Contributions of dopaminergic and non-dopaminergic neurons to VTA-stimulation induced neurovascular responses in brain reward circuits

Abstract

Mapping the activity of the human mesolimbic dopamine system by BOLD-fMRI is a tempting approach to non-invasively study the action of the brain reward system during different experimental conditions. However, the contribution of dopamine release to the BOLD signal is disputed. To assign the actual contribution of dopaminergic and non-dopaminergic VTA neurons to the formation of BOLD responses in target regions of the mesolimbic system, we used two optogenetic approaches in rats. We either activated VTA dopaminergic neurons selectively, or dopaminergic and mainly glutamatergic projecting neurons together. We further used electrical stimulation to non-selectively activate neurons in the VTA. All three stimulation conditions effectively activated the mesolimbic dopaminergic system and triggered dopamine releases into the NAcc as measured by in vivo fast-scan cyclic voltammetry. Furthermore, both optogenetic stimulation paradigms led to indistinguishable self-stimulation behavior. In contrast to these similarities, however, the BOLD response pattern differed greatly between groups. In general, BOLD responses were weaker and sparser with increasing stimulation specificity for dopaminergic neurons. In addition, repetitive stimulation of the VTA caused a progressive decoupling of dopamine release and BOLD signal strength, and dopamine receptor antagonists were unable to block the BOLD signal elicited by VTA stimulation. To exclude that the sedation during fMRI is the cause of minimal mesolimbic BOLD in response to specific dopaminergic stimulation, we repeated our experiments using CBF SPECT in awake animals. Again, we found activations only for less-specific stimulation. Based on these results we conclude that canonical BOLD responses in the reward system represent mainly the activity of non-dopaminergic neurons. Thus, the minor effects of projecting dopaminergic neurons are concealed by non-dopaminergic activity, a finding which highlights the importance of a careful interpretation of reward-related human fMRI data.

Matching stimulation paradigms resolve apparent differences between optogenetic and electrical VTA stimulation

“…A reward-related area which showed deactivation was the ventral pallidum, with reduced activity in the contralateral hemisphere during electrical stimulation. Similarly to previous studies [22,24], we again found no significant activation at the exact fiber position or in the VTA during optogenetic stimulation. In contrast to previous findings, however, the electricalstimulation-induced neuronal activity was too low to cause significant SPECT activation.…”

“…Differences exist in frontal cortex and striatum, depending on the line (DAT::Cre: mPFC and OFC; TH::Cre: striatum and IPN). We speculate that these results are related to stimulation of glutamatergic VTA neurons, a side effect of electrical stimulation but not optogenetic VTA stimulation in the lines used [22,23,47]. It should also be noted that due to the relatively weak impact of dopamine on metabolic signals, one would not expect to find the massive, brain wide activations reported for less-specific stimulation of the dopamine system [24,48].…”

Dopaminergic modulation of the exploration/exploitation trade-off in human decision-making

“…Finally, the BOLD signal obviously does not directly reflect DA release, and the precise physiological relationship between DA release and BOLD signal is still to be revealed (Knutson & Gibbs, 2007;Brocka et al, 2018). Based on pharmacological MRI studies, it has been suggested that striatal DA release may increase the BOLD signal via a D1-dependent mechanism, according to which D1 receptor activation changes the postsynaptic membrane potential and engages metabolic processes, which in turn lead to increased oxygen utilization followed by an elevated local BOLD response (Knutson & Gibbs, 2007).…”

“…Based on pharmacological MRI studies, it has been suggested that striatal DA release may increase the BOLD signal via a D1-dependent mechanism, according to which D1 receptor activation changes the postsynaptic membrane potential and engages metabolic processes, which in turn lead to increased oxygen utilization followed by an elevated local BOLD response (Knutson & Gibbs, 2007). However, a recent optogenetic study in rats suggests that canonical BOLD responses in the reward system may mainly represent the activity of non-dopaminergic neurons, such as glutamatergic projecting neurons (Brocka et al, 2018). Thus, it is also conceivable that L-dopa might have enhanced striatal DA release to some degree without triggering a (detectable) BOLD signal change.…”

“…Needless to say, the BOLD signal provides an indirect index of blood oxygenation rather than a direct measure of DA activity. Hence, an observed BOLD signal change must not necessarily rely on a change in DA transmission, and a change in DA transmission must not necessarily produce a (detectable) BOLD signal change (Brocka et al, 2018). Future research should therefore complement pharmacological fMRI studies with other in vivo techniques that specifically monitor local changes in DA activity, such as molecular imaging with PET and SPECT (single photon emission computed tomography) in humans (Cropley, Fujita, Innis, & Nathan, 2006).…”