Week 1:

While both Santarelli et al and Bessa et al have their advantages and shortcomings, I found that Bessa et al addressed some of the many concerns I had reading the Santarelli paper. The Santarelli paper itself does not test the full gamut of depression symptoms. Instead, it focuses on the anxiety symptoms through the novelty suppressed feeding test and coat score which may be a weakness only in that it does not fully address the spectrum of possible changes antidepressant medication can have in MDD patients. I believe the results would have held more weight had they gone beyond the NSF paradigm in order to better show that these manipulations change multiple aspects of depressive behavior like anhedonia, altered sleep patterns, etc.. A strength of the Bessa et al paper is that it tests more depression-like symptoms, specifically anhedonia and learned helplessness. This paper also managed to address one of the other issues I had with the Santarelli paper by blocking neurogenesis pharmacologically rather than through irradiation.

Pharmacological manipulation initially seemed much more preferable because irradiating the brain seems like a drastic manipulation to subject the brain to. In the control experiments, in which the SVZ and CRB are subject to irradiation to show that neurogenesis in the SGZ is responsible fore AD effects, Figure 5B shows that irradiation in the SVZ hinders any significant reduction of latency due to fluoxetine, potentially calling into question off target effects of the irradiation experiments. However, the results from Santarelli et al were much more convincing when they showed that there did not appear to be behavioral changes due to damage in the hypothalamus and amygdala, both of which are involved in anxiety behavior and are within range of irradiation damage due to the location of the x-ray placement. Additionally, the use of MAM in the Bessa paper, though it was used in quantities shown to have no effect on locomotion or grooming, didn’t exactly capture the conditional manipulations I had hoped for due to the non-specific (subcutaneous) administration of the drug.

I would have been more convinced by a cleaner loss of function experiment, perhaps a conditional knock out of 5-HT1A in the SGZ and then behavioral testing in either paper to show a dependence of AD action on neurogenesis in the SGZ (at least in the case of flouxetine), a gain of function experiment in Santarelli et al in which they promote neurogenesis and see a decrease in latency to drug effects on anxiety, or conditional genetic/pharmacological manipulations of neuronal remodeling in Bessa et al to show a dependence on AD effects on synaptic plasticity. Overall, Bessa et al addressed the issues of off target effects and anxiety-only behavioral testing seen in Santarelli et al but still does not completely convince me that neuronal remodeling, and not neurogenesis, is the true source of antidepressant amelioration of depressive symptoms as they only address topographic dendritic changes without truly showing loss of function through neuronal remodeling manipulations.