Chaudhury and Tye -- Annie Bryant

Both Chaudhury et al. and Tye et al. explored the role of the mesolimbic dopamine (DA) neuron system in depression, as this system has been linked to reward, motivation, and stress. Despite many similarities in their approaches, the two groups diverged in their selection of depression-inducing models: Chaudhury et al. chose a 10-day repeated social defeat stress model (in conjunction with subthreshold defeat), while Tye et al. opted for 8-12 week chronic mild stress (CMS). Right off the bat, the groups report opposite results in response to phasic activation of VTA DA neurons. When Chaudhury et al. exposed mice to subthreshold social defeat and then stimulated channelrhodopsin 2 (ChR2)-expressing VTA DA neurons, they saw that phasic activation increased susceptibility to depressive behavior in the social interaction test. Conversely, when Tye et al. exposed mice to CMS and then stimulated ChR2-expressing VTA DA neurons, they observed reduction in depressive behavior, restoring sucrose preference and escape behavior to non-CMS baseline. Opposing results also arose from halorhodopsin (NpHR)-mediated inhibition of VTA DA neurons. Tye et al. inhibited VTA DA neurons via NpHR and observed reduced struggling behavior in the tail suspension test and reduced sucrose preference, both of which were reversed upon turning off the light. Chaudhury et al. report different effects of NpHR inhibition on the VTA -> nucleus accumbens (NAc) DA neurons versus VTA -> medial prefrontal cortex (mPFC) DA neurons. While inhibition of DA neurons in the VTA -> NAc rendered susceptible mice resilient, inhibition of DA neurons in the VTA -> mPFC left mice susceptible. I was struck by how quickly optogenetic activation or inhibition was able to modulate depressive behaviors like anhedonia and social avoidance. While optogenetic stimulation is clearly not a viable everyday treatment option, this provides insight into ways to more efficiently and directly target circuit dysfunction in depression.

I thought it was relevant that Chaudhury et al. focused on subpopulations of mice that responded differently to chronic social defeat, since humans can have vastly different reactions to similar stressors. One key difference between susceptible versus resilient mice lies in the firing rate of their VTA DA neurons: while susceptible mice show increased firing following stress, resilient mice maintain normal firing rates and patterns. Chaudhury et al. propose this is due to unique cellular adaptations that render resilient neurons immune to stress-induced hyperexcitation. Even more interesting is that when Chaudhury et al. forced phasic activation of these neurons by transducing the resilient mice with ChR2, these mice immediately took on a susceptible phenotype, cowering in the corner when they used to spend even more time in the interaction zone with the target mouse present.  It’s important to recognize the heterogeneity of depression manifestation between individuals when studying mechanisms and potential therapeutic avenues. Chaudhury et al. note that different types of stress (namely, CMS and chronic social defeat) produce different changes in extracellular neurotransmitter levels in multiple brain regions. Since VTA neurons send both glutamatergic and dopaminergic inputs into the nucleus accumbens (NAc), Tye et al. sought to tease out the respective roles of these neurotransmitters in CMS-induced depression and subsequent light-mediated behavioral rescue. By selectively inhibiting glutamate or dopamine transmission with receptor antagonists infused into the NAc, Tye et al. show that only dopamine blockage prevented light-induced rescue. They interpret this to mean that dopamine signaling in the VTA -> NAc circuit is critical for mediating both depression in response to CMS and alleviation of these symptoms with phasic light activation.

The divergent results in these papers are largely due to inherent differences in the two different stress-based depression models. Both authors note that chronic mild stressors (i.e. CMS) inhibit VTA DA neuron activity, while more severe stressors increase their activity. The results described in these studies align with these previous findings. Tye et al. demonstrated that CMS reduced VTA DA neuron firing rate, burst duration, and number of spikes per burst, all indicating reduction in neuron activity. Furthermore, they demonstrated that phasic stimulation of these neurons rescued CMS-induced depressive behaviors, supporting the theory that VTA DA neurons become hypo-active in the context of CMS. Conversely, Chaudhury et al. showed that mice that were susceptible to repeated social defeat exhibited increased firing rates in VTA DA neurons (specifically, those projecting to the nucleus accumbens). Accordingly, phasic stimulation of these neurons exacerbated stress-induced depression, supporting the theory that VTA DA neurons are already hyperactive in severe stress settings. Additionally, Tye et al. point out that VTA neurons respond differently based on pre-exposure and stress severity. In support of this, Chaudhury et al. demonstrate that phasic stimulation of VTA DA neurons in depression-naïve mice did not induce any change in social interaction, sucrose preference, or baseline anxiety. They also show that tonic stimulation of these neurons failed to alter any behavioral metric from baseline, suggesting that phasic activation plus pre-exposure together create a perfect storm for depressive symptoms. However, Tye et al. delivered NpHR-mediated VTA DA neuron inhibition to stress-naïve mice, and the mice did exhibit reduced escape behavior and sucrose preference. Perhaps reduction of steady-state dopamine signaling can exert effects independently of depression, while increased activation only affects those who have already been experiencing stress.

Overall, these authors packed a lot of information into just a few pages, and the scope of their work is really impressive. There is only one major issue that I took with these two papers: Chaudhury et al. oscillated between the subthreshold defeat and repeated social defeat paradigms with seemingly no rhyme or reason. I found this particularly confusing when they performed a binary comparison of activation vs inhibition in the NAc and mPFC and mixed the two different stress paradigms.