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Week 1: Neurogenesis and Antidepressants

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Both Santarelli et al and Bessa et al delve into the role of neurogenesis in the effect of antidepressants. Each article works rather complementary to one another as Bessa expands upon the foundation that Santarelli laid in 2003. They both fall under the umbrella of plasticity, but I believe that they offer two separate facets as Bessa additionally considers morphological plasticity while Santarelli focuses only on neurogenesis and hints at receptor plasticity.    

Santarelli focused exclusively on behavior and neurogenesis. To study this, they used a novelty-suppressed feeding (NSF) behavioral paradigm which is a measure of anxiety by determining latency to feed in a novel environment. Outright, chronic administration of antidepressants of tricyclic and SSRi variety decreased latency to feed. Utilizing BrdU, they found that animals treated with chronic fluoxetine showed an increase of BrdU uptake and neurogenesis. They were able to replicate the effect of long term antidepressant use by chronically activating 5HT1A receptors and knocking out these receptors blocks the behavioral and neurogenic effects of fluoxetine. While irradiating the hippocampus also lead to a similar blockage, there is evidence with the KO 5HT receptor model that behavioral phenotypes may develop independent of adult neurogenesis. They are unable to determine functional differences as they looked only at the amount of BrdU positive cells and behavioral output. Irradiating other parts of the brain does not result in impared NSF with response to antidepressants. This could be in part that they only studied feeding behaviors and perhaps other paradigms of anxiety behaviors could respond differently when studying neurogenesis and various behavioral pathways. Altogether, they propose that hippocampal neurogenesis seemed to be linked to behaviors implicated in depression disease states and that investigating therapies focusing on this particular region may be worthwhile.

Bessa goes further in studying a variety of behaviors, stressors, and markers of plasticity and neurogenesis. They show they are able to induce a depressed-type model that is reversed upon chronic administration of various antidepressants. They also concur with Sanatrelli in that chronic mild stress (CMS) results in a decrease of BrdU positive cells that is reversed upon antidepressant usage. CMS also results in volumetric reduction in various regions of the hippocampus. It also induces atrophy of granular cells, pyramidal cells. All of these effects were reversed by antidepressant use. For CMS induced rats, they also found an increase in thin-type spines over mushroom spines, which is an indicator of instability in the plasticity of the neurons as thin-type spines are less robust than their mushroom counterpart and more susceptible to pruning over time. This remodeling is found in various regions and is the landmark finding of the paper. In addition to hippocampal neurogenesis being promoted by antidepressant use, the behavioral changes are more likely the result of the remodeling and synaptic plasticity rather than exclusively neurogenesis. 

I believe the source of the major protocol differences between the paper seems to be the result of time and publication journal. At the time of Santarelli’s publication, it’s possible the techniques of dendritic morphology were not as developed and studying neurogenesis most likely evolved in the 7+ years from them to Bessa. The biggest result of these differences is also most likely due to publication journal requirements. It’s clear in the Santarelli article that they were limited in the number of pages they could publish and the actual formatting of said pages. The journal of molecular psychiatry appears to be more flexible in publication capabilities as Bessa is able to include numerous methodologies, multiple figures, and less formatting restraints. The Ns of Bessa’s testing also seem to be incredibly robust. It is seldom that I have seen experimental groups larger than 12 for a handful of tests, where upwards of 10+ experimental groups all have at least 24 animals. This statistically makes their results rather strong given the large pool of data. Rather than viewing these articles in opposition, I feel that Bessa is rather a continuation of Santarelli using more modern technologies, more Ns and considering more molecular aspects of the antidepressant interactions. Bessa doesn’t refute Santarelli entirely, but rather expands and proposes that the effect of behavior is more likely the result of morphological changes that the antidepressants cause that then alter circuitry and connectivity within the various implicated circuits. 

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