14 research outputs found
Gene expression patterns in the hippocampus and amygdala of endogenous depression and chronic stress models
The etiology of depression is still poorly understood, but two major causative hypotheses have been put forth: the monoamine deficiency and the stress hypotheses of depression. We evaluate these hypotheses using animal models of endogenous depression and chronic stress. The endogenously depressed rat and its control strain were developed by bidirectional selective breeding from the Wistar–Kyoto (WKY) rat, an accepted model of major depressive disorder (MDD). The WKY More Immobile (WMI) substrain shows high immobility/despair-like behavior in the forced swim test (FST), while the control substrain, WKY Less Immobile (WLI), shows no depressive behavior in the FST. Chronic stress responses were investigated by using Brown Norway, Fischer 344, Lewis and WKY, genetically and behaviorally distinct strains of rats. Animals were either not stressed (NS) or exposed to chronic restraint stress (CRS). Genome-wide microarray analyses identified differentially expressed genes in hippocampi and amygdalae of the endogenous depression and the chronic stress models. No significant difference was observed in the expression of monoaminergic transmission-related genes in either model. Furthermore, very few genes showed overlapping changes in the WMI vs WLI and CRS vs NS comparisons, strongly suggesting divergence between endogenous depressive behavior- and chronic stress-related molecular mechanisms. Taken together, these results posit that although chronic stress may induce depressive behavior, its molecular underpinnings differ from those of endogenous depression in animals and possibly in humans, suggesting the need for different treatments. The identification of novel endogenous depression-related and chronic stress response genes suggests that unexplored molecular mechanisms could be targeted for the development of novel therapeutic agents
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Effect of kainic acid treatment on insulin-like growth factor-2 receptors in the IGF2-deficient adult mouse brain
Insulin-like growth factor-2 (IGF2) is a member of the insulin gene family with known neurotrophic properties. The actions of IGF2 are mediated via the IGF type 1 and type 2 receptors as well as through the insulin receptors, all of which are widely expressed throughout the brain. Since IGF2 is up-regulated in the brain after injury, we wanted to determine whether the absence of IGF2 can lead to any alteration on brain morphology and/ or in the response of its receptor binding sites following a neurotoxic insult. No morphological differences were observed between the brains of IGF2 knockout (IGF2−/−) and wild-type control (IGF2+/+) mice. However, our in vitro receptor autoradiography results indicate that IGF2−/− mice had lower endogenous levels of [125I]IGF1 and [125I]insulin receptor binding sites in the hippocampus and cerebellum as compared to IGF2+/+ mice, while endogenous [125I]IGF2 receptor binding showed a decrease only in the cerebellum. Seven days after kainic acid administration, the [125I]insulin receptor binding sites were significantly decreased in all brain regions of the IGF2+/+ mice, while the levels of [125I]IGF1 and [125I]IGF2 binding sites were decreased only in select brain areas. The IGF2−/− mice, on the other hand, showed increased [125I]IGF1 and [125I]IGF2 and [125I]insulin receptor binding sites in selected regions such as the hippocampus and cerebellum. These results, taken together, suggest that deletion of IGF2 gene does not affect gross morphology of the brain but does selectively alter endogenous [125I]IGF1, [125I]IGF2 and [125I]insulin receptor binding sites and their response to neurotoxicity
Localization of theta alloantigens in mouse brain by immuno- fluorescence and cytotoxic inhibition.
A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis.
XRCC4 was identified via a complementation cloning method that employed an ionizing radiation (IR)-sensitive hamster cell line. By gene-targeted mutation, we show that XRCC4 deficiency in primary murine cells causes growth defects, premature senescence, IR sensitivity, and inability to support V(D)J recombination. In mice, XRCC4 deficiency causes late embryonic lethality accompanied by defective lymphogenesis and defective neurogenesis manifested by extensive apoptotic death of newly generated postmitotic neuronal cells. We find similar neuronal developmental defects in embryos that lack DNA ligase IV, an XRCC4-associated protein. Our findings demonstrate that differentiating lymphocytes and neurons strictly require the XRCC4 and DNA ligase IV end-joining proteins and point to the general stage of neuronal development in which these proteins are necessary