No abstract

During treatment of brain tumors, some head and neck tumors, and other diseases, like arteriovenous malformations, the normal brain is exposed to ionizing radiation. While high radiation doses can cause severe tissue destruction, lower doses can induce cognitive impairments without signs of overt tissue damage. The underlying pathogenesis of these impairments is not well understood but may involve the neural precursor cells in the dentate gyrus of the hippocampus. To assess the effects of radiation on cognitive function, 2-month-old mice received either sham treatment (controls) or localized X irradiation (10 Gy) to the hippocampus/cortex and were tested behaviorally 3 months later. Compared to controls, X-irradiated mice showed hippocampal-dependent spatial learning and memory impairments in the Barnes maze but not the Morris water maze. No nonspatial learning and memory impairments were detected. The cognitive impairments were associated with reductions in proliferating Ki-67-positive cells and Doublecortin-positive immature neurons in the subgranular zone (SGZ) of the dentate gyrus. This study shows significant cognitive impairments after a modest dose of radiation and demonstrates that the Barnes maze is particularly sensitive for the detection of radiation-induced cognitive deficits in young adult mice. The significant loss of proliferating SGZ cells and their progeny suggests a contributory role of reduced neurogenesis in the pathogenesis of radiation-induced cognitive impairments.

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Development of visual system circuitry requires the formation of precise synaptic connections between neurons in the retina and brain. For example, retinal ganglion cells (RGCs) form synapses onto neurons within subnuclei of the lateral geniculate nucleus (LGN) – i.e. the dorsal LGN (dLGN), ventral LGN (vLGN) and intergeniculate leaflet (IGL). Distinct classes of RGCs project to these subnuclei: the dLGN is innervated by image-forming RGCs, while the vLGN and IGL are innervated by non-image-forming RGCs. To explore potential mechanisms regulating class-specific LGN targeting we sought to identify differentially expressed targeting molecules in these LGN subnuclei. One candidate targeting molecule enriched in the vLGN and IGL during retinogeniculate circuit formation was the extracellular matrix molecule reelin. Anterograde labeling of RGC axons in mutant mice lacking functional reelin (relnrl/rl) revealed reduced patterns of vLGN and IGL innervation and misrouted RGC axons in adjacent non-retino-recipient thalamic nuclei. Using genetic reporter mice, we further demonstrated that mistargeted axons were from non-image-forming, intrinsically-photosensitive RGCs (ipRGCs). In contrast to mistargeted ipRGC axons, axons arising from image-forming RGCs and layer VI cortical neurons correctly targeted the dLGN in relnrl/rl mutants. Taken together, these data reveal reelin is essential for the targeting of LGN subnuclei by functionally distinct classes of RGCs.

BackgroundMost retinal ganglion cells (RGCs) convey contrast and motion information to visual brain centers. Approximately 2% of RGCs are intrinsically photosensitive (ipRGCs), express melanopsin and are necessary for light to modulate specific physiological processes in mice. The ipRGCs directly target the suprachiasmatic nucleus (SCN) to photoentrain circadian rhythms, and the olivary pretectal nucleus (OPN) to mediate the pupillary light response. How and when this ipRGC circuitry develops is unknown.ResultsHere, we show that some ipRGCs follow a delayed developmental time course relative to other image-forming RGCs. Specifically, ipRGC neurogenesis extends beyond that of other RGCs, and ipRGCs begin innervating the SCN at postnatal ages, unlike most RGCs, which innervate their image-forming targets embryonically. Moreover, the appearance of ipRGC axons in the OPN coincides precisely with the onset of the pupillary light response.ConclusionsSome ipRGCs differ not only functionally but also developmentally from RGCs that mediate pattern-forming vision.

The data demonstrate the presence of a delayed ERG b-wave in SG711 mice and a functionally redundant role for RGS11 and -7 at the tips of ON-bipolar cell dendrites. These results suggest that RGS11 or -7 works as the major physiological GAP (GTPase acceleration protein) for Galphao1 in ON-bipolar cells.

Two chimpanzees, 1535 and 1536, became persistently infected following inoculation with RNA transcripts from cDNA clones of hepatitis C virus (HCV). Analysis of the HCV genomes from both animals showed an accumulation of amino acid substitutions over time. The appearance of substitutions in the envelope genes was associated with increased antienvelope antibody titers. However, extensive mutations were not incorporated into hypervariable region 1 (HVR1). A comparison of the nonsynonymous substitution rate/synonymous substitution rate was made at various time points to analyze selective pressure. The highest level of selective pressure occurred during the acute phase and decreased as the infection continued. The nonsynonymous substitution rate was initially higher than the synonymous substitution rate but decreased over time from 3.3 ؋ 10 ؊3 (chimpanzee 1535) and 3.2 ؋ 10 ؊3 (chimpanzee 1536) substitutions/site/year at week 26 to 1.4 ؋ 10 ؊3(chimpanzee 1535) and 1.7 ؋ 10 ؊3 (chimpanzee 1536) at week 216, while the synonymous substitution rate remained steady at ϳ1 ؋ 10 ؊3 substitutions/site/year. Analysis of PCR products using single-stranded conformational polymorphism indicated a low level of heterogeneity in the viral genome. The results of these studies confirm that the persistence of infection is not solely due to changes in HVR1 or heterogeneity and that the majority of variants observed in natural infections could not arise simply through mutation during the time period most humans and chimpanzees are observed. These data also indicate that immune pressure and selection continue throughout the chronic phase.Hepatitis C virus (HCV) was first identified in 1989 (6) and is the major causative agent of parenterally transmitted non-A, non-B hepatitis. In general, chronic infections in chimpanzees exhibit only very mild hepatitis, while a wide spectrum of disease is observed in humans, ranging from nonapparent to mild to severe chronic active hepatitis or end-stage cirrhosis and, potentially, hepatocellular carcinoma (25). However, the more serious forms of chronic liver disease in association with HCV in humans are usually not seen until at least the third decade after infection. Very few chimpanzees have been monitored for that length of time; therefore, similar long-range illnesses in this animal model cannot be excluded.The mechanisms leading to viral persistence, which is associated with the more severe forms of liver disease, are as yet undefined. Any single HCV isolate exists as a quasispecies with sequence variability throughout the RNA genome (3,27). This variation could lead to evasion of the host immune response through the selection of neutralizing antibody or cytotoxic Tlymphocyte escape mutants and thereby the establishment of persistent infection. Evidence for both types of escape mutants have been reported in HCV infections (4,7,13,31). Reports have indicated that hypervariable region 1 (HVR1), located in the N terminus of the E2 protein, evolves more rapidly in vivo than the rest of the viral gen...

The link between neural activity and the refinement of projections from retina to the dorsal lateral geniculate nucleus (dLGN) of thalamus is based largely on studies that disrupt presynaptic retinogeniculate activity. Postsynaptic mechanisms responsible for implementing the activity-dependent remodeling in dLGN remain unknown. We tested whether L-type Ca 2ϩ channel activity in the form of synaptically evoked plateau potentials in dLGN cells is needed for remodeling by using a mutant mouse that lacks the ancillary ␤ 3 subunit and, as a consequence, has highly reduced L-type channel expression and attenuated L-type Ca 2ϩ currents. In the dLGNs of ␤ 3 -null mice, glutamatergic postsynaptic activity evoked by optic tract stimulation was normal, but plateau potentials were rarely observed. The few plateaus that were evoked required high rates of retinal stimulation, but were still greatly attenuated compared with those recorded in age-matched wild-type mice. While ␤ 3 -null mice exhibit normal stage II and III retinal waves, their retinogeniculate projections fail to segregate properly and dLGN cells show a high degree of retinal convergence even at late postnatal ages. These structural and functional defects were also accompanied by a reduction in CREB phosphorylation, a signaling event that has been shown to be essential for retinogeniculate axon segregation. Thus, postsynaptic L-type Ca 2ϩ activity plays an important role in mediating the refinement of the retinogeniculate pathway.