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Blog Post 1: Neurogenesis & Anti-depressant Actions

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Santarelli and Bessa et al propose two conflicting opinions on the mechanisms of action for antidepressant drugs. The research itself and how it is reported contains two comparable styles. Santarelli et al does not provide a methods section or detailed statistical analysis. Both studies start by showing that antidepressant drugs (ADs) do indeed have a chronic positive effect of depressive symptoms. Santarelli shows this using only one behavioral test: the novelty suppressed feeding test. Bessa et al uses three behavioral tests (sucrose preference test, forced swim task, and novelty suppressed feeding), and specifically delineates the timelines that each drug works (all 1 week except Fluoxetine takes 2 weeks to take effect). The papers then diverge in style, methods, and ideas. Santarelli’s article jumps to show that Fluoxetine increases BrdU positive cells in the dentate gyrus, and attempt to link this to the idea that hippocampal neurogenesis is the mechanism by which the mice’s behavior is improved. To further prove their point, they aim to irradiate the SGZ area of the dentate gyrus which had been previously shown to integrate into hippocampal activity. Using X-Rays to cause irradiation, they observe that ADs do not ameliorate the depressive symptoms compared to controls. This leads to the conclusion that hippocampal neurogenesis is involved in mood regulation and is needed for anti-depressants to work.

Bessa et al questions Santarelli’s hypothesis and suggest that it is not hippocampal neurogenesis that is responsible for the mechanism underlying ADs, but instead neuronal remodeling and synaptic connections. The paper itself is broken down into clear sections, detailed methods, and an in depth statistical analysis explanation. The results indicate that while there is hippocampal neurogenesis, this cannot be assumed to be the cause of a correlation. They use MAM, a cytostatic agent, instead of X-Rays, which can cause inflammation, to stop neurogenesis. The researchers find that antidepressants reduce depressive symptoms to the same extent in vehicle and MAM treated animals. This disputes Santarrelli’s hypothesis. In addition, they find it is dendritic and spine density that is most affected and depleted when examining depressive symptoms. It is the volume of the hippocampus and PFC that was altered, not the number of neurons, indicating the connections and networks are changed. Bessa et al looked at more brain regions, performed more stains, analysis, and measures, and ultimately provided better evidence that antidepressants work through a mechanism related to synaptic plasticity and not neurogenesis.

It is evident that more recent literature has grown from Bessa et al’s research as depression research has shifted to networks rather than individual structures. Limitations of these studies include the inability to completely and wholly translate the depressive and anxious symptoms of the mice to humans. Further steps would be to explore these mechanisms more in depth and understand specifically how antidepressants trigger synaptic plasticity. Overall, I found these papers very interesting in that they provided a historical glance into much of the current literature we read and the conflict that got us here.
   


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