Examining the Role of Top-Down Signaling and Tegmental Activity in Nucleus Accumbens Dopamine Release
Fast-scan cyclic voltammetry
medial Prefrontal Cortex (mPFC)
nucleus accumbens (NAc)
ventral tegmental area (VTA)
AdvisorCowen, Stephen L.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction, presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractThe capacity to assess the value of future outcomes based on current context is critical for learning, adaptive decision making, and motivation. In the brain this requires the integration of many complex signals from multiple brain regions into a unitary value signal. Midbrain dopamine neurons are among the most notable neural substrates associated with outcome valuation and have been shown to be essential for economic decision making, motivation, and error-driven learning. The mechanisms by which complex behavioral and environmental stimuli are distilled down to value signals by dopamine neurons and their afferents remain incompletely understood. This work seeks to better understand the patterns of top-down input and local control that give rise to phasic dopamine release. To examine how cortical input influences phasic dopamine release, we used fast-scan cyclic voltammetry (FSCV) to measure dopamine release evoked by varying frequencies of electrical stimulation in the medial prefrontal cortex. We found that there is a non-linear response to frequency such that 20 Hz stimulation optimizes dopamine release in the nucleus accumbens (NAc) even when controlling for stimulus duration. These data suggest that specific frequencies of cortical activation preferentially activate dopamine neurons and may have implications for cortical control of dopamine release in circumstances when value encoding must be optimized (e.g., during cognitively demanding tasks involving working memory and attention). Though electrical and optogenetic stimulation are valuable tools for dissecting functional circuits, they modulate activity in ways that are not physiological and therefore, they cannot be used to assess how endogenous patterns of neural activity influence dopamine release. To address this, we developed a novel instrument capable of simultaneous measurement of dopamine release (FSCV) and neural activity (electrophysiology). This system was validated in vitro and in vivo to show reliable recovery of single-unit activity and local field oscillations while recording changes in phasic dopamine. The real-time correlation of these signals enables the investigation of patterns of activity that drive dopamine release and how dopamine entrains cell assemblies in downstream structures. Though the relationship between dopamine neuron activity and dopamine release is seemingly intuitive, technological limitations have limited the capacity to measure these signals simultaneously. To better understand how tegmental activity gives rise to changes in dopamine release, we implemented the instrument described above to record FSCV in the nucleus accumbens and single-unit activity in the VTA. As expected, we observed changes in firing rate of putative dopaminergic neurons associated with the onset of phasic dopamine release events. We also observed a number of non-dopaminergic neurons with reliable peri-event changes in firing. Although we expected the majority of non-dopaminergic cells to decrease their activity preceding dopamine release events, the majority increased, suggesting that local mechanisms other than disinhibition of dopamine neurons contribute to phasic dopamine release. We also anticipated that changes in firing rate of putative dopamine neurons would be directly correlated with release. Instead, the majority of dopamine neurons increased firing at the onset of dopamine release, returned to baseline, and then increased again at the peak of dopamine release. Taken together, these data suggest that the dopamine neuron activity is not perfectly correlated with dopamine release and that processing within the VTA and RMTg may involve an intricate network of non-dopaminergic neurons that facilitate dopamine cell activity and dopamine release.
Degree ProgramGraduate College