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Developmental lead effects on behavior and brain gene expression in male and female BALB/cAnNTac mice.

ABSTRACT: Lead (Pb) was one of the first poisons identified, and the developing nervous system is particularly vulnerable to its toxic effects. Relatively low, subclinical doses, of Pb that produce no overt signs of encephalopathy can affect cognitive, emotional, and motor functions. In the present study, the effects of developmental Pb-exposure on behavioral performance and gene expression in BALB/cAnNTac mice were evaluated. Pups were exposed to Pb from gestational-day (gd) 8 to postnatal-day (pnd) 21 and later evaluated in exploratory behavior, rotarod, Morris water maze, and resident-intruder assays as adults. Pb-exposure caused significant alterations in exploratory behavior and water maze performance during the probe trial, but rotarod performance was not affected. Pb-exposed males displayed violent behavior towards their cage mates, but not to a stranger in the resident-intruder assay. Gene expression analysis at pnd21 by microarray and qRT-PCR was performed to provide a molecular link to the behavior changes that were observed. Pb strongly up-regulated gene expression within the signaling pathways of mitogen activated protein kinases (MAPKs), extra-cellular matrix (ECM) receptor, focal adhesion, and vascular endothelial growth-factor (VEGF), but Pb down-regulated gene expression within the pathways for glycan structures-biosynthesis 1, purine metabolism, and N-glycan biosynthesis. Pb increased transcription of genes for major histocompatibility (MHC) proteins, the chemokine Ccl28, chemokine receptors, IL-7, IL7R, and proteases. The qRT-PCR analysis indicated an increase of gene expression in the whole brain for caspase 1 and NOS2. Analysis of IL-1β, caspase 1, NOS2, Trail, IL-18 and IL-33 gene expression of brain regions indicated that Pb perturbed the inter-regional expression pattern of pro-inflammatory genes. Brain region protein concentrations for IL-10, an anti-inflammatory cytokine, showed a significant decrease only within the cortex region. Results indicate that Pb differentially affects the behavior of male and female mice in that females did less exploration and the males were selectively more aggressive. Gene expression data pointed to evidence of neuroinflammation in the brain of both female and male mice. Pb had more of an effect in the males on expression of vomeronasal receptor genes associated with odor detection and social behavior.

SUBMITTER: Kasten-Jolly J

PROVIDER: S-EPMC3463649 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Anxiety disorders and nicotine use are significant contributors to global morbidity and mortality as independent and comorbid diseases. Early-life stress, potentially via stress-induced hypothalamic-pituitary-adrenal axis (HPA) dysregulation, can exacerbate both. However, little is known about the factors that predispose individuals to the development of both anxiety disorders and nicotine use. Here, we examined the relationship between anxiety-like behaviors and nicotine responses following adolescent stress. Adolescent male and female BALB/cJ mice were exposed to either chronic variable social stress (CVSS) or control conditions. CVSS consisted of repeated cycles of social isolation and social reorganization. In adulthood, anxiety-like behavior and social avoidance were measured using the elevated plus-maze (EPM) and social approach-avoidance test, respectively. Nicotine responses were assessed with acute effects on body temperature, corticosterone production, locomotor activity, and voluntary oral nicotine consumption. Adolescent stress had sex-dependent effects on nicotine responses and exploratory behavior, but did not affect anxiety-like behavior or social avoidance in males or females. Adult CVSS males exhibited less exploratory behavior, as indicated by reduced exploratory locomotion in the EPM and social approach-avoidance test, compared to controls. Adolescent stress did not affect nicotine-induced hypothermia in either sex, but CVSS males exhibited augmented nicotine-induced locomotion during late adolescence and voluntarily consumed less nicotine during adulthood. Stress effects on male nicotine-induced locomotion were associated with individual differences in exploratory locomotion in the EPM and social approach-avoidance test. Relative to controls, adult CVSS males and females also exhibited reduced corticosterone levels at baseline and adult male CVSS mice exhibited increased corticosterone levels following an acute nicotine injection. Results suggest that the altered nicotine responses observed in CVSS males may be associated with HPA dysregulation. Taken together, adolescent social stress influences later-life nicotine responses and exploratory behavior. However, there is little evidence of an association between nicotine responses and prototypical anxiety-like behavior or social avoidance in BALB/cJ mice.

Project description:AimsRestraint stress is one of the most widely used experimental methods for generating rodent models of stress-induced neuropsychiatric disorders, such as depression and anxiety. Although various types of restraint apparatuses have been used to expose animals to stress, the magnitudes of the effects of stress exposure via different types of restraint apparatuses on physiology and behavior have not been compared in the same environment. Here, we investigated the effects of stress exposure via two types of restraint apparatuses on body weight, locomotor activity, anxiety- and depression-related behaviors, and plasma corticosterone levels in mice.MethodsAdult male BALB/cAJcl mice were restrained by placing them in either a well-ventilated plastic conical tube or a tapered plastic film envelope for 6 hours per day for 10 or 21 consecutive days. Mice were weighed during and after the stress period and were subjected to a battery of behavioral tests, including light/dark transition, open field, elevated plus maze, Porsolt forced swim, tail suspension, and sucrose preference tests, starting on the day after the last stress session. Plasma corticosterone levels were measured in another cohort of mice on the 1st and the 21st stress sessions and after the Porsolt forced swim test.ResultsExposure to repeated stress via the two above mentioned types of restraint apparatuses caused body weight loss, heightened locomotor activity, altered immobility during forced swim, and increased plasma corticosterone levels, and some of these results differed between the restraint stress protocols. Film-restraint-stressed mice had significantly lower body weights than tube-restraint-stressed mice. Film-restraint-stressed mice exhibited significantly higher or lower immobility during forced swim than tube-restraint-stressed mice, depending on the test time. Additionally, the stress-induced increase in plasma corticosterone levels was found to be higher in film-restraint-stressed mice than in tube-restraint-stressed mice.ConclusionOur results indicate that film-restraint stress has more pronounced effects on body weight, depression-related behavior, and corticosterone response than tube-restraint stress in mice. These findings may help guide which restraint stress procedures to use, depending on the objectives of a given study, in generating animal models of stress-induced neuropsychiatric disorders.

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Developmental lead effects on behavior and brain gene expression in male and female BALB/cAnNTac mice.

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