Neuroscience
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Circadian behavioral rhythms in mammals are controlled by a central clock located in the suprachiasmatic nucleus (SCN). PER2, the protein product of the clock gene, Period 2 (Per2), is expressed rhythmically in the SCN [Beaule C, Houle LM, Amir S (2003) Expression profiles of PER2 immunoreactivity within the shell and core regions of the rat suprachiasmatic nucleus: Lack of effect of photic entrainment and disruption by constant light. J Mol Neurosci 21:133-148] and has been implicated in the control of circadian behavioral rhythms based on the evidence that genetic mutations in Per2 abolish free running locomotor activity rhythms in mice [Zheng B, Larkin DW, Albrecht U, Sun ZS, Sage M, Eichele G, Lee CC, Bradley A (1999) The mPer2 gene encodes a functional component of the mammalian circadian clock. ⋯ We found that transient suppression of PER2 in the SCN disrupted free running locomotor activity rhythms for up to 10 days in rats. Infusions of control dsRNA into the SCN or infusions of dsRNA to Per2 immediately dorsal to the SCN had no effect. These results constitute evidence for a direct link between PER2 expression in the SCN and the expression of behavioral circadian rhythms in mammals.
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It has previously been reported that dopaminergic grafts derived from early donor age, embryonic age 12-day-old (E12) rat embryos produced a fivefold greater yield of dopamine neurons than those derived from conventional E14 donors. The present study addresses whether E12 grafts are able to ameliorate lesion-induced behavioral deficits to the same extent as E14 grafts. In a unilateral rat model of Parkinson's disease, animals received grafts derived from either E12 or E14 donor embryos, dispersed at four sites in the lesioned striatum. ⋯ However, E12 grafts resulted in cell yields greater than previously reported for untreated primary tissue, with mean TH-positive cell counts in excess of 25,000 neurons, compared with E14 TH cell counts of 4000-5000 cells, representing survival rates of 75% and 12.5%, respectively, based on the expected adult complement. The equivalence of graft induced behavioral recovery between the two graft groups is attributed to a threshold number of cells, above which no further improvement is seen. Such high dopamine cell survival rates should mean that multiple, functioning grafts can be derived from a single embryonic donor, and if similar yields could be obtained from human tissues then the goal of one embryo per patient would be achieved.
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Regulation of adult hippocampal neurogenesis in mice responds to behavioral stimuli, including physical activity (RUN) and the exposure to enriched environments (ENR). If studied after days or weeks, these stimuli and the pathological stimulus of kainic acid-induced seizures (KA) show differential effects on different developmental stages of adult neurogenesis. The question thus arose, whether such differential effects would also be apparent under very acute conditions. ⋯ Twenty-four hours after the stimulus adult neurogenesis showed a very similar response to the three paradigms, in that cell proliferation increased. Detailed analysis, however, revealed the following new results: (1) KA, but not RUN and ENR stimulated the division of radial glia-like type-1 cells, (2) KA led to the disappearance of proliferative undetermined progenitor cells (type-2a), (3) only RUN increased proliferation of type-2a cells, (4) ENR and KA, in contrast, acted on lineage-determined progenitor cells (type-2b and type-3) even under acute conditions, and (5) only in the case of KA the short-term stimulus resulted in measurably increased survival of newborn neurons 4 weeks later. These results confirm and specify the idea that in the course of neuronal development in the adult hippocampus, precursor cells acutely sense and distinguish various forms of "activity" differentially and translate these stimuli into defined responses based on their stage of development.
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Recent data have indicated that the neuropeptide cocaine amphetamine-regulated transcript (CART) may be a downstream mediator of the effect of CB1 receptor antagonist on appetite regulation. In order to identify possible interactions between CART and central CB1R expressing neurons, a detailed mapping of CART and CB1R expression and immunoreactivity in the brain was initiated. Single radioactive in situ hybridizations revealed a predominant overlap between CART and CB1R mRNA in hypothalamic and lower brainstem nuclei. ⋯ Further attempts to immunohistochemically characterize the distribution of CB1R were, however, deemed impossible as any of eight commercially available antibodies/antisera gave rise to non-specific staining patterns. Furthermore, the staining pattern obtained was not discriminate between CB1R knockout mice and wild type mice. Collectively, we demonstrate at the messenger level that CB1R expressing perikarya colocalize with CART expressing neurons in hypothalamic and brainstem areas known to be important in appetite control, whereas interactions at the protein level necessitate a demand for cautious interpretations of immunohistochemical results.
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Inflammation following ischemic stroke is known to contribute to injury. NADPH oxidase (NOX) is a major enzyme system originally studied in immune cells that leads to superoxide (O.*) generation. Apocynin is a NOX inhibitor that has been studied as a potential treatment in experimental stroke. ⋯ Using hydroethine fluorescence to delineate O.* in the brain, neurons and some microglia/macrophages, but not vascular endothelial cells were found to contain O.*. Apocynin at protective doses markedly prevented ischemia-induced increases in O.*. Our data suggested that apocynin can protect against experimental stroke, but with a narrow therapeutic window.