Key insight into complex depression circuitry through different methods- Sierra Smith

First and foremost, I was impressed with the agreement of the results reported in both Tye et al. and Chaudhury et al. published in the same volume of nature. Although each group took to differing methods of inducing depressive phenotypes, one primarily using repeated social-defeat stress while the other using chronic mild stress, each was able to produce highly similar yet unique insights into the circuitry of dopamine neurons in the VTA and their projections and how it relates to depression models in rodents. Each group was able to show the necessity of the VTA-NAc pathway bidirectionally in certain depressive phenotypes such as anhedonia during sucrose preference testing (used by both groups), yet each group also took their own approach to investigating the underlying circuitry involved in this effect.

I was fascinated with the direction taken near the end of the Tye et al. paper where the researchers were able to measure extremely temporally precise firing of individual NAc neurons in response to illumination of ChR2 expressing VTA neurons. I was even more excited that the firing patterns could be specifically correlated to kick events as a measurement of escape behavior in a forced-swim test. I was surprised that, among the NAc neurons found to be responding specifically to either light illumination or kick-events, some showed phasic excitation while others showed phasic inhibition. This just highlights the highly complex regulatory circuitry involved in encoding information related to the reward pathway and depressive phenotype.

Another interesting thought I had after reading both papers was that both sets of authors highlighted ketamine as a very powerful and broad-acting drug that has some acute anti-depressive effects, and used this drug's mechanism of action to help explain some of the more perplexing results obtained in these studies. In the Tye paper, ketamine's known effects were used to justify how complex of a role glutamine could play in the depressive phenotypes related to the tail suspension test, and why the surprising result of increased escape behavior was seen from glutamate inhibition. In the Chaudhury paper, the very acute onset of anti-depressant effects from ketamine administration is also mentioned to further provide support of the highly complex regulatory mechanisms underlying depression, and how there is still much to be discovered about the interwoven roles of the dopamine and serotonin systems among others that play into clinical depression.


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