ABSTRACT
Previous research has shown that neonatal handling has prolonged protective effects associated with stress resilience and aging, yet little is known about its effect on stress-induced modulation of infectious disease. We have previously demonstrated that social disruption stress exacerbates the acute and chronic phases of the disease when applied prior to Theiler's virus infection (PRE-SDR) whereas it attenuates disease severity when applied concurrently with infection (CON-SDR). Here, we asked whether neonatal handling would protect adult mice from the detrimental effects of PRE-SDR and attenuate the protective effects of CON-SDR on Theiler's virus infection. As expected, handling alone decreased IL-6 and corticosterone levels, protected the non-stressed adult mice from motor impairment throughout infection and reduced antibodies to myelin components (PLP, MBP) during the autoimmune phase of disease. In contrast, neonatal handling X PRE/CON-SDR elevated IL-6 and reduced corticosterone as well as increased motor impairment during the acute phase of the infection. Neonatal handling X PRE/CON-SDR continued to exacerbate motor impairment during the chronic phase, whereas only neonatal handling X PRE-SDR increased in antibodies to PLP, MOG, MBP and TMEV. Together, these results imply that while handling reduced the severity of later Theiler's virus infection in non-stressed mice, brief handling may not be protective when paired with later social stress.
Subject(s)
Cardiovirus Infections/immunology , Handling, Psychological , Social Behavior , Stress, Psychological/immunology , Theilovirus/immunology , Acute Disease , Age Factors , Animals , Animals, Newborn , Chronic Disease , Interleukin-6/immunology , Male , Mice , Mice, Inbred BALB C , Motor Activity/immunology , Myelin Proteins/immunologyABSTRACT
Previous studies have established a link between adverse early life events and subsequent disease vulnerability. The present study assessed the long-term effects of neonatal maternal separation on the response to Theiler's murine encephalomyelitis virus infection, a model of multiple sclerosis. Balb/cJ mouse pups were separated from their dam for 180-min/day (180-min MS), 15-min/day (15-min MS), or left undisturbed from postnatal days 2-14. During adolescence, mice were infected with Theiler's virus and sacrificed at days 14, 21, or 35 post-infection. Prolonged 180-min MS increased viral load and delayed viral clearance in the spinal cords of males and females, whereas brief 15-min MS increased the rate of viral clearance in females. The 15-min and 180-min MS mice exhibited blunted corticosterone responses during infection, suggesting that reduced HPA sensitivity may have altered the immune response to infection. These findings demonstrate that early life events alter vulnerability to CNS infection later in life. Therefore, this model could be used to study gene-environment interactions that contribute to individual differences in susceptibility to infectious and autoimmune diseases of the CNS.
Subject(s)
Immune System/physiology , Theilovirus/metabolism , Animals , Corticosterone/metabolism , Encephalitis/immunology , Encephalitis/virology , Environment , Female , Male , Mice , Mice, Inbred BALB C , Models, Genetic , Spinal Cord/pathology , Time Factors , Tissue Distribution , Viral LoadABSTRACT
Stressful life events have been associated with the onset and/or exacerbation of multiple sclerosis (MS). Our previous studies have indicated that restraint stress (RS) reduces inflammation and virus-induced chemokine expression in the Theiler's virus-induced demyelination (TVID) model of MS. Here we report that RS significantly reduced the virus-induced interferon-gamma mRNA levels in the brain. Additionally, mRNA levels of lymphotoxin-beta, tumor necrosis factor-alpha, and interferon-gamma in the brain were negatively correlated with viral titers in the brain. These results indicated an immunosuppressive effect of stress during early TVID causing impaired viral clearance, which may be a potential exacerbating factor for later demyelination.
Subject(s)
Brain/immunology , Cardiovirus Infections/immunology , Cytokines/biosynthesis , Stress, Psychological/immunology , Animals , Blotting, Western , Brain/pathology , Brain/virology , Disease Models, Animal , Inflammation/immunology , Male , Mice , Mice, Inbred CBA , Multiple Sclerosis/immunology , RNA, Messenger/analysis , Restraint, Physical , Reverse Transcriptase Polymerase Chain Reaction , Theilovirus/immunologyABSTRACT
Pain reactivity is often assessed in rodents by measuring the latency of tail withdrawal from radiant heat (the tail-flick test). Using this test, the authors show that the magnitude of antinociception observed in spinal rats depends on test location; antinociception is observed at, and distal to, where shock is applied, but not at more proximal sites (Experiments 1 & 2). Experiment 3 evaluates the generality of this observation by testing 3 other shock schedules that are known to elicit distinct forms of antinociception. In all but 1 case, the magnitude of antinociception varied as a function of test location. Experiment 4 shows that morphine also has a greater impact at distal test locations. Experiment 5 assessed the impact of tailshock on reactivity to radiant heat applied to the foot. Of the 5 distinct forms of shock-induced antinociception studied, only 2 produce a robust antinociception at this test location.
