Wheel running and environmental enrichment differentially modify exon‐specific BDNF expression in the hippocampus of wild‐type and pre‐motor symptomatic male and female Huntington's disease mice

Abstract

Brain-derived neurotrophic factor (BDNF) is an essential neurotrophin and regulation of its expression is complex due to multiple 5' untranslated exons which are separately spliced to a common coding exon to form unique mRNA transcripts. Disruption of BDNF gene expression is a key to the development of symptoms in Huntington's disease (HD), a fatal neurodegenerative condition. Abnormal epigenetic modifications are associated with reduced gene expression in late-stage HD but such regulation of BDNF gene expression has yet to be investigated. We hypothesized that BDNF gene expression is altered in the HD hippocampus of pre-motor symptomatic R6/1 transgenic HD mice, correlating with a change in the DNA methylation profile. The effects of wheel-running and environmental enrichment on wild-type mice, in association with a proposed environment-mediated correction of BDNF gene expression deficits in HD mice, were also investigated. Using real-time PCR, levels of total BDNF mRNA were found to be reduced in the hippocampus of both male and female HD mice. Wheel-running significantly increased total BDNF gene expression in all groups of mice except male HD mice. In contrast, environmental enrichment significantly increased expression only in male wild-type animals. Further quantification of BDNF exon-specific transcripts revealed sex-specific changes in relation to the effect of the HD mutation and differential effects on gene expression by wheel-running and environmental enrichment. The HD-associated reduction of BDNF gene expression was not due to increased methylation of the gene sequence. Furthermore, environment-induced changes in BDNF gene expression in the wild-type hippocampus were independent of the extent of DNA methylation. Overall, the results of this study provide new insight into the role of BDNF in HD pathogenesis in addition to the mechanisms regulating normal BDNF gene expression.

First use of creatine hydrochloride in premanifest Huntington disease

“…The paradigm of environmental enrichment employs increased mental, physical and social stimulation in animal models to enhance neurological input, thereby modulating brain activity and physical parameters to impact on disease progression [62][63][64][65][66][67] . A number of studies have shown the benefits of such an approach in Huntington's disease transgenic animal models, with evidence for it being able to delay the onset of motor abnormalities, slow disease progression, reduce impairments to weight loss, balance and physiological factors, and increase both neurogenesis and CNS levels of neurotransmitter receptors, neurotrophins and factors related to synaptic signal transduction pathways [68][69][70][71][72][73][74][75][76][77][78][79][80][81][82] .…”

“…Exercise induces increased BDNF expression in rodents 104,105 and in human populations [106][107][108] and cortical expression is upregulated in animal models, including models of Huntington's disease, after exercise or environmental enrichment 77,82,109,110 .…”

Female C57BL/6 mice show consistent individual differences in spontaneous interaction with environmental enrichment that are predicted by neophobia

“…Rodents with anhedonia, as can be induced by long-term impoverished caging [26] and also varies with strain [27] with enrichments that to other rodents act as valued incentives. Overall, variation between rodents in neophobia and anhedonia may thus help explain why not just strain, but also sex, age and individual characteristics can influence experimental outcomes, even when enrichments are carefully standardized [28][29][30][31][32][33][34][35]. Here, we therefore used individual variation in responses to standardized enrichments to conduct preliminary tests of the hypotheses that neophobia and anhedonia affect the extent to which mice interact with environmental enrichments.…”

“…Changes to the enrichments and cage layout occurred weekly at cage cleaning, following the protocols of prior studies [35,39,40]; on this day, mice were denied access to the enriched cage. Enriched cages were always re-provisioned in the same way so that all 19 remained identical.…”

Reprint of Female C57BL/6 mice show consistent individual differences in spontaneous interaction with environmental enrichment that are predicted by neophobia

“…Rodents with anhedonia, as can be induced by long-term impoverished caging [26] and also varies with strain [27] may also fail to show much interaction with enrichments that to other rodents act as valued incentives. Overall, variation between rodents in neophobia and anhedonia may thus help explain why not just strain, but also sex, age and individual characteristics can influence experimental outcomes, even when enrichments are carefully standardized [28][29][30][31][32][33][34][35]. Here, we therefore used individual variation in responses to standardized enrichments to conduct preliminary tests of the hypotheses that neophobia and anhedonia affect the extent to which mice interact with environmental enrichments.…”