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Epigenetics

Memory, Learning and BDNF  gene expression. Epigenetics. Epigenetics Overview:. I. Mechanism for stable maintenance of gene expression that involves physically 'marking' DNA or its associated proteins.     A. Addresses issues of where, when & how gene is expressed

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Epigenetics

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  1. Memory, Learning and BDNF gene expression Epigenetics

  2. Epigenetics Overview: • I. Mechanism for stable maintenance of gene expression that involves physically 'marking' DNA or its associated proteins. •     A. Addresses issues of where, when & how gene is expressed •     B. May play critical role in cancer, depression, psychosomatic diseases & memory formation.  •         1. If an identical twin has cancer it does not mean their "clone" will as well.

  3. Mechanisms • 1. Tagging of Histones •     a) Acetylation: Gene expression activated during         transcription •     b) Phosphorylation: activated •     c) Ubiquitylation: silenced • 2. DNA changes: •     a) Methylation: Downregulation of • transcription (silenced): (Jirtle 2003) • 3. RNAi: disrupts gene expression •     a) non-coding RNA •     b) X-chromosome inactivation •     c) Circadian Rhythmicity

  4. The Epigenome and LTPJunko et al (2009) • I. Long Term Potentiation (LTP): EPSPs that last > 10 min. due to upregulation of receptors that depolarize the cell. WOW! •     A. Mice bred null for ras-grf1/ ras-grf 2 vs. control wildtype •         1. 1/2 of each group exposed to EE •             -Magnitude of LTP remains high for MONTHS in EE mice! •         2. 15 day old mice exposed to 14 days of EE and allowed to mate • -WE CAN CHANGE OUR  •     DESTINY!!

  5. Brain-Derived Neurotrophic Factor (BDNF) • - Important for neurons to grow and connect to each other, and contributes to long-term potentiation • - Both are part of "neural plasticity" = the ability of the brain to change as a result of experience • -Shown in  aplysia that long term memories cannot be formed when BDNF is blocked (University of California - Irvine (2006, September 6). Proteins Necessary For Brain Development Found To Be Critical For Long-term Memory. ScienceDaily. Retrieved May 5, 2011, from http://www.sciencedaily.com/releases/2006/09/060905225522.htm)

  6. Experiment:"Epigenetic Regulation of bdnf Gene Transcription in the Consolidation of Fear Memory" (Lubin et al, 2008) • 3 groups of rats: •     1) fear conditioned = associative contextual conditioning •     2) naive = novel context learning •     3) shock-alone  • mRNA levels were measured in the CA1 region of hippocampus 0.5, 2, and 24 hours after conditioning and DNA methylation changes at bdnf gene were measured 

  7. Results •    * site-specific initiation of bdnf transcription •         - associative fear conditioning = increase in exon        IV-containing transcripts •     - context learning = exon I and VI transcribed •   *DNA methylation consistent with bdnf transcription

  8. Experiment: "Lasting Epigenetic Influence of Early-Life Adversity on the BDNF Gene"(Roth et al, 2009) • -Stress-induced changes in behavior may be connected to changes in neural plasticity in prefrontal cortex (PFC) and the hippocampus • -Newborn rats were exposed to a stressed-abusive mother, a positive caregiving mother, or their own natural mother • RESULTS •     - Rats with adverse early-life experiences showed an increase in methylation and decrease of expression of BDNF gene in PFC, which lasted into adulthood •     - Maltreatment (initially) caused increase in mRNA levels in hippocampus, as did rats who were exposed to positive caregiving mothers     exposure to new things! • -increased methylation of BDNF gene was passed on to next generation

  9. Conclusion • Epigenetics plays an important role in memory and learning. •         - selective methylation at bdnf gene in hippocampus and                  PFC • Epigenetic changes can be maintained, and even inherited. • Understanding epigenetic mechanisms could lead to improved treatments for a wide array of illnesses, both physical and psychiatric. • Some treatments already available....

  10. Sources • Holt. (2007). Epigenetics:Environmental factors can alter the way our genes are expressed, making even identical twins different. PBS. NOVA.  • Junko, et. al. (2009). Transgenerational Rescue of a Genetic Deficit in LTP and Memory Formation by Juvenile Enrichment. Journal of Neuroscience. 1496-1502.  • Cloud, J. (2010). Why Your DNA Isn't Your Destiny. New York Times.  • University of California - Irvine (2006, September 6). Proteins Necessary For Brain Development Found To Be Critical For Long-term Memory. ScienceDaily. Retrieved May 5, 2011, from http://www.sciencedaily.com/releases/2006/09/060905225522.htm • Lubin, F. D., Roth, T. L., Sweatt, D. (2008). Epigenetic Regulation of bdnf Gene Transcription in the Consolidation of Memory. The Journal of Neuroscience. 10576-10586. • Roth, T. L., Lubin, F. D., Funk, A.J., Sweatt, D. (2009). Lasting Epigenetic Influence of Early-Life Adversity on the BDNF Gene. Biol Psychiatry. 760-769.

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