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Post 1: Rodent Models of Neurogenesis and Antidepressants

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Santarelli et al. (2003) and Bessa et al. (2009) both investigate the theory that antidepressants increase neurogenesis and/or neural plasticity in the hippocampus of depressed patients. While both articles support the role of stress in inducing depression, that depression may decrease neural plasticity, and that antidepressants promote neural plasticity, they disagree on whether increased neurogenesis is required for the behavioral and molecular benefits of antidepressants.

Both Santarelli and Bessa use rodents as models to analyze the link between neurogenesis and the behavioral and molecular effects of antidepressants, but Bessa’s article demonstrates clearer, more advanced methods and analysis, reflective of its later publication. For one, Santarelli primarily uses novelty-suppressed feeding (NSF) as a behavioral assay for depression, while Bessa uses a sucrose preference test and forced swimming test for depression, as well as an NSF test for anxiety. The use of NSF alone is insufficient as a behavioral measure of depression as it is representative of anxiety; while anxiety and depression and highly co-morbid, they are not mutually exclusive, and it is thus flawed to make conclusions about depressive behaviors using NSF alone. Additionally, Santarelli’s use of X-irradiation as a way to prevent neurogenesis in the hippocampus may produce confounding factors due to its ability to induce unpredictable mutations and inflammation. Bessa specifically points out the possible problems with X-rays and elects instead to use methylazoxymethanol (MAM) to block neurogenesis.

The articles’ understanding and application of neural plasticity also may contribute to their opposing conclusions: Santarelli’s paper suggests that only neurogenesis—the creation of new neurons in hippocampal regions—is under consideration for the effects of antidepressants whereas Bessa takes on a broader definition of neural plasticity that includes many changes in neuronal morphology in both the hippocampus and prefrontal cortex. Santarelli’s measurement of neurogenesis in terms of amounts of new cells (i.e. “doubling of BrdU-labeled cells in WT mice”) is also vague and creates some ambiguity. The more precise measurements of neural volume, dendritic length, number of dendrites, dendritic branching, spine type ratio, and neuron number in specific brain regions and neuron types by Bessa lead to a much clearer representation of the structural changes that accompany depression, neural plasticity, and antidepressant use.

Through these differential methods and analyses, Santarelli and Bessa come to alternative conclusions, with Bessa coming to the more prudent conclusion that adult neurogenesis is not necessary for antidepressants to elicit its behavioral effects. Today, over 10 years after the publication of Bessa’s paper, the cause of depression, actions of antidepressants, and extent of adult neurogenesis in humans is still under dispute. While these experiments could not solve these mysteries, they succeeded in supporting previous discoveries and contributing to research on one of the most common psychological disorders of modern times.


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