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Post 2: VTA, Dopamine, and Depression

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In Tye’s 2012 paper, she utilized optogenetic stimulation of VTA dopamine neurons to study the role of said cell firing in depression. She found that inhibition of VTA DA neurons induces depression behaviors. Phasic activation of these neurons leads to symptom reversal in these mice with increased escape behaviors in tail suspension and sucrose preference. Further, she wanted to study cell firing in lasting depression-induced with a chronic mild stress paradigm. In this case, phasic activation of these cells also reversed symptoms. She wanted to see the necessity of dopamine and glutamate receptors. In the case of a glutamate agonist, struggling behaviors increased overall. Dopamine-blockade reduced struggling and is required for escape behaviors. Phasic activation of these VTA DA neurons requires functional DA receptors and the NAc neurons encode for this activation and escape behavior. Altogether, she found that VTA DA neuron firing underlies anticipating receipt of rewards and VTA GABA firing can underlie anhedonia. This phasic firing is necessary for the presentation of depression-like and anti-depressive behaviors. Though, context is important because the dopamine system is highly complex and varying degrees of stress can alter dopamine firing. 

In Chaudbury’s 2012 paper published at the same time, he found a direct link between neuronal firing patterns of VTA DA neurons utilizing optogenetics and in vivo electrophysiology. Optogenetic effectors were expressed in TH-cre neurons of the VTA. They exposed mice to subthreshold social defeat and stimulation of these neurons with channelrhodopsin. They found that phasic, not tonic, stimulation increased social avoidance and decreased sucrose preference. This phasic firing of the VTA DA neurons also induced a susceptible stress model. This effect was not seen in naive animals. They were also able to induce a susceptible model in a post-social defeat resilient mouse by using phasic stimulation. As seen in Tye’s paper, light stimulation can cause membrane property changes and increases the excitability of VTA DA neurons. They wanted to study the difference between the role of the VTA-NAc and VTA-mPFC pathway by utilizing fluorescent and rabies based tracers to study neurons that project to these regions and then manipulating them. They found that phasic firing in the VTA-NAc pathway induced the susceptible phenotype and inhibition of the pathway induced the resilient phenotype. For the mPFC pathway, phasic stimulation had no behavioral effect while inhibition induced a susceptible phenotype with no change in sucrose preference. Altogether they propose that the VTA-NAc pathway is vital for the determining of susceptibility and resilience following a social defeat. The firing pattern of these neurons encodes for depression and reward behaviors but is most likely behavior dependent as the severity of stress can alter the function of DA neurons. The increased expression of hyperpolarization0activated cation channels in VTA DA neurons is most likely responsible for the effect of the phasic firing from these neurons. They present another piece in the complex role that VTA DA neurons have in an individual’s adaptation to repeated stress and depression.

While these papers present opposing ideas of how the neuronal firing patterns of VTA DA neurons affect depressive behaviors, I feel that they each cover the reason why this is so. Both papers present that the mesolimbic dopamine pathway is highly complex on its own, not even considering its role in depression. The difference in their results may likely be due to the differences in their behavioral paradigms and the context the animals experienced. As stated in both papers, chronic mild stress is far less severe than a social defeat paradigm. In a less severe stress model, it’s been shown that dopamine neurons have a decrease in function while in severe stress they increase activity. It’s possible that because Chaudbury utilized a more severe stress paradigm, that’s could explain why they came to opposing views of the phasic stimulation of VTA DA neurons. Both papers utilizing incredibly similar tools and had the same resources from the Diseroth lab, so it’s unlikely these results stem from a technical difference in the application of optogenetics. Both papers conclude that the neuronal firing response is context-dependent, and each paper explored a different context with Tye using a milder stress paradigm. I would be fascinated to see if Tye used tonic firing in her optogenetic stimulation and if she found a difference in the different types of stimulation. Overall, I think both papers work together to show the conclusion that the VTA DA pathway is highly complex and plays a highly complex role in depressive behaviors. 

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