Age influences the effects of nicotine and monoamine oxidase inhibition on mood-related behaviors in rats

Epidemiological studies have demonstrated a comorbidity of smoking with depression and anxiety, particularly during adolescence. However, few animal studies have considered possible synergistic interactions between nicotine and other tobacco smoke constituents, such as monoamine oxidase (MAO) inhibitors, in the regulation of mood. The aim of the study was to test the hypothesis that nicotine combined with the irreversible MAO inhibitor, tranylcypromine, will differentially affect depression- and anxiety-related behaviors in adolescent and adult rats. Nicotine (0, 0.05, 0.2 mg/kg, s.c.) and tranylcypromine (3 mg/kg, i.p.) were tested separately, or together, on male rats aged postnatal days 30 and 68, in three mood-related behavioral tests: forced swim test (FST), elevated plus maze (EPM), and open field. Nicotine (0.2 mg/kg) in adults significantly decreased floating time in the FST and increased time spent in the open arm of the EPM, with no change in locomotor activity. Tranylcypromine pretreatment combined with nicotine (0.2 mg/kg) significantly increased locomotor activity and time spent in the center of the open field. Whereas nicotine alone had no significant effect on adolescents, it significantly increased locomotor activity and decreased floating time in the FST when combined with tranylcypromine pretreatment. There is an age-dependent effect of nicotine, alone and in combination with MAO inhibition, on mood-related behaviors. Whereas nicotine alone induces mood improvement in adults, it has no effect on adolescents. Nicotine combined with tranylcypromine has unique, age-dependent effects. Thus, experimental studies of smoking should consider both age and other tobacco constituents, such as MAO inhibitors, as critical factors

Evidence of Latitudinal Migration in Tri-colored Bats, Perimyotis subflavus

Background: Annual movements of tri-colored bats (Perimyotis subflavus) are poorly understood. While this species has been considered a regional migrant, some evidence suggests that it may undertake annual latitudinal migrations, similar to other long distance North American migratory bat species. Methodology/Principal Findings: We investigated migration in P. subflavus by conducting stable hydrogen isotope analyses of 184 museum specimen fur samples and comparing these results (dDfur) to published interpolated dD values of collection site growing season precipitation (dDprecip). Results suggest that the male molt period occurred between June 23 and October 16 and 33 % of males collected during the presumed non-molt period were south of their location of fur growth. For the same time period, 16 % of females were south of their location of fur growth and in general, had not travelled as far as migratory males. There were strong correlations between dDfur from the presumed molt period and both growing season dD precip (males – r 2 = 0.86; p,0.01; females – r 2 = 0.75; p,0.01), and latitude of collection (males – r 2 = 0.85; p,0.01; females – r 2 = 0.73; p,0.01). Most migrants were collected at the northern (.40uN; males and females) and southern (,35uN; males only) extents of the species ’ range. Conclusions/Significance: These results indicate a different pattern of migration for this species than previously documented, suggesting that some P. subflavus engage in annual latitudinal migrations and that migratory tendency varie

Social Isolation-Induced Aggression Potentiates Anxiety and Depressive-Like Behavior in Male Mice Subjected to Unpredictable Chronic Mild Stress

Accumulating epidemiological evidence shows that life event stressors are major vulnerability factors for psychiatric diseases such as major depression. It is also well known that social isolation in male mice results in aggressive behavior. However, it is not known how social isolation-induced aggression affects anxiety and depressive-like behavior in isolated male mice subjected to unpredictable chronic mild stress (CMS), an animal model of depression.C57/B6 male mice were divided into 3 groups; non-stressed controls, in Group I; isolated mice subjected to the CMS protocol in Group II and aggression by physical contact in socially isolated mice subjected to the CMS protocol in Group III. In the sucrose intake test, ingestion of a 1% sucrose solution by mice in Groups II and III was significantly lower than in Group I. Furthermore, intake of this solution in Group III mice was significantly lower than in Group II mice. In the open field test, mice in Group III, showed reduced locomotor activity and reduced entry and retention time in the central zone, compared to Groups I and II mice. Moreover, the distances moved in 1 hour by Group III mice did not differ between night and morning. In the light/black box test, Groups II and III animals spent significantly less time in the light box compared to Group I animals. In the tail suspension test (TST) and forced swimming test (FST), the immobility times of Group II and Group III mice were significantly longer than in Group I mice. In addition, immobility times in the FST were significantly longer in Group III than in Group II mice.These findings show that social isolation-induced aggression could potentiate anxiety and depressive-like behaviors in isolated male mice subjected to CMS

Hippocampal Gene Expression Analysis Highlights Ly6a/Sca-1 as Candidate Gene for Previously Mapped Novelty Induced Behaviors in Mice

In this study, we show that the covariance between behavior and gene expression in the brain can help further unravel the determinants of neurobehavioral traits. Previously, a QTL for novelty induced motor activity levels was identified on murine chromosome 15 using consomic strains. With the goal of narrowing down the linked region and possibly identifying the gene underlying the quantitative trait, gene expression data from this F2-population was collected and used for expression QTL analysis. While genetic variation in these mice was limited to chromosome 15, eQTL analysis of gene expression showed strong cis-effects as well as trans-effects elsewhere in the genome. Using weighted gene co-expression network analysis, we were able to identify modules of co-expressed genes related to novelty induced motor activity levels. In eQTL analyses, the expression of Ly6a (a.k.a. Sca-1) was found to be cis-regulated by chromosome 15. Ly6a also surfaced in a group of genes resulting from the network analysis that was correlated with behavior. Behavioral analysis of Ly6a knock-out mice revealed reduced novelty induced motor activity levels when compared to wild type controls, confirming functional importance of Ly6a in this behavior, possibly through regulating other genes in a pathway. This study shows that gene expression profiling can be used to narrow down a previously identified behavioral QTL in mice, providing support for Ly6a as a candidate gene for functional involvement in novelty responsiveness

Signaling pathways responsible for the rapid antidepressant-like effects of a GluN2A-preferring NMDA receptor antagonist

In a previous study we found that the preferring GluN2A receptor antagonist, NVP-AAM077, elicited rapid antidepressant-like effects in the forced swim test that was related to the release of glutamate and serotonin in the medial prefrontal cortex. In the present work we sought to examine the duration of this behavioral effect as well as the molecular readouts involved. Our results showed that NVP-AAM077 reduced the immobility in the forced swim test 30?min and 24?h after its administration. However, this effect waned 7 days later. The rapid antidepressant-like response seems to be associated with increases in the GluA1 subunit of ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, mammalian target of rapamycin (mTOR) signaling, glia markers such as glial fibrillary acidic protein (GFAP) and excitatory amino acid transporter 1 (EAAT1), and a rapid mobilization of intracellular stores of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex.Acknowledgements: M.G.-S. was recipient of a contract from the Sistema Nacional de Garantía Juvenil co-funded by the European Social Fund. We also thank Novartis for the generous gift of NVP-AAM077. This work was supported by the Instituto de Salud Carlos III, Subdirección General del Evaluación y Fomento de la Investigación (FIS Grants PI13/00038 and PI16/00217) that were co-funded by the European Regional Development Fund (‘A way to build Europe’). Funding from the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III is also acknowledged

Aging of the mammalian gastrointestinal tract: a complex organ system

Gastrointestinal disorders are a major cause of morbidity in the elderly population. The gastrointestinal tract is the most complex organ system; its diverse cells perform a range of functions essential to life, not only secretion, digestion, absorption and excretion, but also, very importantly, defence. The gastrointestinal tract acts not only as a barrier to harmful materials and pathogens but also contains the vast number of beneficial bacterial populations that make up the microbiota. Communication between the cells of the gastrointestinal tract and the central nervous and endocrine systems modifies behaviour; the organisms of the microbiota also contribute to this brain–gut–enteric microbiota axis. Age-related physiological changes in the gut are not only common, but also variable, and likely to be influenced by external factors as well as intrinsic aging of the cells involved. The cellular and molecular changes exhibited by the aging gut cells also vary. Aging intestinal smooth muscle cells exhibit a number of changes in the signalling pathways that regulate contraction. There is some evidence for age-associated degeneration of neurons and glia of the enteric nervous system, although enteric neuronal losses are likely not to be nearly as extensive as previously believed. Aging enteric neurons have been shown to exhibit a senescence-associated phenotype. Epithelial stem cells exhibit increased mitochondrial mutation in aging that affects their progeny in the mucosal epithelium. Changes to the microbiota and intestinal immune system during aging are likely to contribute to wider aging of the organism and are increasingly important areas of analysis. How changes of the different cell types of the gut during aging affect the numerous cellular interactions that are essential for normal gut functions will be important areas for future aging research

Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes.

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an "intrinsic" spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion-positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype.See related commentary by Szulzewsky and Cimino, p. 904.This article is highlighted in the In This Issue feature, p. 890

Tracking Cats: Problems with Placing Feline Carnivores on δ18O, δD Isoscapes

Several felids are endangered and threatened by the illegal wildlife trade. Establishing geographic origin of tissues of endangered species is thus crucial for wildlife crime investigations and effective conservation strategies. As shown in other species, stable isotope analysis of hydrogen and oxygen in hair (δD(h), δ(18)O(h)) can be used as a tool for provenance determination. However, reliably predicting the spatial distribution of δD(h) and δ(18)O(h) requires confirmation from animal tissues of known origin and a detailed understanding of the isotopic routing of dietary nutrients into felid hair.We used coupled δD(h) and δ(18)O(h) measurements from the North American bobcat (Lynx rufus) and puma (Puma concolor) with precipitation-based assignment isoscapes to test the feasibility of isotopic geo-location of felidae. Hairs of felid and rabbit museum specimens from 75 sites across the United States and Canada were analyzed. Bobcat and puma lacked a significant correlation between H/O isotopes in hair and local waters, and also exhibited an isotopic decoupling of δ(18)O(h) and δD(h). Conversely, strong δD and δ(18)O coupling was found for key prey, eastern cottontail rabbit (Sylvilagus floridanus; hair) and white-tailed deer (Odocoileus virginianus; collagen, bone phosphate).Puma and bobcat hairs do not adhere to expected pattern of H and O isotopic variation predicted by precipitation isoscapes for North America. Thus, using bulk hair, felids cannot be placed on δ(18)O and δD isoscapes for use in forensic investigations. The effective application of isotopes to trace the provenance of feline carnivores is likely compromised by major controls of their diet, physiology and metabolism on hair δ(18)O and δD related to body water budgets. Controlled feeding experiments, combined with single amino acid isotope analysis of diets and hair, are needed to reveal mechanisms and physiological traits explaining why felid hair does not follow isotopic patterns demonstrated in many other taxa

Evaluating genetic markers and neurobiochemical analytes for fluoxetine response using a panel of mouse inbred strains

RationaleIdentification of biomarkers that establish diagnosis or treatment response is critical to the advancement of research and management of patients with depression.ObjectiveOur goal was to identify biomarkers that can potentially assess fluoxetine response and risk to poor treatment outcome.MethodsWe measured behavior, gene expression, and the levels of 36 neurobiochemical analytes across a panel of genetically diverse mouse inbred lines after chronic treatment with water or fluoxetine.ResultsGlyoxylase 1 (GLO1) and guanine nucleotide-binding protein 1 (GNB1) mostly account for baseline anxiety-like and depressive-like behavior, indicating a common biological link between depression and anxiety. Fluoxetine-induced biochemical alterations discriminated positive responders, while baseline neurobiochemical differences differentiated negative responders (p < 0.006). Results show that glial fibrillary acidic protein, S100 beta protein, GLO1, and histone deacetylase 5 contributed most to fluoxetine response. These proteins are linked within a cellular growth/proliferation pathway, suggesting the involvement of cellular genesis in fluoxetine response. Furthermore, a candidate genetic locus that associates with baseline depressive-like behavior contains a gene that encodes for cellular proliferation/adhesion molecule (Cadm1), supporting a genetic basis for the role of neuro/gliogenesis in depression.ConclusionWe provided a comprehensive analysis of behavioral, neurobiochemical, and transcriptome data across 30 mouse inbred strains that has not been accomplished before. We identified biomarkers that influence fluoxetine response, which, altogether, implicate the importance of cellular genesis in fluoxetine treatment. More broadly, this approach can be used to assess a wide range of drug response phenotypes that are challenging to address in human samples.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-011-2574-z) contains supplementary material, which is available to authorized users