Neuroscience Matters FUTURE DIRECTIONS There are a few critiques that can be done on this study since there were limitations found in the research as well as many unanswered questions. The authors of this study have simply started to pave the way for the use of microbiota as a future treatment of anxiety and mood disorders, but there is still a long ways to go before we get there. The study was only able to find a link between the alteration of gut microbiota with changes in behavior, hormone levels, and mRNA expression in the brain. There are therefore many possible future directions that can be taken from here to fix some of the study’s limitations and in hopes of leading us closer to the treatment of these psychiatric diseases and possibly others. Firstly, this study had several limitations that may have influenced their results. The authors only looked at changes in the expression of mRNA in the hippocampus and amygdala however mRNA expression does not directly translate to protein expression. A change in mRNA expression does not mean that there is an equivalent up- or down-regulation of the protein expression for these receptors. A useful future study would therefore be to look at the difference in the actual protein expression of these receptors to give us sturdier evidence that there is a link between these changes with the difference in behavior observed. Another possible line of research stemming from this study could look at the expression of 5HT1A receptors in germ-free mice in different brain areas, such as the dorsolateral prefrontal cortex, an area frequently linked to higher cognitive functions and mood regulation, which are debilitated in patients diagnosed with major depression8. A final addition that could be made to this study in the future would be to test for depression in the mice rather than simply anxiety like behavior. This is important to create a clear link between the gut microbiota and actual mood disorders rather than simply anxious behavior. Depression could be induced in mice either through forced swim test or the tail suspension test to see how long the mice struggle before giving up and showing learned helplessness, a depressive behavior. Looking to see if it is easier to induce depression in SPF mice compared to GF mice would link the composition of the gut microbiome with an individual’s vulnerability to mood disorders like depression. This can therefore lead us not only to the use of gut microbiota as a possible cure for these disorders but also a preventative treatment, which is especially important due to the high relapse rates found in disorders like depression. Secondly, a potential future direction to take from here would be to look at the effect of fecal transplants in mice to see if a specific composition of gut microbiota is linked with depression. This could be done by inducing depression in mice with the techniques previously mentioned and then transplanting their microbiota into perfectly healthy normal SPF mice, like the ones used in the study by Neufeld K. M. et al. If the SPF mice begin to show depressive behavior after transplantation than it will be clear that the
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composition of the gut microbiota can actually cause depression and different symptoms of mood disorders. Similar research has already been done with obesity, resulting in a link between obesity in mice and the composition of the microbiome. Fecal microbial transplants have already been performed in humans to effectively treat some disease, for example Clostridium difficile infection (CDI), so it is known to be an effective and safe treatment that could potentially be accepted for clinical use9. In conclusion, this ground breaking study along with the future possible studies in this field will get us closer to the treatment of anxiety and mood disorders. This will be done by altering the gut microbiota through one of the many possible techniques available, for example diet, probiotics, antibiotics, microbial pills, or fecal transplants. These treatments may finally lead us to the cure for several diseases that have a large impact on our society today. REFERENCES
1. Cryan J., and Dinan T. (2012). Mind-Altering microorganisms: the impact of the gut microbiota on brain and behaviour. Neuroscience, 13: 701-712. 2. P. Bercik, S. M. Collins, and E. F. Verdu. (2012). Microbes and the gut-brain axis. Neurogastroenterology and motility, 24:405-413. 3. Neufeld, K. M., Kang, N., Bienenstock, J., & Foster, J. A. (2011). Reduced anxiety‐like behavior and central neurochemical change in germ‐free mice. Neurogastroenterology & Motility, 23(3):255-264. 4. Nemeroff B. C. and Owens M. J. (2002). Treatment of mood disorders. Nature neuroscience supplement, 5:1068-1070. 5. Frangou S. (2008). Brain structural changes in mood disorders. Psychiatry, 8(3):105-106. 6. Kazlauckas V. et al. (2011). Distinctive effects if unpredictable subchronic stress on memory, serim corticosterone and hippocampal BDNF levels in high and low exploratory mice. Behavioural Brain Research, 218(1):80-86. 7. Lopez de Armentia M. and Sah P. (2003). Development and subunit composition of synaptic NMDA receptors in the amygdala: NR2B synapses in the adult central amygdala. The Journal of Neuroscience, 23(17):6876-6883. 8. López-Figueroa, A. L., Norton, C. S., López-Figueroa, M. O., Armellini-Dodel, D., Burke, S., Akil, H., ... & Watson, S. J. (2004). Serotonin 5-HT1A, 5-HT1B, and 5-HT2A receptor mRNA expression in subjects with major depression, bipolar disorder, and schizophrenia. Biological psychiatry, 55(3), 225-233. 9. Borody T.J. and Khoruts A. (2012). Fecal microbiota transplantation and emerging applications. Nature reviews gastroenterology and hepatology, 9:88.
This work was supported by the Human Biology department, Neuroscience, at The University of Toronto. The authors thank Dr. Bill Ju for his inspirational lectures and motivation to explore neuroscience, and the students in HMB420 for feedback received in class on their presentation. Address correspondence to: Charlotte Chiarella-Redfern and Anastasiya Slyepchenko Email: charlotte.chiarella.redfern@mail.utoronto.ca anastasiya.slyepchenko@mail.utoronto.ca Copyright © 2013 Charlotte Chiarella-Redfern and Anastasiya Slyepchenko , Human Biology Program
Neuroscience Matters | Issue 02 | 2014