1. Memory, Learning and BDNF gene expression
Epigenetics
Memory, Learning and BDNF gene expression

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
book.

4. The Epigenome and LTP Junko 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!
        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

7. 1) fear conditioned = associative contextual conditioning
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 
- bdnf gene expression in the hippocampus after contextual and spacial learning essential for normal learning and memory

8. 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

9. -increased methylation of BDNF gene was passed on to next generation
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
- Abuse and neglect in childhood are known to increase susceptibility to cognitive deficits and psychiatric disorders
-Epigenetics, specifically DNA methylation, is a critical aspect of neural plasticity

10. 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....

11. 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  
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
Lubin, F. D., Roth, T. L., Sweatt, D. (2008). Epigenetic Regulation of bdnf Gene Transcription in the Consolidation of Memory. The Journal of Neuroscience
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