Week 2- Depression and Optogenetics

Tye et. al (2012) used a variety of different tests, such as the tail suspension test, open field test, and the sucrose preference test to look at depressive behavior in responses to changes in the dopamine neurons in the ventral tegmental area (VTA). The VTA projects to the nucleus accumbens, hippocampus, amygdala, and the medial prefrontal cortex. This is considered the reward pathway, so research has linked this pathway with depression. Tye et. al (2012) used optogenetic stimulation with different behavioral tests to examine how these neurons are interacting with the depressive phenotype. Tye et. al (2012) found that dopamine neurons are responsible for the depressive phenotypes by also examining the effect of antagonizing glutamate neurons. The glutamate neurons increased the overall struggling in the tail suspension test (Tye et. al, 2012). Tye et. al (2012) also examined the VTA dopamine neurons after chronic mild stress, and found that illuminating these neurons promoted escape-related behavior by increasing the kick movements in the mice. In the Chaudhury et. al (2012) paper, they used optogenetic phasic stimulation to examine behavioral depression models of social-defeat paradigm and the sucrose preference test. Chaudhury et. al (2012) found that phasic stimulation of the VTA dopamine neurons in particularly the nucleus accumbens pathway reduced sucrose preference and reduced the time until social-defeat in the social defeat paradigm. Chaudhury et. al (2012) focused on resilience phenotypes and found that inhibition of the VTA to nucleus accumbens projection increased the amount of time spent in the interaction zone in the social-defeat paradigm and increased sucrose preference suggesting that these mice were more resilient. Chaudhury et. al (2012) however did not find a link between the VTA to medial prefrontal cortex dopamine neurons and changes in depressive behavior of the mice. From these two similar studies we can see how the different behavioral paradigms were used to test depressive phenotypes in mice. Both studies showed a link between the VTA and nucleus accumbens dopamine neurons and changes in the depressive behavior. Tye et. al (2012) notes that chronic mild stress can create a lasting depression phenotype that can be reversed by phasic activation of VTA dopamine neurons to the nucleus accumbens. However, Chaudhury et. al (2012) argues that phasic activation of VTA dopamine neurons to the nucleus accumbens induce a phenotypic depressive behavior. I think we must consider the different behavioral paradigms that were used to test each of their hypothesis. It is clear that the VTA dopamine neurons to the nucleus accumbens is involved in the modulation of the depressive phenotype. The social-defeat paradigm may be considered a high stress situation, because the intruder mouse is being attacked by the resident mouse. However, these other behavioral tests may be targeting different aspects of depression. As one study pointed out, in humans there can be differences in symptoms of depression. For example, in appetite, some individuals that are depressed have increased appetite and others have decreased. I think it is important to look at behavioral paradigms that focus on more constant aspects of depression, although this can be hard to do in animal models. I also think that there are a lot of mechanisms underlying what causes depression in individuals, so there may be other changes going on in the brain or even specifically the VTA pathway that need to be further examined. For example, how the VTA can activate the amygdala but then inhibit the nucleus accumbens. This may be playing an important role in the behavioral effects seen in depression.