Optogenetics

The papers for this week’s discussion, Tye’s et al and Chaudhury’s et al, were both on the role of dopamine neurons on depression and in fact shared many of the same tests and methods.  However, it was a little bit surprising that their conclusions were contradicting.

Tye et al study objective consisted on exploring midbrain dopamine neurons and if these caused induction and relief of stress provoked behavior.  In order to do so, Tye et al used the approach of activating and inhibiting the VTA (ventral tegmental area) dopamine neurons.   As seen by Figure 1, when the VTA TH neurons were optogenetically inhibited they observed the expected depression like behaviors such as decreased sugar preference and decrease in time struggling when put in stressful conditions.

Then they wanted to study the role of these neurons in relieving this stressful behavior.   Therefore they used mice that had undergone chronic mild stress for a period of approximately 12 weeks, as to exhibit depressive like symptoms and a control group without the CMS.  Then, only part of each of the two groups had activated the VTA dopamine neurons by using ChR2 to express it precisely with light.   Effectively, in general those under chronic mild stress struggled for less time than those without stress.  However, there were significant results among the ChR2 CMS and the control CMS group under light, since the ChR2 struggled for a much greater time period in general. These same expected results for the ChR2 relieving stressful behavior under light were seen when the sugar tests were assessed.

Tye et al studied controls such as the locomotion of all groups of mice to assure that this wasn’t the cause for the mice to struggle less or more time in stressful situations, and that it was indeed the inhibition or activation of the neurons.  Also, studied VTA neurons in CMS and non CMS rats and saw that CMS does alter normal bursting activity. I don’t really understand why they studied this in rats instead of mice, since the rest of the study is in mice.  I don’t believe they will see different results if they studied it in mice, however I understand they should keep using the same animal models throughout the whole experimentation.

Contrary to Tye et al’s conclusions, Chaudhury et al observed that inhibition of these neurons relieved depressive like behavior while activation of these induced this behavior.  This is very surprising as you can see so many similar techniques among the two studies but there were somethings I would change and try to do identical in future experiments to see how they differentiate.  For example, Chaudhury et al studies the difference between tonic and phasic stimulation in the VTA while Tye et al only mentions phasic stimulation.  Also, differing viruses and types of stress were used in these studies.  This is very realistic in the sense that humans are never identical and different chemicals and viruses have different effects on us, however for the purposes of understanding the specifics of dopamine neurons I would try to control all of these variables.