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

Background: Optogenetic stimulation has grown into a popular brain stimulation method in basic neuroscience while electrical stimulation predominates in clinical applications. In order to explain the effects of electrical stimulation on a cellular level and evaluate potential advantages of optogenetic therapies, comparisons between the two stimulation modalities are necessary. This comparison is hindered, however, by the difficulty of effectively matching the two fundamentally different modalities. Objective: Comparison of brain-wide activation patterns in response to intensity-matched electrical and optogenetic VTA stimulation. Methods: We mapped optogenetic and electrical self-stimulation rates in the same mice over stimulation intensity and determined iso-behavioral intensities. Using functional Tc-99(m)-HMPAO SPECT imaging of cerebral blood flow in awake animals, we obtained brain-wide activation patterns for both modalities at these iso-behavioral intensities. We performed these experiments in two mouse lines commonly used for optogenetic VTA stimulation, DAT::Cre and TH::Cre mice. Results: We find iso-behavioral intensity matching of stimulation gives rise to similar brain activation patterns. Differences between mouse lines were more pronounced than differences between modalities. Conclusions: Previously found large differences of electrical and optogenetic stimulation might be due to unmatched stimulation intensity, particularly relative electrical overstimulation. These findings imply that therapeutic electrical VTA stimulation might be relatively specific if employed with optimized parameters. (C) 2019 Published by Elsevier Inc.