Neurotrophins cooperate with neural activity to modulate CNS neuronal survival and dendritic differentiation. In a previous study, we demonstrated that a critical balance of neurotrophin and neural activity is required for Purkinje cell survival in cocultures of purified granule and Purkinje cells (Morrison and Mason, 1998). Here we investigate whether TrkB signaling regulates dendrite and spine development of Purkinje cells. BDNF treatment of purified Purkinje cells cultured alone did not elicit formation of mature dendrites or spines. In cocultures of granule and Purkinje cells, however, continuous treatment with BDNF over a 2 week postnatal culture period increased the density of Purkinje cell dendritic spines relative to controls without causing a shift in the proportions of headed and filopodia-like spines. The increase in spine number was blocked by adding TrkB-IgG to the medium together with BDNF. Although BDNF alone did not consistently modify the morphology of dendritic spines, treatment with TrkB-IgG alone yielded spines with longer necks than those in control cultures. None of these treatments altered Purkinje cell dendritic complexity. These analyses reveal a role for TrkB signaling in modulating spine development, consistent with recently reported effects of neurotrophins on synaptic function. Moreover, spine development can be uncoupled from dendrite outgrowth in this reductionist system of purified presynaptic and postsynaptic neurons.

Systemic inflammation shifts the brain microenvironment towards a proinflammatory state. However, how peripheral inflammation mediates changes in the brain remains to be clarified. We aimed to identify hippocampal cells and cytokines that respond to endotoxemia. Mice were intraperitoneally injected with lipopolysaccharide (LPS) or saline, and examined 1, 4, and 24 h after injection. Tissue cytokine concentrations in the spleens and hippocampi were determined by multiplex assays. Another group of mice were studied immunohistologically. Fourteen cytokines showed an increased concentration in the spleen, and 10 showed an increase in the hippocampus after LPS injection. Cytokines increased at 4 h (CCL2, CXCL1, CXCL2, and interleukin-6) were expressed by leptomeningeal stromal cells, choroid plexus stromal cells, choroid plexus epithelial cells, and hippocampal vascular endothelial cells, all of which were located at the brain–immune interface. Receptors for these cytokines were expressed by astrocytic endfeet. Cytokines increased at 24 h (CCL11, CXCL10, and granulocyte-colony stimulating factor) were expressed by astrocytes. Cells of the brain–immune interface therefore respond to endotoxemia with cytokine signals earlier than hippocampal parenchymal cells. In the parenchyma, astrocytes play a key role in responding to signals by using endfeet located in close apposition to the interface cells via cytokine receptors.

Our aim was to identify risk factors for falling and establish a method to assess risk for falls in adults with intellectual disabilities. In a cross-sectional survey of 144 Japanese adults, we found that age, presence of epilepsy, and presence of paretic conditions were independent risk factors. The Tinetti balance and gait instrument was successfully administered to this population and resulted in high diagnostic accuracy (sensitivity 88.9%, specificity 91.9%) for identifying individuals at risk when the cutoff score was set at 25. Participants whose balance and gait deteriorated showed a decrease in the Tinetti score of at least 2 points per year. Thus, the Tinetti instrument may be an effective tool to detect an increased risk of fall in this population.

SummaryOxidative stress, an imbalance between endogenous levels of oxygen radicals and antioxidative defense, increases with aging. However, it is not clear which of these two factors is the more critical. To clarify the production of oxygen radicals increases with age, we examined oxygen radical-dependent chemiluminescent signals in ex vivo brain slices using a novel photonic imaging method. The chemiluminescent intensity was significantly decreased by the membrane permeable superoxide dismutase (SOD)/catalase mimic, but not by Cu,Zn-SOD. Inhibitors for complex I, III, and IV of the mitochondrial electron transport chain transiently enhanced the chemiluminescent signal. The superoxide-dependent chemiluminescent intensity in senescence accelerated mouse (SAM) brain tissues increases with age. Moreover, the slope of the age-dependent increase was steeper in SAMP10, a strain characterized by a short lifespan and atrophy in the frontal cerebral cortex, than the senescenceresistant strain SAMR1, which has a longer lifespan. An increase in chemiluminescence with age was also observed in C57/BL6 mice, Wistar rats, and pigeons, although levels of chemiluminescence were lower in the pigeons than murines. The rate of age-related increases of superoxidedependent chemiluminescence was inversely related to the maximum lifespan of the animals. The activity of superoxide dismutase was unchanged during the aging process in the brain. This suggested that superoxide production itself may increase with age. We speculated that reactive oxygen may be a signal to determine the aging process.

The olfactory mucosa (OM) is exposed to environmental agents and therefore vulnerable to inflammation. To examine the effects of environmental toxin-initiated OM inflammation on the olfactory bulb (OB), we induced persistent rhinitis in mice and analyzed the spatial and temporal patterns of histopathological changes in the OM and OB. Mice received unilateral intranasal administration of lipopolysaccharide (LPS) or saline three times per week, and were immunohistologically analyzed at 1, 3, 7, 14 and 21 days after the first administration. LPS administration induced an inflammatory response in the OM, including the infiltration of Ly-6G-, CD11b-, Iba-1- and CD3-positive cells, the production of interleukin-1β by CD11b- and Iba-1-positive cells, and loss of olfactory sensory neurons (OSNs). In the OB, we observed activation of microglia and astrocytes and decreased expression of tyrosine hydroxylase in periglomerular cells, vesicular glutamate transporter 1, a presynaptic protein, in mitral and tufted projection neurons, and 5T4 in granule cells. Thus, the OM inflammation exerted a detrimental effect, not only on OSNs, but also on OB neurons, which might lead to neurodegeneration.

No abstract

Experimental allergic encephalomyelitis (EAE) serves as a model for multiple sclerosis and is considered to be a CD4+ Th1 cell–mediated autoimmune disease. To investigate the role of platelet-activating factor (PAF) in this disease, PAF receptor (PAFR) KO (PAFR-KO) and wild-type (WT) mice, on a C57BL/6 genetic background, were immunized with myelin oligodendrocyte glycoprotein 35–55. The levels of PAF production and PAFR mRNA expression in the spinal cord (SC) correlated with the EAE symptoms. PAFR-KO mice showed lower incidence and less severe symptoms in the chronic phase of EAE than WT mice. However, no difference was observed in T cell proliferation, Th1-cytokine production, or titer of IgG2a between both genotypes. Before onset, as revealed by microarray analysis, mRNAs of inflammatory mediators and their receptors—including IL-6 and CC chemokine receptor 2—were down-regulated in the SC of PAFR-KO mice compared with WT mice. Moreover, in the chronic phase, the severity of inflammation and demyelination in the SC was substantially reduced in PAFR-KO mice. PAFR-KO macrophages reduced phagocytic activity and subsequent production of TNF-α. These results suggest that PAF plays a dual role in EAE pathology in the induction and chronic phases through the T cell–independent pathways.

Background: Rhinitis and rhinosinusitis are olfactory disorders caused by inflammation of the nasal passage and paranasal sinuses. Although patients with chronic rhinosinusitis have smaller olfactory bulbs (OBs), there is limited knowledge regarding the influence of chronic nasal inflammation on OB neurons. Objective: Repeated intranasal administration of LPS that induced persistent nasal inflammation in mice caused a loss of olfactory sensory neurons (OSNs) and gliosis and synaptic loss in the OBs within 3 weeks. The present study aimed to clarify the effects of long-term LPS treatment on the OB neurocircuit. Methods: LPS was repeatedly administered into a mouse nostril for up to 24 weeks. For the recovery analyses, the mice received LPS for 10 weeks and were subsequently maintained without additional treatment for another 10 weeks. The effects of these treatments on the OBs were examined histologically. Three or more mice were analyzed per group. Results: Long-term repeated LPS administration caused OB atrophy, particularly in the layers along which OSN axons travel and in the superficial external plexiform layer, in which tufted cells form synapses with interneurons. Interestingly, the OBs recovered from atrophy after cessation of LPS administration: OB volume and superficial external plexiform layer thickness returned to pretreatment levels after the nontreatment period. In contrast, OSN regeneration was incomplete. Conclusion: These results suggest that chronic nasal inflammation induces structural changes in a specific OB circuit related to tufted cells, whereas tufted cells retain a high degree of plasticity that enables recovery from structural damages after inflammation subsides.