Long term behavioral and epigenetic alterations following chronic stress exposure in middle-aged mice and effectof iHDAC administration
Data showed thatchronic stress exposure during middle-age inducespersistent stress symptoms such as increased anxiety and depression state leading to long-lasting emotional disorders that can extend to cognitive deficits. Changes in epigenetic regulations, such as histonesacetylation and methylation, have been identified as a key mechanism through whichstressexposures induce emotional and cognitive alterations. In this study, we investigated the long-lasting behavioral impacts of chronic stress exposuresand their epigenetic correlates with aging. C57bl/6 mice underwent an unpredictable chronic mild stress procedure (UCMS) for 6 weeks at either 5month-(adult) or 10-month-old(middle-age) while age-matched controls remained undisturbed (non-stressed groups). All mice underwent a battery of behavioral testing when getting the age of 18 monthsand then,were killed for immunohistochemical detection of the transcriptional repressive histone H3tri-methylation at lysine 27(H3K27me3)andthe transcriptional permissivehistone H3acetylationat lysine 9(H3K9ac). Trait anxiety in the elevated plus-maze, but not reactive anxiety in the marble burying test, as well as despair in tail suspension tests were increased inmice that had experienced UCMS at 10monthsas compared to controls. Spatial memory in water-maze and working memory were also further impaired. Principal component analysis confirmed a clear-cut separation of the behavioral patterns in these two groups ofmice. These behavioral impairments were associated with changesin histone H3K27me3in CA1area of the ventralhippocampus, the prefrontal cortex and lateral nucleus of the amygdalabut no variations of H3K9ac was foundin any area.In contrast, mice exposed to UCMS at 5-month-old, did not display any persistent deficits nor any epigenetic changes when getting aged.In conclusion, these results indicate that chronic stress stronger impactson behavioral emotionality and cognitive aging in association with epigenetic regulatory changes in middle-aged adults. Although adulthood has been associated with an increase in stress resistance, a second phase of vulnerability to stress emergesat midlife and interfereswith brain aging.In another hand we also investigated the effectof chronic administration of theiHDACSodium Butyrate (NaB) onlong termbehavioral and epigenetic alterationsfollowing chronic stressin middle-aged mice. NaB partially reversed behavioral alterations and induced epigeneticlong-termmodifications.
Keywords: Chronic stress, behavior, ageing, anxiety, depression, spatial memory, working memory, epigenetic, H3K9ac, H3K27me3, HDACi, NaB.
(En cours de révision)
The Histone H3 Lysine 9 Methyltransferase G9a/GLP complex activity is required for long-term consolidation of spatial memory in mice.
Kyrian Nicolay-Kritter, Jordan Lassalle, Jean-Louis Guillou and Nicole Mons
M. Etienne Coutureau, Président
Mme Catherine Belzung, Rapporteur
Mme Monique Majchrzak, Rapporteur
M.Jean-Louis Guillou, Examinateur