Attenuation of depressive susceptibility via dopaminergic circuitry activation

I was intrigued by Tye et Al.'s discussion point towards the end where they begin to discuss the possible sources of variance between their paper and other papers in the past that demonstrated that phasic activation of ontogenetically induced light stimulation of VTA-Nacc circuit increases susceptibility to depressive behavior. They discuss the fact that different stressors may attenuate or increase responses to this neural circuit depending on the severity of the stressor. Could for example, a severe stressor require activation of dopaminergic cells projecting to the nucleus accumbens, due to the degree of harshness, while a more mild stressor may not need this added dopaminergic response?

Chaudhury et al., showed that phasic activation of the VTA-Nacc circuit attenuates sucrose preference, and social interaction in ChR2 mice. This did not happen with tonic activation which is a surprising find. Why would phasic, and not tonic activation of this dopaminergic circuit increase susceptibility to depressive symptoms? One critical analysis is that tonic activation may be a more stable phenotypic expression of dopaminergic activation yielding a consistent dopaminergic tone that could facilitate resilience, while phasic activation is representative of an incoherent stream of neural firing in this circuitry. Phasic activation seems less likely to be the case in nature, and if it does occur, it is more probable to occur during mental states of disorganization, and a lack of concentration that is seen in non-depressed models.

Chaudhury furthermore shows (consistent with the findings of Tye et Al. at least in part) that a Cre dependent halorhodopsin induced de-activation of Cre-VTA-mPFC circuit increases depressive susceptibility, as seen by the reduction in social interaction time. This finding is what I would have expected, as I believe dopaminergic input into the medial prefrontal cortex represents cognitive reframing techniques associated with coping, and neural reorganization. I hypothesize that the inputs into the pre frontal cortex help in re constructing meanings associated with stimuli, and are associated with behavioral resilience. The mPFC is an area of higher order thinking, and it would be plausible to conjecture this area serves a role in cognitive reframing during stressful events.

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