Hernandez, G., Trujillo-Pisanty, I., Cossette, M.-P., Conover, K., and Shizgal, P. (2012). Role of dopamine tone in the pursuit of brain stimulation reward. J. Neurosci. 32, 11032–11041. doi: 10.1523/JNEUROSCI.1051-12.2012 In agreement with the Freiburg group and Panksepp, we hold that research on MFB self-stimulation in rodents will continue to have translational implications. We hope that future research into this seminal phenomenon, coupled with allied experimental work in non-human primates and humans, will yield a fuller understanding, both of the psychological and neural mechanisms underlying the antidepressant effect of deep-brain stimulation, and of the neural foundations of reward and motivation. Data Availability Statement

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Janssen, N. P., Hendriks, G. J., Baranelli, C. T., Lucassen, P., Voshaar, R. O., Spijker, J., et al. (2021). How Does Behavioural Activation Work? A Systematic Review of the Evidence on Potential Mediators. Psychother. Psychosomat. 90, 85–93. doi: 10.1159/000509820 POWERED BY BATTERIES: Each experiment requires 2 AA batteries (12 total, not included) to power the modules. You must connect batteries to run the experiments. Although many factors have been proposed as mediators for the antidepressant effect of behavioral activation, a recent systematic review of 21 potential mediators was inconclusive ( Dimidjian et al., 2011; Janssen et al., 2021). Consequently, to understand how behavioral activation works, the authors proposed that researchers should turn to the basic behavioral neuroscience of reward seeking ( Janssen et al., 2021). Non-contingent delivery of free stimulation trains prior to a trial increases the vigor of subsequent stimulation-seeking behavior, a phenomenon called the “priming effect ( Gallistel, 1966; Edmonds and Gallistel, 1974).” Such non-contingent pretrial stimulation also exerts a powerful influence on reward selection. When a long delay intervened between delivery of non-contingent. pretrial stimulation, thirsty rats chose an arm of a T-maze that led to water, whereas after zero or short delays, they chose an alternate arm that led to a goal box in which rewarding stimulation was delivered ( Deutsch et al., 1964). Such energizing and directing effects are the two defining characteristics of motivation. That they can arise following non-contingent delivery of stimulation provides a conceptual link between the intracranial self-stimulation phenomenon and the hypothesis that deep-brain stimulation of the MFB may offset motivational anhedonia. That said, the priming effect of MFB stimulation can be construed as a rapidly decaying aftereffect of exposure to strong, episodic rewards ( Sax and Gallistel, 1991). If the priming effect is to be linked convincingly to the antidepressant action of MFB stimulation in humans, it must be demonstrated that continuous non-contingent stimulation can exert a motivational influence on self-stimulation performance. Below, we discuss how such an experiment could be done. Measurement of Electrical Intracranial Self-Stimulation Gallistel, C. R., and Karras, D. (1984). Pimozide and amphetamine have opposing effects on the reward summation function. Pharmacol. Biochem. Behav. 20, 73–77. doi: 10.1016/0091-3057(84)90104-7

Research on the role of dopaminergic neurons in reward seeking has accomplished so much and achieved such prominence as to overshadow the established and potential contributions of other neural populations. The ascending dopaminergic projection from the midbrain is merely one of over 50 distinguishable components of the MFB ( Nieuwenhuys et al., 1982). Which of the others contribute to the evaluation and pursuit of rewards and in what ways? The convergence model encourages us to give greater consideration to the non-dopaminergic components, which include descending projections that pass through or near the midbrain region housing dopamine cell bodies and continue deeply into the brainstem ( Nauta et al., 1982). van der Meer, M., Kurth-Nelson, Z., and Redish, A. D. (2012). Information Processing in Decision-Making Systems. Neuroscientist 18, 342–359. doi: 10.1177/1073858411435128 Witten, I. B., Steinberg, E. E., Davidson, T. J., Yizhar, O., Ramakrishnan, C., Stuber, G. D., et al. (2011). Recombinase-driver rat lines: tools, techniques, and optogenetic application to dopamine-mediated reinforcement. Neuron 72, 721–733. doi: 10.1016/j.neuron.2011.10.028 Dougherty, D. D., Rezai, A. R., Carpenter, L. L., Howland, R. H., Bhati, M. T., O’Reardon, J. P., et al. (2015). A Randomized Sham-Controlled Trial of Deep Brain Stimulation of the Ventral Capsule/Ventral Striatum for Chronic Treatment-Resistant Depression. Biol. Psychiat. 78, 240–248. doi: 10.1016/j.biopsych.2014.11.023

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Carlezon, W., and Chartoff, E. (2007). Intracranial self-stimulation (ICSS) in rodents to study the neurobiology of motivation. Nat. Protoc. 2, 2987–2995. doi: 10.1038/nprot.2007.441 Breton, Y.-A., Marcus, J. C., and Shizgal, P. (2009). Rattus Psychologicus: construction of preferences by self-stimulating rats. Behav. Brain Res. 202, 77–91. doi: 10.1016/j.bbr.2009.03.019 Patkar, A. A., Masand, P. S., Pae, C. U., Peindl, K., Hooper-Wood, C., Mannelli, P., et al. (2006). A randomized, double-blind, placebo-controlled trial of augmentation with an extended release formulation of methylphenidate in outpatients with treatment-resistant depression. J. Clin. Psychopharmacol. 26, 653–656. doi: 10.1097/01.JCP.0000246212.03530.FD

Wiegert, J. S., Mahn, M., Prigge, M., Printz, Y., and Yizhar, O. (2017). Silencing Neurons: Tools, Applications, and Experimental Constraints. Neuron 95, 504–529. doi: 10.1016/j.neuron.2017.06.050 Chakraborty, T., Driscoll, M. K., Jeffery, E., Murphy, M. M., Roudot, P., Chang, B.-J., et al. (2019). Light-sheet microscopy of cleared tissues with isotropic, subcellular resolution. Nat. Methods 16, 1109–1113. doi: 10.1038/s41592-019-0615-4 Thomas, C., Ye, F. Q., Irfanoglu, M. O., Modi, P., Saleem, K. S., Leopold, D. A., et al. (2014). Anatomical accuracy of brain connections derived from diffusion MRI tractography is inherently limited. PNAS 111, 16574–16579. doi: 10.1073/pnas.1405672111