memory learning and bdnf gene expression l.
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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 overview
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.
mechanisms
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
the epigenome and ltp junko et al 2009
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!!
brain derived neurotrophic factor bdnf
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)
slide7
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 
results
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
experiment lasting epigenetic influence of early life adversity on the bdnf gene roth et al 2009
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
conclusion
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....
sources
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.