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Abstract: Background and aims: Increased vagal activity is associated with obesity and metabolic risk in children and adolescents. The aim of the present cross-sectional study was to examine the association of parasympathetic function, as assessed by heart rate recovery (HRR) from a maximal exercise cycle-ergometer test, with obesity traits and related cardiometabolic risk factors in Spanish children and adolescents. Methods and results: A sample of 437 Spanish 9-year-old-children and 235 15-year-old-adolescents participated in the study. The variables measured were anthropometric characteristics (height, body mass and waist circumference) and physical activity using the Actigraph accelerometer. Additional measured outcomes included fasting insulin, triglycerides, high-density lipoprotein cholesterol (HDLc) and blood pressure. A metabolic risk score was computed as the mean of the standardised outcomes scores. The HRR was calculated as the difference between peak heart rate and heart rate 1, 3 and 5 min after cessation of the maximal ergometer test. Diastolic blood pressure was associated with all the HRR parameters in 9-year-old-girls. In 9-year-old-boys, the 3-min HRR was inversely associated with systolic blood pressure (p < 0.05) and Homeostasis Model Assessment (HOMA) (p < 0.05). Five minute HRR was inversely associated with waist circumference (p < 0.05), sum of five skinfolds (p < 0.01) and HOMA (p = 0.004). There were no significant associations in adolescents. In 9-year-old-girls, the adjusted 5-min HRR showed significant differences between quartile 2 and 4 of metabolic risk (p = 0.011). In all samples, the adjusted HRR (1-, 3- and 5-min HRR) did not show significant differences across quartiles. Conclusion: HRR was inversely associated with obesity traits and related cardiometabolic risk factors mainly in healthy boys. [Copyright &y& Elsevier]

The median raphe nucleus is involved in controlling and maintaining hippocampal activity through its projection to inhibitory neurons in medial septum and hippocampus. It has been shown that anterogradely axonal-traced fibers originating in the median raphe nucleus project onto calbindin-containing neurons in hippocampus and parvalbumin-containing neurons in medial septum. Parallel immunohistochemistry studies showing serotonin fibers contacting calbindin- and parvalbumin-positive neurons have led to the assumption that raphe fibers projecting on these types of neurons are mainly serotonergic. However, in both dorsal and median raphe nucleus there is a large amount of non-serotonergic neurons which also are projecting neurons, indicating that a part of the raphe fibers projecting to hippocampus and septum may be non-serotonergic. Our aim was to determine whether there is a non-serotonergic projection from the raphe nucleus onto calbindin- and parvalbumin-containing neurons in hippocampus and septum. Biotin dextran amine was used as the anterograde neuronal tracer and injected into either dorsal or median raphe nucleus. By use of triple immunofluorescence-labeling we analyzed the serotonergic content of the biotin dextran amine-labeled fibers contacting parvalbumin- and calbindin-positive neurons. Surprisingly, we found a significant non-serotonergic projection from both dorsal and median raphe nuclei onto calbindin- and parvalbumin-containing interneurons in septum and hippocampus, with a preference in hippocampus for projecting onto calbindin-positive neurons. These results indicate that the raphe nuclei may exert their control on hippocampal and septal activity not only through a serotonergic projection, but also through a significant non-serotonergic pathway. [Copyright &y& Elsevier]

Abstract: Changes in brain-derived neurotrophic factor (BDNF) expression have been implicated in the etiology of psychiatric disorders. To investigate pathological mechanisms elicited by perturbed BDNF signaling, we examined mutant mice with central depletion of BDNF (BDNF2L/2LCk-cre). A severe impairment specific for the serotonin 2A receptor (5-HT2AR) in prefrontal cortex was described previously in these mice. This is of much interest, as 5-HT2ARs have been linked to neuropsychiatric disorders and anxiety-related behavior. Here we further characterized the serotonin receptor alterations triggered by BDNF depletion. 5-HT2A ([3H]-MDL100907) and 5-HT1A ([3H]-WAY100635) receptor autoradiography revealed site-specific alterations in BDNF mutant mice. They exhibited lower 5-HT2A receptor binding in frontal cortex but increased binding in hippocampus. Additionally, 5-HT1A receptor binding was decreased in hippocampus of BDNF mutants, but unchanged in frontal cortex. Molecular analysis indicated corresponding changes in 5-HT2A and 5-HT1A mRNA expression but normal 5-HT2C content in these brain regions in BDNF2L/2LCk-cre mice. We investigated whether the reduction in frontal 5-HT2AR binding was reflected in reduced functional output in two 5-HT2A-receptor mediated behavioral tests, the head-twitch response (HTR) and the ear-scratch response (ESR). BDNF2L/2LCk-cre mutants treated with the 5-HT2A receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) showed a clearly diminished ESR but no differences in HTR compared to wildtypes. These findings illustrate the context-dependent effects of deficient BDNF signaling on the 5-HT receptor system and 5-HT2A-receptor functional output. [ABSTRACT FROM AUTHOR]

• Long-lasting social isolation effects have been tested in the Roman rats. • Social isolation produces divergent effects in RHA-I vs RLA-I rats. • RHA-I rats show PPI deficits, anxiety and hyperactivity induced by social isolation. • Social isolation differentially impairs spatial memory in the Roman strains. • Long-lasting social isolation produces an increment in volume of mPFC. Social isolation rearing of rodents is an environmental manipulation known to induce or potentiate psychotic-like symptoms and attentional and cognitive impairments relevant for schizophrenia. When subjected to a 28-week isolation rearing treatment, the Roman high-avoidance (RHA-I) rats display the common behavioral social isolation syndrome, with prepulse inhibition (PPI) deficits, hyperactivity, increased anxiety responses and learning/memory impairments when compared to their low-avoidance (RLA-I) counterparts. These results add face validity to the RHA-I rats as an animal model for schizophrenia-relevant behavioral and cognitive profiles and confirm previous results. The aim here was to further investigate the neuroanatomical effects of the isolation rearing, estimated through volume differences in medial prefrontal cortex (mPFC), dorsal striatum (dSt) and hippocampus (HPC). Results showed a global increase in volume in the mPFC in the isolated rats of both strains, as well as strain effects (RLA > RHA) in the three brain regions. These unexpected but robust results, might have unveiled some kind of compensatory mechanisms due to the particularly long-lasting isolation rearing period, much longer than those commonly used in the literature (which usually range from 4 to 12 weeks). [ABSTRACT FROM AUTHOR]

Highlights: [•] Roman Low- and High-Avoidance (RLA and RHA) rats differ in 5-HT2AR binding. [•] 5-HT2AR binding correlated with impulsivity in RHA rats. [•] SERT binding was significantly higher in RHA rats compared to RLA rats. [•] We found marked differences in mGluR2 protein levels between RLA and RHA rats. [•] We found marked differences in mGluR2/3 binding between RLA and RHA rats. [Copyright &y& Elsevier]

Abstract: Background: Physical fitness is gaining in importance in all population groups, including elderly, but data are still scarce. The aim of this study was to report gender and age specific physical fitness levels in non-institutionalized Spanish elderly. Methods: A representative sample of 3136 elderly (≥65y), 724 men and 2412 women, from 6 Regions of Spain: Madrid, Aragón, Castilla y León, Castilla-La Mancha, Extremadura and Canarias were assessed in the elderly EXERNET multi-center study between 2008 and 2009. The authors assessed static balance, muscular strength, flexibility, agility, walking speed and cardiorespiratory fitness using eight different fitness tests: one leg balance, chair stand, arm curl, chair sit-and-reach, back scratch, 8-foot up-and-go, 30-m walk, and 6min walk tests. Results: The authors derived gender and age-specific normative values for physical fitness in the non-institutionalized Spanish elderly. The figures showed greater physical fitness in the elderly men than in women, except for the flexibility test, and a trend toward decreased physical fitness in both genders as their age increased. Conclusions: The normative values hereby provided will enable evaluation and correct interpretation of independent non-institutionalized Spanish elderly fitness status. [Copyright &y& Elsevier]

Abstract: Many psychiatric disorders are characterized by cognitive and emotional alterations that are related to abnormal function of the frontal cortex (FC). FC is involved in working memory and decision making and is activated following exposure to a novel environment. The serotonin 2A receptor (5-HT2AR) is highly expressed in the FC where its activation induces hallucinations, while blockade of 5-HT2ARs contributes to the therapeutic effects of atypical antipsychotic drugs. The purpose of the present study was to investigate the involvement of 5-HT2AR in FC activation following exposure to a novel environment. As an output of FC activation we measured expression of activity-regulated cytoskeletal-associated protein (Arc). Novelty-exposure (open-field arena) robustly up-regulated FC Arc mRNA expression (∼160%) in mice compared to home-cage controls. This response was inhibited with the 5-HT2AR antagonists ketanserin and MDL100907, but not with the selective 5-HT2CR antagonist SB242084. Novelty-exposure also induced Arc mRNA expression in hippocampus (∼150%), but not in cerebellum or brainstem. Pretreatment with 5-HT2AR antagonist ketanserin did not repress the Arc induction in hippocampus, indicating that the involvement of 5-HT2AR in this response is restricted to the FC. Similarly, the novelty-induced stress as determined by increasing levels of plasma corticosterone, was not influenced by 5-HT2AR antagonism suggesting that Arc mRNA and stress are activated via distinct mechanisms. Taken together, our results demonstrate that the induction of Arc in the FC following exposure to a novel environment is dependent on the 5-HT2AR, and that the simultaneous release of corticosterone is regulated via another system independent of 5-HT2AR activation. [Copyright &y& Elsevier]

Abstract: Both brain-derived neurotrophic factor (BDNF) and the serotonin receptor 2A (5-HT2A) have been related to depression pathology. Specific 5-HT2A receptor changes seen in BDNF conditional mutant mice suggest that BDNF regulates the 5-HT2A receptor level. Here we show a direct effect of BDNF on 5-HT2A receptor protein levels in primary hippocampal neuronal and mature hippocampal organotypic cultures exposed to different BDNF concentrations for either 1, 3, 5 or 7 days. In vivo effects of BDNF on hippocampal 5-HT2A receptor levels were further corroborated in (BDNF +/−) mice with reduced BDNF levels. In primary neuronal cultures, 7 days exposure to 25 and 50ng/mL BDNF resulted in downregulation of 5-HT2A, but not of 5-HT1A, receptor protein levels. The BDNF-associated downregulation of 5-HT2A receptor levels was also observed in mature hippocampal organotypic cultures, excluding confounding effects of BDNF on immature tissue. BDNF +/− mice showed significant increased 5-HT2A receptor levels in hippocampus confirming the association between 5-HT2A receptor and BDNF levels in vivo. In conclusion, our results point to a regulatory role of BDNF on 5-HT2A receptor levels. This interaction may be an important mechanism in the role of BDNF in affective disorders emphasizing the need for further elucidating the specificity and the mechanism behind this regulation. [Copyright &y& Elsevier]

The rodent Continuous Performance Test (rCPT) is an analogue of human CPTs where mice have to discriminate between target and non-target stimuli. The rCPT offers a readout of attentional performance and impulsive behaviour. This study aimed to determine if female C57BL/6 J mice could be trained in the rCPT since previously published rCPT studies have only used male mice and to study whether the effects of methylphenidate (MPH), atomoxetine (ATX), and dexamphetamine (AMPH) on attention and impulsivity depend on baseline (reference) levels of performance. 48 female mice underwent rCPT training. Effects of MPH (1, 2, and 3 mg/kg), ATX (1, 3, and 5 mg/kg) and AMPH (0.3, 0.6, and 1 mg/kg) were assessed in a variable stimulus duration probe. Drugs were administered intraperitoneally and sequentially tested following a Latin-square design. Data were analysed using a repeated measurements mixed effect model and reference-dependent effects were studied. ATX and AMPH improved performance as seen by increases in discriminability. These improvements were a result of a decreased false-alarm rate. AMPH showed a reference-dependent effect, improving the task performance of low-performing mice and decreasing the performance of high-performing mice. MPH also showed this reference-dependent effects, albeit to a lesser extent. ATX and AMPH decreased premature responses and increased response criterion, but no reference-dependent effects were observed for these parameters. This study presents a novel method to analyse baseline-dependent effects. It shows that the rCPT can be successfully used in pharmacological studies in female mice and demonstrates that the effect of ADHD medication is in line with the inverted U-shape theory of performance-arousal relationship. • C57BL/6 J female mice were trained in the rodent Continuous Performance Test (rCPT). • The effects of methylphenidate, atomoxetine, and amphetamine were investigated. • A novel analysis method was used and showed baseline-dependent effects of the drugs. • Low-performing animals benefited most from the pharmacological treatment. • This analysis method and the rCPT are suitable to assess attention and impulsivity. [ABSTRACT FROM AUTHOR]