Epigenetics

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Epigenetics

• Memory, Learning and BDNF gene expression

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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.

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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
•  

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The Epigenome and LTPJunko et al (2009)

• I. Long Term Potentiation (LTP) EPSPs that last
  gt 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!!

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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.sciencedail
  y.com/releases/2006/09/060905225522.htm)
•  

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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 

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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

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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

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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....

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Sources

• Holt. (2007). EpigeneticsEnvironmental 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/2006/09/06090
  5225522.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 In?uence of Early-Life
  Adversity on the BDNF Gene. Biol Psychiatry.
  760-769.