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

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. http://www.pbs.org/wgbh/nova/body/epigenetics.html

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.

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!         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) - 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)  

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

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

-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

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 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.