether these can be normalized by late antidepressant treatment, as would match human depression. Neurogenesis was analysed by stereological quantification of the number of immature doublecortin (DCX)-immunopositive cells, in particular young (class I) and more mature (class II) DCX(+) cells, to distinguish differential effects of stress or drug treatment on these subpopulations. Using this social defeat paradigm, the total DCX(+) cell number was significantly reduced. This was most profound for older (class II) DCX(+) cells with long apical dendrites, whereas younger, class I cells remained unaffected. Treatment with the broad-acting tricyclic antidepressant imipramine, only during the last 3 weeks of the 3-month period after social defeat, completely restored the reduction in neurogenesis by increasing both class I and II DCX(+) cell populations. We conclude that despite the lack of elevated corticosterone plasma levels, neurogenesis is affected in a lasting manner by a decline in a distinct neuronal population of more mature newborn cells. Thus, the neurogenic deficit induced by this social defeat paradigm is long-lasting, but can still be normalized by late imipramine treatment.

Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: Implications for depression and antidepressant action.

Adult hippocampal neurogenesis, a once unorthodox concept, has changed into one of the most rapidly growing fields in neuroscience. The present report results from the ECNP targeted expert meeting in 2007 during which cellular plasticity changes were addressed in the adult brain, focusing on neurogenesis and apoptosis in hippocampus and frontal cortex. We discuss recent studies investigating factors that regulate neurogenesis with special emphasis on effects of stress, sleep disruption, exercise and inflammation, a group of seemingly unrelated factors that share at least two unifying properties, namely that they all regulate adult hippocampal neurogenesis and have all been implicated in the pathophysiology of mood disorders. We conclude that although neurogenesis has been implicated in cognitive function and is stimulated by antidepressant drugs, its functional impact and contribution to the etiology of depression remains unclear. A lasting reduction in neurogenesis following severe or chronic stress exposure, either in adult or early life, may represent impaired hippocampal plasticity and can contribute to the cognitive symptoms of depression, but is, by itself, unlikely to produce the full mood disorder. Normalization of reductions in neurogenesis appears at least partly, implicated in antidepressant action.

Effects of divided attention on the production of filled pauses and repetitions.

The purpose of the present study was to examine effects of divided attention on the production of filled pauses and repetitions. Attention was divided by means of a dual-task paradigm. Eighteen nonstuttering adult subjects performed a picture story-telling task, with and without simultaneously performing a tactile-form recognition task. Results indicate that the number of filled pauses and repetitions increased in a situation of divided attention. This suggests that the production of filled pauses and repetitions, which are considered to be reactions to problems in speech planning, is governed by processes that operate relatively independently of the available attentional resources. It was speculated that these disfluencies could be automatic reactions to the increased planning difficulties induced by the concurrent task.

Trends in total and high density lipoprotein cholesterol and their determinants in The Netherlands between 1993 and 1997.

BACKGROUND: The aim of this study is to describe trends in plasma total and high density lipoprotein (HDL) cholesterol in The Netherlands between 1993 and 1997 and to examine whether these trends in cholesterol could be explained by changes in body mass index, smoking, alcohol intake, use of cholesterol lowering medication, intake of saturated fat, trans fatty acids and dietary cholesterol. METHODS: Each year a random sample of men and women aged 20-59 years living in three towns in The Netherlands was invited to participate in the study. In total more than 21 000 people were examined. RESULTS: Between 1993 and 1997 plasma total cholesterol decreased significantly by 0.19 mmol/l in men and by 0.27 mmol/l in women. During this period HDL cholesterol remained stable in both men and women. Small decreases were observed in the intake of saturated fat, trans fatty acids and dietary cholesterol in both men and women. The use of cholesterol lowering medication and for women oral contraceptives and prescribed oestrogens increased significantly. After adjustment for these determinants in multivariate analyses the trend in total cholesterol remained highly significant. CONCLUSIONS: Between 1993 and 1997 the mean total cholesterol level decreased significantly while the mean HDL cholesterol remained stable in both men and women in The Netherlands. The observed trend in total cholesterol could only for a small part be explained by changes in the determinants studied.

alpha-Linolenic acid intake is not beneficially associated with 10-y risk of coronary artery disease incidence: the Zutphen Elderly Study.

BACKGROUND: Data on the relation between alpha-linolenic acid intake and coronary artery disease (CAD) are limited. Other dietary components appear to modify the reported relation between alpha-linolenic acid intake and CAD. OBJECTIVE: We examined whether dietary alpha-linolenic acid intake was inversely associated with risk of CAD. DESIGN: We prospectively studied 667 men aged 64-84 y from the Zutphen Elderly Study who were free of CAD at baseline. Dietary intake was assessed by using a cross-check dietary history method. RESULTS: During the 10-y follow-up, we documented 98 cases of CAD. After adjustment for age, standard coronary risk factors, and intake of trans fatty acids and other nutrients, alpha-linolenic acid intake was not significantly associated with CAD risk. The relative risk of CAD for the highest compared with the lowest tertile of alpha-linolenic acid intake was 1.68 (95% CI: 0.86, 3.29). alpha-Linolenic acid intake from sources containing trans fatty acids was also nonsignificantly, yet positively, associated with CAD risk. alpha-Linolenic acid intake from foods that did not contain trans fatty acids was not associated with CAD risk, the relative risk of CAD for the highest compared with the lowest tertile was 1.15 (95% CI: 0.63, 2.11). CONCLUSION: We did not observe a beneficial effect of dietary alpha-linolenic acid intake on the risk of 10-y CAD incidence. Investigating this hypothesis was complicated by the association between intakes of alpha-linolenic acid and trans fatty acids. Given the results of current prospective studies, a protective cardiac effect of alpha-linolenic acid is questionable.

Effects of time pressure on mechanisms of speech production and self-monitoring.

The purpose of the present study was to examine effects of time pressure on mechanisms of speech production and self-monitoring. The most widely accepted monitoring theory (Levelt, 1989) suggests that monitoring proceeds through language perception, that is, speech error detection is primarily based on the parsing of one's own inner and overt speech. Twenty-four subjects described visual networks at two different rates (normal and fast). The time pressure manipulation affected a number of temporal characteristics: the error to cutoff and cutoff to repair times were shorter in the fast than in the normal condition. The results indicate that the monitor adjusts its speed of error detection and repair planning to the faster speech output rate. The time pressure manipulation did not affect the accuracy of error detection. The implications for the perception theory of monitoring are discussed.

Association between trans fatty acid intake and 10-year risk of coronary heart disease in the Zutphen Elderly Study: a prospective population-based study.

BACKGROUND: Evidence on the relation between trans fatty acid intake and coronary heart disease is limited. We investigated this relation in a Dutch population with a fairly high trans fatty acid intake, including trans fatty acids from partly hydrogenated fish oils. METHODS: We prospectively studied 667 men of the Zutphen Elderly Study aged 64-84 years and free of coronary heart disease at baseline. We used dietary surveys to establish the participants' food consumption patterns. Information on risk factors and diet was obtained in 1985, 1990, and 1995. After 10 years of follow-up from 1985-95, there were 98 cases of fatal or non-fatal coronary heart disease. FINDINGS: Between 1985 and 1995, average trans fatty acid intake decreased from 4.3% to 1.9% of energy. After adjustment for age, body mass index, smoking, and dietary covariates, trans fatty acid intake at baseline was positively associated with the 10-year risk of coronary heart disease. The relative risk for a difference of 2% of energy in trans fatty acid intake at baseline was 1.28 (95% CI 1.01-1.61). INTERPRETATION: A high intake of trans fatty acids (all types of isomers) contributes to the risk of coronary heart disease. The substantial decrease in trans fatty acid intake, mainly due to industrial lowering of trans contents in Dutch edible fats, could therefore have had a large public-health impact.

Prearticulatory and postarticulatory self-monitoring in Broca's aphasia.

The present study examined to what extent patients with Broca's aphasia and healthy controls rely upon prearticulatory and postarticulatory monitoring processes for detecting and repairing errors in speech production. Monitoring skills were investigated in a speaking situation with normal auditory feedback, a speaking situation with white noise, and a situation in which errors had to be detected in other-produced speech. The results demonstrated that the Broca's aphasics repaired a lower percentage of errors than the controls in the situation with normal auditory feedback, whereas their performance in the noise-masked condition was comparable. In contrast to the controls, the aphasics did not suffer from the presence of white noise. In addition, the proportion of covert repairs was higher for the Broca's aphasics than for the healthy controls. These findings indicate that Broca's aphasics concentrate primarily on prearticulatory monitoring. Possible explanations for this strong reliance on prearticulatory monitoring processes are discussed.

Arginine intake and risk of coronary heart disease mortality in elderly men.

From experimental studies, the hypothesis is derived that the amino acid arginine, the precursor of NO, could restore the impaired endothelial function and increased platelet activation observed in atherosclerosis. We investigated whether dietary intake of arginine is associated with reduced coronary heart disease risk in elderly persons. The study population consisted of 806 men aged 64 to 84 years at baseline who participated in the Zutphen Elderly Study, a population-based cohort followed up for 10 years. Information about habitual food consumption was collected by use of the cross-check dietary history method. Ninety (11.2%) of the 806 men died from coronary heart disease. Mean+/-SD baseline arginine intake was 4. 35+/-1.07 g/d. Meat was the main source of arginine intake (37.1%), followed by bread (13.1%) and milk and milk products (12.1%). Arginine intake was not associated with coronary heart disease mortality. After adjustment for age, the relative risk (RR) for the medium tertile of arginine intake was 0.72 (95% CI 0.44 to 1.18), and the RR for the highest tertile was 0.71 (95% CI 0.43 to 1.19, P: for trend=0.19) compared with the lowest tertile of arginine intake. After additional adjustment for history of coronary heart disease and diabetes mellitus, energy intake, body mass index, smoking habit, physical activity, and other relevant dietary and biological risk factors, the RR was 1.86 (95% CI 1.06 to 3.27) for the medium intake and 1.56 (95% CI 0.83 to 2.93) for the highest intake (P: for trend=0.17). These results do not support the hypothesis that dietary arginine intake lowers the risk of coronary heart disease mortality.

Fish consumption and coronary heart disease mortality in Finland, Italy, and The Netherlands.

Fish consumption seems to protect against death from coronary heart disease (CHD). If this association is due to n-3 polyunsaturated fatty acids, especially fatty fish may be responsible for this protective effect. The association between total, lean, and fatty fish consumption and the risk of CHD mortality was examined in 1,088 Finnish, 1,097 Italian, and 553 Dutch men participants in the Seven Countries Study who were aged 50-69 years and free of CHD around 1970. After 20 years of follow-up, 242 (22.2%) men in Finland, 116 (10.6%) men in Italy, and 105 (19.0%) men in the Netherlands had died of CHD. Cox proportional hazards analysis showed no association between total fish consumption and CHD mortality. After adjustments were made for age, body mass index, smoking, energy intake, and relevant dietary variables, the pooled relative risk for the highest quartile of total fish compared with no fish consumption in the three countries was 1.08 (95% confidence interval: 0.76, 1.53). Lean fish consumption also was not associated with CHD mortality in any country. Fatty fish compared with non-fatty-fish consumption was associated with lower CHD mortality; the adjusted, pooled relative risk for fatty fish consumers was 0.66 (95% confidence interval: 0.49, 0.90). These data suggest that especially fatty fish is protective against CHD mortality.

Viscoelastic properties of an exocellular polysaccharide produced by a Lactococcus lactis.

The viscoelastic properties of a well-characterized exocellular polysaccharide (EPS) produced by the lactic acid bacterium Lactococcus lactis subsp. cremoris strain B40 were investigated. Dynamic rheological measurements were made as a function of frequency and EPS concentration. The bead-spring model of Rouse could reasonably describe the dynamic properties. Concentrated EPS solutions have a significant elasticity (G' > G") at high frequencies. The relatively high G' values at high concentrations and high frequencies are indicative of significant normal stress differences, and we put forward a hypothesis that suggests that these normal stresses may explain the contribution of EPSs to the ropy behavior of yogurts.