Sunday, January 22, 2017

Week 1: Santarelli & Bussa


It appears to me that Santarelli approached the paper expecting a more conclusive set of results, and published a rather lazy exploration of the question at hand. Santarelli attempts to tackle the mystery surrounding the three+ week clinical response period of anti-depressants by suggesting the resulting increase of neurogenesis as an effect of these drugs is evidence of neurogenesis's causation of depressive symptoms. Within Neuroscience, this is a tired framework. This is the same style of thought that suggests the positive of effect of SSRIs on depression is evidence of the role of serotonin within depression, rather than using a complete exploration of the different mechanisms and resulting cascades of the serotonin system to draw conclusions. Bessa produced a much stronger exploration of this question, and rather embarrassingly exposes the flaw in Santarelli's claim that hippocampal neurogenesis is essential for behavioral improvement, by simply blocking neurogenesis and still producing behavioral improvement.

Bessa does build on Santarelli's exploration of the effects of chronic stress and its role in triggering depressive symptoms. While Santarelli focused on the decrease in neurogenesis produced by stress, Bessa additionally explores the impairment of synaptic plasticity, the dendritic arborization of the hippocampus and the parallel effects in the PFC. In Bessa's own words this provides a much "wider context" of the "neurotropic hypothesis of depression" and relies on a framework of system-wide explorations of cause and effect and a reluctance to name coincidence to be correlation. The paper also improved on the Santarelli analysis by including a sucrose preference test and a forced swimming test in addition to the novelty-suppressed feeding test, which provides a more reliable breadth of evidence on the behavioral improvement being analyzed. This exposed flaws in their model of depression, as NSF focuses on anxiety as a symptom, versus anhedonia and learned helplessness.

The results of Bessa's paper did confirm the validity of Santarelli in using the chronic mild stress model as an animal model of depression. I think their assertion that the neurogenesis occurring in the hippocampus is leading to increased modulatory projections into the amygdala is an exciting interpretation, as it explains why pro-neurogenesis is essential only in reducing the anxiety seen within the NSF model. Their exploration of the volumetric changes within the PFC and HF also aligns with emerging understandings of depression. Thus when their cross reference between the depressive symptoms shows dendritic atrophy and loss of synaptic contacts, this provides much more convincing evidence of the neurotrophic hypothesis of depression. Additionally, through their demonstration of the increased levels of expression of NCAM1 as a result of AD,  they provide evidence of underlying mechanisms, beyond neurogenesis, that are affecting these behavioral changes. I still find Bessa's paper to be inconclusive and incomplete but a much stronger and broader analysis of the question at hand.

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