I enjoyed this week’s papers, as they deviated from the research topic discussed by the past four papers and discussed alternative methods for treatment of depression. They both also exhibited different animal model techniques which I found interesting- especially the learned safety behavioral model.
The paper published by Pollak et. al. explored the antidepressant like effects of the behavioral technique of learned safety. In learned safety, a conditioned stimulus (pulsed tone) is negatively paired with an aversive unconditioned stimulus (a foot shock). In this paradigm, learned safety mice (when compared to fear conditioned mice or controls) exhibit a reduction in contextual fear, behavioral despair and anhedonia, two symptoms of depression. Even more impressively, this learned behavior paradigm showed improvements similar to that of antidepressants, specifically Fluoxetine. Learned safety not only showed positive behavioral effects, but improved molecular pathways as well. Pollak et. al. demonstrated that learned safety increases BDNF and promotes survival of newborn cells in dentate gyrus of the hippocampus, an area that Fluoxetine is known to enhance. They even took it a step further by ablating hippocampal neurogenesis to confirm the molecular effects of learned safety. From this, it was learned that after 1 day of training, the mice with the learned safety mice with ablated hippocampal neurons showed no improvement of symptoms. However, after 2 days, learned safety had an effect in these same mice. They interpreted this as “retarding safety learning”, but I feel as though this weakens their argument a bit, and shows that learned safety can occur without hippocampal neurogenesis. Another big point of the paper was the fact D2 and substance P are involved in the Learning Safety pathway. When D2 receptors and Substance P receptors were blocked, safety response was enhanced. Pollak et. al. translated these findings and suggested that down regulation of D2 receptors and substance P with safety training reduces stress. After reading of the effects of learned safety, I am curious as to how this could be translated to human treatment of depression, as shocking feet would not be acceptable. Perhaps for people with anxiety or OCD, the US could be a video of something provoking the anxiety, and when paired with a CS, it could help reduce their stress. I also think pairing learned safety with an antidepressant could lead to even more drastic results, as hinted at in Figure 3B.
Li et. al’s paper also discussed an exciting fast acting alternative for depression treatment. The main focus of this paper, a glutamate NMDA antagonist Ketamine was shown to rapidly reverse the physiological and behavioral damage caused by chronic stress exposure. The actions of Ketamine was shown to be dependent on the mTOR signaling pathway. Li et. al. also attempted to fathom the molecular pathways by which Ketamine acts. This paper used the Chronic Unpredictable Stress paradigm to induce stress in the mice, and then after 21 days measured the effects of ketamine with the Forced Swim Test (behavioral despair) and Sucrose Preference Test (anhedonia). Ketamine was shown to reverse these depressive effects (increases sucrose preference and lowers behavioral despair), as well as another antagonists tested called Ro 25-6981. In later experiments, they proved that Ketamine action is reliant on the mTOR pathway, and that Ketamine could increase the amount of pre and postsynaptic proteins, as well as 5-HT and hypocretin signaling in the PFC that were compromised during CUS. I thought this study was thorough and always solidified their findings by removing the variable in question, to prove that the system cannot function without it. As mentioned at the end of the journal, I believe that these fast acting antagonists should be focused on, as their rapid response could provide better relief for a patient, and doesn’t take two weeks remodeling synapses and dendritic spines as SSRIs do. I think an optimal treatment would be combining these fast acting NMDA antagonists, and the learned safety, as they are both treatments that act quickly and will cover more ground because they work through different pathways.
When reflecting upon the previous papers and now this one, I wonder about ketamine and its effects on the dentate gyrus. If I recall correctly, the dentate gyrus is an area negatively affected by the chronic unpredictable stress in mice in the way of lower synaptic density or reduced neurogenesis. With administration of Ketamine, this current study indicated positive changes in the PFC and pyramidal neurons, but will the dentate gyrus still need SSRIs or another method to bring its physiology back up to normal? Or will the positive changes in the PFC mediate a fix of the dentate gyrus through pathways
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