Activating VTA-NAc Dopamine Neuron Enhancing Resilience

Friedman, A. K., Walsh, J. J., Juarez, B., Ku, S. M., Chaudhury, D., Wang, J., . . . Han, M.-H. (2014). Enhancing Depression Mechanisms in Midbrain Dopamine Neurons Achieves Homeostatic Resilience. Science, 344(6181), 313-319. doi:10.1126/science.1249240

This paper is really a good read, easy to grasp what it to says. So, basically, in a series of experiments, the authors found that activation of the ventral tegmental area (VTA) dopamine (DA) neurons will make the susceptible mice, which could be selected by social defeat stress paradigm, more resilient. The novelty of this paper lies in the fact that VTA DA neuron activities were previously found to be the positive correlated to depression-like behaviours.

Backgrounds: 

1) Tyrosine hydroxylase-driven green fluorescent protein (TH-GFP) transgenic mice were used in these series of experiments, because of they allow to visualize and reliably record from VTA DA neurons.

2) Mice can be distinguished to resilient and susceptible ones by the social interaction ratio in social defeat stress paradigm (n = control:30, susceptible:14, resilient:10). 

    Without any other manipulations, the resilient TH-GFP mice showed low VTA DA neuron activities, just like control mice, while the VTA DA neurons of susceptible mice exhibited a much higher level of activities (figure from S1I).

3) the I_h current, which is recorded by whole-cell voltage-clamp in GFP+ VTA DA neuron, in resilient mice is larger than susceptible mice, although the authors predicted that it will be lower. So this is surprising!

Then, the authors measure the K+ channels and found that the K+ channel-mediated peak and sustained currents are also higher among resilient mice.

So the K+ channel may play a critical role, so the authors measured the excitabilities of VTA DA neuron. After current injections, the spike number of resilient mice drop to "baseline" as control, while the susceptible mice's spike number increased.

The K+ channels are important and extremely high level of firing driven by I_h current will trigger self-tuning K+ channel, so the authors manipulate I_h current by in vivo infusion of and I_h potentiator, lamotrigine. The magic happened, single in vivo infusion increased social-avoidance (an index of social defeat stress), repeated 5-day local infusion of lamotrigine reversed social avoidance, as well as the sucrose preference! This means that the 5-day infusion of lamotrigine enhanced the overall resilience of the susceptible mice. This behavioural effect is accompanied by normalized VTA DA neuron activities. Further measurements found that the K+ current also increased with the I_h current. 

Given that lamotrigine not only impacts I_h current but also has other effects on neurons, the authors tried to find a specific effect of the I_h current. To do this, the authors used other types of mice (TH-Cre mice and Cre-inducible loxP-STOP-loxP herpes simplex virus with enhanced yellow fluorescent protein (HSV-LS1LHCN2-eYFP) and HSV-LS1L-eYFP as control). The results supported their hypothesis. [didn't totally understand the details].

The next question is: whether direct excessive activation of VTA DA neurons in susceptible mice could induce a functional K+ channel counteraction that would normalize the hyperactivity of these neurons and depression related behaviours. This is a bold question. To do this, the authors used optogenetic methods to activate the VTA DA neurons. Five days 20-minute photostimulation decreased the depression related behaviours.

Also, the authors observed that the above effects only occur for VTA DA neuron that project to NAc, not mPFC.

So this is the main story of this article, a lot of work, and many experimental manipulations. Further reading of this paper is needed because many details are not covered in the article. Instead, second-read the supplementary materials may be helpful.