Week 3: Dopamine circuits and recovery from stress

Tye et al.

This paper used optogenetic stimulation to induce depressive-like behavior and to stop depressive-like behavior in mice exposed to CMS-induced stress. They measured depressive-like behavior as social avoidance shown by decreased social interaction and anhedonia shown by decreased sucrose preference. They induced depressive-like behavior by expressing halorhodopsin in VTA dopamine neurons and optogenetically activating them (depressing the neurons). They also showed that deactivating them (removing illumination) immediately reverses the depressive-like behavior. Then they exposed mice to chronic mild stress and used optogenetic stimulation to activate channelrhodopsin expressed in the VTA dopamine neurons. Activation of channelrhodopsin opens these channels to increase dopamine transmission. Depressive-like behavior was present in mice without illumination and were reduced in mice with ChR2 that have been exposed to CMS. They also investigated the neuronal activity of the VTA DA neurons of mice exposed to CMS and mice not exposed to CMS and found that while the mean spike rates were similar between the groups, the patterns of the spikes were very different. In non-CMS mice, the spikes occurred more in bursts and bursts were longer. This is like the phasic illumination used to activate channelrhodopsin which activated the dopamine neurons and reduced depressive-like behavior.

I had some questions about the method in this paper. Why does the open-field test use 4 rounds, when other tests use 3 rounds (2 light off, 1 light on)? Why do they measure velocity in the open-field test? Why not something like distance traveled? Why is there a range of duration for the chronic mild stress paradigm (8-12 weeks)? Were mice exposed to the paradigm for different amounts of time?

Chaudhury et al.

They exposed mice to 10 days of social defeat while inducing phasic firing in their VTA dopamine neurons and this decreased their social interaction and sucrose preference. In another experiment, they exposed mice to 10-day social-defeat stress and then measured their social interaction while under illumination and mice with ChR2 showed reduced interaction. They also found that activating ChR2 in resilient mice made them immediately susceptible (reduced social interaction). Interestingly, this susceptibility persisted until the next day when they measured sucrose preference which was also reduced, so these effects of activating ChR2 were not only instant but also long lasting.

What does the “subthreshold” mean in subthreshold social-defeat stress paradigm?

They measured their social interaction by how much the mice entered the interaction zones which involve movement. However, these experiments did not measure the mice’s locomotor ability like the other research paper did with the open-field test. The social interaction test they used and even the sucrose preference test involve some degree of movement that could have been affected by the optogenetic activation. One could assume that the optogenetic activation did not have an effect on general movement but the effects on depressive-like phenotypes are reversed here (compared to Tye et al.) so it is possible that the effects on movement are different here as well.

I noticed that both papers were careful to use “depressive-like” or “depressive-related” behavior, symptoms, etc. instead of just “depressive”. I’m guessing this is because these are animal models of depression so it would be inaccurate to label whatever it is the animals are experiencing as depression since we don’t know what the animals are really feeling or thinking.

These papers read like the Nature paper from last week. They are very condensed and do not have the traditional research paper sections.