Week 2: Neurogenesis & Anti-depressant actions

The Santarelli et al. paper supports the theory that hippocampal neurogenesis is essential for the behavioral effects of antidepressants to be present. The Bessa et al. paper responds to the Santarelli et al. paper, proposing it is not neurogenesis that is necessary for antidepressant effects but neuronal plasticity.


The results from the experiments in the Santarelli et al. paper show that:

• Chronic antidepressants (fluoxetine, imipramine, and desipramine) reduced latency to feed in the NSF test, used as a proxy for anxiety levels.
• Fluoxetine requires the 5-HT1A receptor to reduce latency to feed and to increase neurogenesis.
• Irradiation reduces neurogenesis.
• Antidepressants do not reduce latency to feed in irradiated mice.
• Antidepressants do not cause recovery from chronic stress in irradiated mice.

The Bessa et al. paper starts off by confirming the foundational result of the Santarelli et al. paper. It shows that antidepressants reduce depressive-like behaviors assessed by a sucrose preference test and a forced swimming test in addition to the NSF test used by Santarelli et al. and that antidepressants restore/increase neurogenesis. However, Bessa et al. also shows that antidepressants attenuate depressive-like behaviors both in animals treated with MAM and those treated without. Pilot studies showed that MAM reduces neurogenesis. With these results, they claim that neurogenesis is not required for behavioral effects of antidepressants since these effects were not significantly different between animals with control levels of neurogenesis and animals treated with MAM to prevent neurogenesis.

Alternatively, they propose that neural plasticity is required for the behavioral effects of antidepressants. Their results show that:

• CMS causes dendritic atrophy and loss of synaptic connections, change in ratio of mushroom and thin spines.
• Antidepressants reverse depression behavior and restores synaptic connections in animals exposed to CMS, independent of neurogenic status.
• CMS causes atrophy of dendrites of neurons in the hippocampus and PFC, disrupting communication between the two brain regions.

These results serve as evidence for their theory that rewiring neural circuits is needed for the behavioral effects of antidepressants.

Bessa et al.’s response to Santarelli et al. is essentially, “correlation does not equal causation.” Bessa et al. demonstrate the absence of a causal relationship between neurogenesis and the behavioral effects of antidepressants by showing antidepressants have the same effects even when neurogenesis is inhibited. However, the same response applies to Bessa et al. Their results show that neural circuits are being rewired as a result of antidepressant treatment but they do not show that without the rewiring of the neural circuitry, antidepressants will not have the same effect. This could be very difficult to accomplish but unless they can show that this rewiring is required by experimenting with its removal, their research has the same shortcomings as the paper to which they are responding and demonstrates a correlation rather than a causation.

Another weakness of Santarelli et al.’s paper is that it discusses depression and anxiety disorders and the drugs with which they are experimenting are antidepressants. However, for almost all of the experiments, they used only the NSF test which primarily assesses anxiety. Bessa et al. do a better job of evaluating depressive-like behavior by using the sucrose preference test and FST to assess other symptoms of depression. I found it interesting that Bessa et al.’s paper responds directly to Santarelli’ et al.’s paper but they chose to use different rodents in their research. A future direction for this research could be to investigate the effect of irradiation on neuronal plasticity in the hippocampus. Santarelli et al. showed that antidepressants do not help irradiated mice recover from chronic stress or reduce their latency to feed (anxiety) and if this is not being caused by a lack of neurogenesis, perhaps the irradiation also impacted the neuronal circuitry.

Paper styles - The Santarelli et al. paper was not structured with the traditional research article sections whereas the Bessa et al. paper was very much so. The Santarelli et al. paper also did not have as much detail in the paragraphs as the Bessa et al. paper and a significant amount of information, not just about the results but also about the method, were found in the figures and their descriptions. These observations could be the result of the journal in which these articles were published. The audience of Science consists of researchers from all areas of science so a higher-level, more condensed article is better suited for them since they may not have much knowledge of biology or psychiatry and excessive detail could be confusing. The audience of Molecular Psychiatry on the other hand is much more narrow so they will likely understand specific details of the research better and they will also likely expect all of that information.