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A short summary video of the conclusion

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Conclusion to Epigenetic regulation of BDNF

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This video was made for HMB360 Winter 2017

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1. Adachi, M., Barrot, M., Autry, A., Theobald, D., & Monteggia, L. (2008). Selective Loss of Brain-Derived Neurotrophic Factor in the Dentate Gyrus Attenuates Antidepressant Efficacy. Biological Psychiatry, 63(7), 642-649. http://dx.doi.org/10.1016/j.biopsych.2007.09.019

2. Aid T, Kazantseva A, Piirsoo M, Palm K, Timmusk T. (2007) Mouse and rat BDNF gene structure and expression revisited. J Neurosci Res, 85, 525-535. doi: 10.1002/jnr.21139

3. Agis-Balboa, R.C., Pavelka, Z., Kerimoglu, C., Fischer, A., (2013). Loss of HDAC5 impairs memory function: implications for Alzheimer’s disease. J Alzheimers Dis, 33, 35-44. doi: 10.3233/JAD-2012-121009

4. Hasler, G. (2010). Pathophysiology of depression: do we have any solid evidence of interest to    clinicians?. World Psychiatry, 9(3), 155-161. http://dx.doi.org/10.1002/j.2051- 5545.2010.tb00298.x

5. Koppel, I., & Timmusk, T. (2013). Differential regulation of Bdnf expression in cortical neurons   by class-selective histone deacetylase inhibitors. Neuropharmacology, 75, 106-115. http://dx.doi.org/10.1016/j.neuropharm.2013.07.015

6. Malhi, G. S., Parker, G. B., Crawford, J., Wilhelm, K., & Mitchell, P. B. (2005). Treatment-resistant depression: resistant to definition? Acta Psychiatr Scand, 112, 302-309. doi: 10.1111/j.1600-0447.2005.00602.x

7. Meylan, E. M., Halfon, O., Magistretti, P. J., & Cardinaux, J. (2016). The HDAC inhibitor SAHA improves depressive-like behavior of CRTC1-deficient mice: Possible relevance for treatment-resistant depression. Neuropharmacology, 107, 111-121. doi:10.1016/j.neuropharm.2016.03.012

8. Pizarro, J., Lumley, L., Medina, W., Robison, C., Chang, W., & Alagappan, A. et al. (2004).      Acute social defeat reduces neurotrophin expression in brain cortical and subcortical  areas in mice. Brain Research, 1025(1-2), 10-20. http://dx.doi.org/10.1016/j.brainres.2004.06.085

9. Renthal, W., Maze, I., Krishnan, V., Covington, H. E., Xiao, G., Kumar, A., . . . Nestler, E. J. (2007). Histone deacetylase 5 epigenetically controls behavioral adaptations to chronic emotional stimuli. Neuron, 56(3), 517-529. doi:10.1016/j.neuron.2007.09.032

10. Richards, D. (2011). Prevalence and clinical course of depression: A review. Clinical Psychology Review, 31(7), 1117-1125. http://dx.doi.org/10.1016/j.cpr.2011.07.004

11. Shirayama Y., Chen A.C., Nakagawa S., Russell D.S., Duman R.S. (2002). Brain-derived          neurotrophic factor produces antidepressant effects in behavioral models of depression.        Journal of Neuroscience, 22(8), 3251-3261. https://dx.doi.org/20026292

12. Sleiman, S. F., Henry, J., Al-Haddad, R., Hayek, L. E., Haidar, E. A., Stringer, T., . . . Chao, M. V. (2016). Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. ELife,5. doi:10.7554/elife.15092

13. Sun, H., Kennedy, P. J., & Nestler, E. J. (2012). Epigenetics of the depressed brain: role of histone acetylation and methylation. Neuropsychopharmacology, 38(1), 124-137. doi:10.1038/npp.2012.73

14. Tompson, M. (2000). Identifying and treating adolescent depression. Western Journal Of Medicine, 172(3), 172-176. http://dx.doi.org/10.1136/ewjm.172.3.172

15. Tsankova, N. M., Berton, O., Renthal, W., Kumar, A., Neve, R. L., & Nestler, E. J. (2006). Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nature Neuroscience, 9(4), 519-525. doi:10.1038/nn1659

16. Tsankova, N. M., Renthal, W., Kumar, A., & Nestler, E. J. (2007). Epigenetic regulation in psychiatric disorders. Nature Reviews Neuroscience, 8(5), 355-367. doi:10.1038/nrn2132

17. Yoshida, T., Ishikawa, M., Niitsu, T., Nakazato, M., Watanabe, H., & Shiraishi, T. et al. (2012).   Decreased Serum Levels of Mature Brain-Derived Neurotrophic Factor (BDNF), but Not  Its Precursor proBDNF, in Patients with Major Depressive Disorder. Plos ONE, 7(8), e42676. http://dx.doi.org/10.1371/journal.pone.0042676

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A short summary video of the introduction.

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An epigenetic model of BDNF-related depression

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This video was made for HMB360 Winter 2017

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Depression was induced using Learned Helplessness (LH) model in a two way shuttle box with inescapable footshocks.

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Epigenetic regulation of BDNF in the learned helplessness-induced animal model of depression

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Figure 8: Using shRNA to knockdown HDAC5 expression in the hippocampus ameliorated depression-like behavarios in LH mice. Scrambled shRNA had no effect.

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Figure 7: The authors used western blot  to examine levels of HDAC 1-5. Only HDAC5 was significantly upregulated in LH mice compared to both LH-R and control mice.

Using ChIP assay next, they saw that binding of HDAC5 to the BDNF exon IV promoter was significantly higher in LH mice.

No difference in binding was observed between groups at other exons.

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Su et al. 2016. Figure 5, 7, and 8: HDAC5 and BDNF Regulation in Depression

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Su et al. 2016. Figure 5, 7, and 8: HDAC5 and BDNF Regulation in Depression

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Figure 5: SB and VPA are broad HDAC inhibitors.

(B) Both HDAC inhibitors improved depression-like behaviors.

(D) SB injection recovered hippocampal BDNF protein levels. The same was seen with VPA injections.

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The gene contains at least 8 untranslated exons and one 3' coding exon (exon IX).
Image from Aid et al. 2007

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Figure 3B: Hippocampal BDNF mRNA levels were lower in LH mice.

qPCR used to screen transcription of each BDNF exon

LH mice had significantly lower transcription of exon IV and IX compared to LH-R and control mice.

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Figure 2: (A,B) Immobility duration during the Forced Swim Test (FST) and Tail Suspension Test (TST) was used as a measure of depressive behavior.

LH mice spent significantly more time immobile compared to LH-R and control mice.

Suggested that the LH procedure  induced depression-like behaviors in LH but not LH-R mice.

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Su et al. 2016. Figure 2C and 3B: BDNF Expression in the Hippocampus

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Su et al. 2016. Figure 2C and 3B: BDNF Expression in the Hippocampus

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Figure 2C: Western blot analysis shows reduced levels of hippocampal BDNF protein in LH mice

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Su et al. 2016. Figure 1 and 2: LH procedure induced depression-like behaviors 

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Su et al. 2016. Figure 1 and 2: LH procedure induced depression-like behaviors 

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Figure 1: (A) Timeline of the experiment. Mice were separated into control and experimental groups. The experimental group was trained on days 2 to 4, and tested on day 5.

(B) Approximately 70% of the mice failed the escape test 25 or more times, and were classified as having learned helplessness (LH). The rest were considered learned helplessness resilient (LH-R).

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Better understanding of the role of epigenetic regulation in depression
●Epigenetic dysregulation was previously suggested to play an important role in neuropsychiatric diseases (Tsankova et al., 2007).
Opening up potential novel treatment target - HDAC inhibition
●A number of people with depression are resistant to currently available treatment (Malhi et al., 2005).
●A recent study also found that HDAC inhibition decreases depression in a mouse model (Meylan, 2016).

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This study aimed to investigate the interaction between HDAC5 and BDNF and the role this plays in depression.

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Prevalence of Major Depressive Disorder (MDD) is on the rise, affecting mostly young females aged 15-24 (RIchards, 2011). Those who suffer from the illness become affected by a period of low mood that they cannot recover from, usually lasting for at least 2 weeks. (Hasler, 2010; Tompson et al., 2000)

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Stucture of the protein thought to play a role in depression in LH mice.
(http://www.paininmotion.be/EN/news-2015-BDNF-proteiin-structure.html)

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Depression - The Mental Illness of Today

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Depression - The Mental Illness of Today

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A creative film from 2015 depicting depression in a relatable way to many who suffer from the disorder.

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Figure 9: Epigenetic regulation reported to be involved in depression in humans and animal models. In depressed brain, HDAC5 level is decreased in nucleus accumbens, whereas its level is increased in hippocampus. Adapted from “Epigenetics of the Depressed Brain: Role of Histone Acetylation and Methylation,” by H. S. Sun, P. J. Kennedy, and E. J. Nestler (2013).

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●BDNF, especially exon IV, is downregulated in LH group, which exhibits depression-like behaviour.
●HDAC5 is suggested to be an epigenetic regulator of BDNF because in LH group, HDAC5 is upregulated, and the binding of HDAC5 to exon IV of BDNF is increased.
●When HDAC5 is knocked down, depressive behaviour in LH mice was decreased.