BTBR T+tf/J (BTBR) mice have recently been reported to have behaviors that resemble those of autistic individuals, in that this strain has impairments in social interactions and a restricted repetitive and stereotyped pattern of behaviors. Since immune responses, including autoimmune responses, are known to affect behavior, and individuals with autism have aberrant immune activities, we evaluated the immune system of BTBR mice, and compared their immunity and degree of neuroinflammation with that of C57BL/6 (B6) mice, a highly social control strain, and with F1 offspring. Mice were assessed at postnatal day (pnd) 21 and after behavioral analysis at pnd70. BTBR mice had significantly higher amounts of serum IgG and IgE, of IgG anti-brain antibodies (Abs), and of IgG and IgE deposited in the brain, elevated expression of cytokines, especially IL-33 IL-18, and IL-1β in the brain, and an increased proportion of MHC class II-expressing microglia compared to B6 mice. The F1 mice had intermediate levels of Abs and cytokines as well as social activity. The high Ab levels of BTBR mice are in agreement with their increased numbers of CD40hi/I-Ahi B cells and IgG-secreting B cells. Upon immunization with KLH, the BTBR mice produced 2–3 times more anti-KLH Abs than B6 mice. In contrast to humoral immunity, BTBR mice are significantly more susceptible to listeriosis than B6 or BALB/c mice. The Th2-like immune profile of the BTBR mice and their constitutive neuroinflammation suggests that an autoimmune profile is implicated in their aberrant behaviors, as has been suggested for some humans with autism.

BackgroundThe hippocampus is essential for declarative memory synthesis and is a core pathological substrate for Alzheimer's disease (AD), the most common aging-related dementing disease. Acute increases in plasma cortisol are associated with transient hippocampal inhibition and retrograde amnesia, while chronic cortisol elevation is associated with hippocampal atrophy. Thus, cortisol levels could be monitored and managed in older people, to decrease their risk of AD type hippocampal dysfunction. We generated an in silicomodel of the chronic effects of elevated plasma cortisol on hippocampal activity and atrophy, using the systems biology mark-up language (SBML). We further challenged the model with biologically based interventions to ascertain if cortisol associated hippocampal dysfunction could be abrogated.ResultsThe in silicoSBML model reflected the in vivoaging of the hippocampus and increased plasma cortisol and negative feedback to the hypothalamic pituitary axis. Aging induced a 12% decrease in hippocampus activity (HA), increased to 30% by acute and 40% by chronic elevations in cortisol. The biological intervention attenuated the cortisol associated decrease in HA by 2% in the acute cortisol simulation and by 8% in the chronic simulation.ConclusionBoth acute and chronic elevations in cortisol secretion increased aging-associated hippocampal atrophy and a loss of HA in the model. We suggest that this first SMBL model, in tandem with in vitroand in vivostudies, may provide a backbone to further frame computational cortisol and brain aging models, which may help predict aging-related brain changes in vulnerable older people.

Oxidative stress is implicated in the pathogenesis of many neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. The depletion of glutathione (GSH) a powerful antioxidant renders cells particularly vulnerable to oxidative stress. Isolated neuronal and glial cell culture studies suggest that glia rather than neurons have greatest reserves of GSH, implying that neurons are most sensitive to oxidative stress. However, pathological in vivo studies suggest that GSH associated enzymes are elevated in neurons rather than astrocytes. The active, reduced form of GSH is rapidly degraded thus making it difficult to identify the location of GSH in post-mortem tissue. Therefore, to determine whether GSH is more highly expressed in neurons or astrocytes we perfused mouse brains with a solution containing NEM which reacts with the sulfhydryl group of GSH, thus locking the active form in situ, prior to immunostaining with an anti-GS-NEM antibody. We obtained brightfield and fluorescent digital images of sections stained with DAPI and antibodies directed against GS-NEM, glial fibrillary acidic protein (GFAP) in regions containing the hippocampus, striatum, frontal cortex, midbrain nuclei, cerebellum and reticular formation neurons. GSH was most abundant in neurons and white matter in all brain regions, and only in occasional astrocytes lining the third and fourth ventricles. High levels of GSH in neurons and white matter, suggests astrocytes rather than neurons may be particularly vulnerable to oxidative stress.

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Polychlorinated biphenyls (PCBs) are persistent lipophilic environmental contaminants which are found in fatty tissues of humans and wild-life alike. Maternal transfer of PCBs to offspring is easily achieved across the placenta and via lactation. In male rats, perinatal PCB exposure induces behavioral abnormalities, in addition to hypothyroxinemia and white matter changes. There are sex differences in white matter volume synthesis and density in adult and aged rodents. Yet whether PCB exposure effects on white matter are sex-specific is unclear, because the previous studies were conducted in male offspring. Furthermore, although hypothyroxinemia induced by PCB exposure is thought to trigger white matter changes, PCBs also affect interleukin-6 (IL-6) expression, and IL-6 regulates white matter growth. We hypothesized that perinatal PCB exposure would have sex-specific effects on white matter development associated with altered IL-6 levels. We found that female offspring had higher levels of myelin basic protein (MBP) than males did, at postnatal day (PND) 7, 18 and 21. PCB exposure induced hypothyroxinemia in males and females at PND7, 14, 21, and 42. PCB exposure also increased MBP and reduced glial fibrillary acidic protein (GFAP) levels in males at PND21, but had the opposite effect in females. In addition, at PND 14 and 21, PCB exposure elevated IL-6 levels in male offspring only. The induction of sex-specific changes in white matter proteins, in the absence of sex differences in thyroxine levels after PCB exposure, suggests that serum thyroxine levels do not directly contribute to the white matter alterations. Instead, IL-6 may contribute to increased MBP levels in males, whereas in females estromimetic and thyromimetic PCB metabolites may affect white matter development. This data adds to an increasing body of literature showing that perinatal insults induce sex-specific effects in offspring.

Alterations in the volume, density, connectivity and functional activation of white matter tracts are reported in some individuals with autism and may contribute to their abnormal behaviors. The BTBR (BTBR T+tf/J) inbred strain of mouse, is used to model facets of autism because they develop low social behaviors, stereotypical and immune changes similar to those found in people with autism. Previously, it was thought a total absence of corpus callosal interhemispheric connective tissues in the BTBR mice may underlie their abnormal behaviors. However, postnatal lesions of the corpus callosum do not precipitate social behavioral problems in other strains of mice suggesting a flaw in this theory. In this study we used digital pathological methods to compare subcortical white matter connective tracts in the BTBR strain of mice with those found in the C57Bl/6 mouse and those reported in a standardized mouse brain atlas. We report, for the first time, a novel connective subcortical interhemispheric bridge of tissue in the posterior, but not anterior, cerebrum of the BTBR mouse. These novel connective tissues are comprised of myelinated fibers, with reduced myelin basic protein levels (MBP) compared to levels in the C57Bl/6 mouse. We used electrophysiological analysis and found increased corpus callosum connectivity in the posterior hemispheres of the BTBR strain compared with the anterior hemispheres. The conduction velocity was slower than that reported in normal mice. This study shows there is novel abnormal interhemispheric connectivity in the BTBR strain of mice, which may contribute to their behavioral abnormalities.

We suggest that hyperphosphorylated tau accumulation particularly in tyrosine hydroxylase containing neurones may impair central regulation of baroreflex responses in patients with CSH. Future clinic-pathological investigations should reveal whether medullary degeneration is the cause of CSH symptoms.

Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are widespread environmental contaminants associated with changes in behavior and neurochemical function in laboratory animals and behavioral deficits in children. PCBs and PBDEs are found in food, especially in seafood and dairy products, and coexposure to these contaminants is likely. We examined the effects of an environmentally relevant mixture of PCBs (Fox River Mix [FRM]) and a PBDE mixture (DE-71) alone and in combination on synaptosomal and medium dopamine (DA) levels and the levels of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in striatal synaptosomes derived from postnatal days (PND) 7, PND14, or PND21 rats. FRM elevated medium DA and reduced synaptosomal DA concentrations with greater potency than equimolar concentrations of DE-71. The effects of FRM, but not DE-71, were dependent on the age of the animals from which the synaptosomes were derived, with greater effects observed in synaptosomes from the youngest animals. We used Bliss' model of independence to assess the possible interaction(s) of a 1:1 mixture of FRM and DE-71 on synaptosomal DA function and found that the effects of the FRM/DE-71 mixture were additive. Furthermore, as for FRM alone, the effects of the FRM/DE71 mixture were greater in synaptosomes prepared from PND7 rats than in synaptosomes from PND14 and PND21 rats. Because the effects of these contaminants are additive, it is necessary to take into account the cumulative exposure to organohalogen contaminants such as PCBs and PBDEs during risk assessment.