title: Impaired basal and running-induced hippocampal neurogenesis coincides with reduced Akt signaling in adult R6/1 HD mice.
abstract: Huntington's disease (HD) is a fatal neurodegenerative disorder affecting a range of cellular and molecular functions in the brain. Deficits in adult hippocampal neurogenesis (AHN) have been documented in the R6/1 mouse model of HD. Here we examined basal and running-induced neuronal precursor proliferation in adult female and male R6/1 HD mice. We further tested whether sequential delivery of voluntary running followed by environmental enrichment could synergistically enhance functional AHN in female R6/1 HD mice. R6/1 HD mice engaged in significantly reduced levels of voluntary running, with males showing a more severe deficit. Basal neural precursor proliferation in the hippocampal sub-granular zone remained unchanged between female and male R6/1 HD mice and neither sex significantly responded to running-induced proliferation. While discrete provision of running wheels and enriched environments doubled AHN in adult female R6/1 HD mice it did not reflect the significant 3-fold increase in female wildtypes. Nevertheless, triple-label c-Fos/BrdU/NeuN immunofluorescence and confocal microscopy provided evidence that the doubling of AHN in female R6/1 HD mice was functional. Intrinsic cellular dysfunction mediated by protein aggregates containing mutant huntingtin (mHtt) did not appear to coincide with AHN deficits. In the hippocampus of female R6/1 HD mice, proliferating precursors and 6 week old adult-generated neurons were devoid of mHtt immuno-reactive aggregates, as were endothelial, microglial and astroglial cells populating the neurogenic niche. Serum transforming growth factor-β concentrations remained unaltered in female R6/1 HD mice as did the hippocampal levels of proliferating microglia and glial fibrillarly acidic protein expression. Examining the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis showed no change in base-line serum GH between genotypes. However, despite a reduced distance, acute running increases serum GH in both female wildtype and R6/1 HD mice. Serum IGF-1 levels were increased in female R6/1 HD mice compared to wildtypes during daytime inactive period, while hippocampal levels of the IGF-1 receptor remained unchanged. Running induced Akt phosphorylation in the hippocampus of female wildtype mice, which was not reflected in R6/1 HD mice. Total Akt levels were decreased in the hippocampus of both control and running R6/1 HD mice. Our results show adult-generated hippocampal neurons in female R6/1 HD mice express c-Fos and that running and Akt signaling deficits may mediate reduced basal and running-induced AHN levels.
authors: The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, 3010, Australia. mark.ransome@florey.edu.au
authors: Mark I
authors: MI
authors: Ransome
authors: Anthony J
authors: AJ
authors: Hannan
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004268:DNA-Binding Proteins; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D013006:Growth Hormone / Q000097:blood; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism / Q000473:pathology*; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D005082:Physical Exertion; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012420:Running; D012727:Sex Characteristics; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000097:blood
chemical_list: D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D009687:Nuclear Proteins; D016760:Proto-Oncogene Proteins c-fos; D016212:Transforming Growth Factor beta; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D051057:Proto-Oncogene Proteins c-akt