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Blog post 1: Neurogenesis and Antidepressants

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Both articles by Santarelli et al. (2003) as well as the Bessa et al. (2009) looked at the requirement of neurogenesis in the action of Antidepressant drugs used to treat mood behaviors. The Santarelli et al. (2003) paper supports the hypothesis that antidepressants (fluoxetine, imipramine, desipramine) may be mediated by an increase in neurogenesis in the stress induced hippocampus of mice models. The Bessa et al, (2009) paper, in contrast, rejected this hypothesis and instead suggested that the effects of antidepressant drugs are associated with neuronal remodeling and plasticity. 

Immediately after reading both articles I was more inclined to appreciate the work done by Bessa et al. over Santarelli et al. The Bessa et al. paper is highly structured with a distinct section for an abstract, introduction, methods, results and conclusion. Their sections were highly informative as they defined each important term involved and comprehensively explained the methods and materials involved in their study. This is in stark contrast to the Santarelli, et al. paper which proved to be a dense and confusing read. The Santarelli et al, paper was just a large amalgamation of haphazard introductory context, methods and experimental results all present in a block format that did not allow for an easy flow of reading. 

This disorganization does not stop at structure and seems to continue into their research as well. Focusing specifically on the methods of neurogenesis inhibition used by both articles, they diverge with the Bessa et al. paper utilizing more supported techniques. Santarelli et. al’s main technique of neurogenesis blocking is low-dose x-irradiation of the hippocampus. As seen in Fig. 4a, lead shielding was used to administer the radiation specifically to the area of interest; the SGZ of the hippocampus. They seem to begin with antidepressant administration along with x-ray exposure, as well as the novelty- suppressed feeding test without any time for recovery of the animals. As explained in the Bessa et al. paper, this seems as though it may provide further changes in the brain that interferes with the variable being tested. X-irradiation is associated with inflammation in the brain and subsequently may trigger widespread immune response leading to disruptions and possible confounding factors in their study. If the method of neurogenesis inhibition is questionable, that leads to further questioning of the results obtained. Apoptosis of the SGZ induced by irradiation and attenuation of AD response is interpreted by Santarelli et al. as the need for neurogenesis for AD mechanisms, however their results could also be interpreted as the disruption of AD mechanisms due to lack of neuronal projections at all as x-irradiation is shown to stimulate apoptotic behavior and no analysis of BrDu cells in response to irradiation was done. Bessa et al. on the other hand, used a cytostatic agent used to arrest neurogenesis; MAM or methylazoxymethanol. This method was carried out using subcutaneous injection and therefore did not stimulate immune responses in the brain, but elsewhere in the body of the animal.

 Furthermore, the rats were given an appropriate amount of time to recover and tests for general health were administered prior to any behavioral paradigm or drug administration. To be certain that MAM inhibited neurogenesis, analysis of cells and proteins associated with neurogenesis were taken into account. Immunohistochemistry revealed the decrease in density of BrdU positive cells (staining cells in the synthesis phase of the cell cycle) in the animals with MAM administration (Fig. S1b) and the density of Ki-67-positive cells (nuclear protein expressed in all phases of the cell cycle except rest) was also decreased in animals with MAM (Fig. 1d). Figures 1f,g,h also showed labelled cell growth. This definitively demonstrates the ability of MAM to block neurogenesis. It seems as though Bessa et al. approached their study with more structure and scientifically sound methods overall as compared to Santarelli et al. The actual results of both papers have coinciding and conflicting answers and the hypothesis, although well presented by Bessa et al. could be subjected to more experimentation and debate.

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