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 Gale, S.D., and Murphy, G.J. (2014). Distinct representation and distribution of visual information by specific cell types in mouse superficial superior colliculus. J Neurosci 34, 13458–13471. Arluison, M., Brochier, G., Vankova, M., Leviel, V., Villalobos, J., and Tramu, G. (1994). Demonstration of peptidergic afferents to the bed nucleus of the stria terminalis using local injections of colchicine. A combined immunohistochemical and retrograde tracing study. Brain Res Bull 34, 319–337.

Action Circuits (Uk) Ltd, Luton - Cylex

Ollmann, M.M., Wilson, B.D., Yang, Y.K., Kerns, J.A., Chen, Y., Gantz, I., and Barsh, G.S. (1997). Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278, 135–138. Larsson, K. (1975). Sexual impairment of inexperienced male rats following pre- and postpuberal olfactory bulbectomy. Physiol Behav 14, 195–199. Choe, H.K., Reed, M.D., Benavidez, N., Montgomery, D., Soares, N., Yim, Y.S., and Choi, G.B. (2015). Oxytocin mediates entrainment of sensory stimuli to social cues of opposing valence. Neuron 87, 152–163. Cai, H., Haubensak, W., Anthony, T.E., and Anderson, D.J. (2014). Central amygdala PKC-δ + neurons mediate the influence of multiple anorexigenic signals. Nat Neurosci 17, 1240–1248. The maximum firing frequency of human dopamine neurons has yet to be determined, as far as we know. That said, the pulse frequency employed in the deep-brain stimulation of the human MFB, 130 Hz, is well above the maximum firing frequency that dopaminergic neurons can sustain in the rodent ( Tsai et al., 2009; Witten et al., 2011; Covey and Cheer, 2019). The Centrality of the Dopamine Neurons?In Panksepp’s portrayal, the MFB constitutes the core of the SEEKING system. The primary evidence for this is the fact that animals willingly and eagerly turn on electrical stimulation delivered via electrodes arrayed all along the MFB ( Panksepp and Yovell, 2014), i.e., they engage in intracranial self-stimulation. Panksepp recognized the neuroanatomical and neurochemical heterogeneity of the MFB, but he and his colleagues ascribed indispensable status to the ascending projections of the midbrain dopamine neurons, which they viewed as energizing the SEEKING system. In that way, the dopamine neurons engage the SEEKING system in intracranial self-stimulation ( Ikemoto and Panksepp, 1999), addiction ( Alcaro et al., 2007) and relief of depression ( Panksepp and Yovell, 2014). Panksepp co-authored several of the early reports documenting the antidepressant effect of MFB stimulation ( Coenen et al., 2009b, 2011, 2012), and his portrayal of the SEEKING system provided the initial theoretical foundation for interpreting this effect. Ng, M., Fleming, T., Robinson, M., Thomson, B., Graetz, N., Margono, C., Mullany, E.C., Biryukov, S., Abbafati, C., Abera, S.F., et al. (2014). Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384, 766–781. The reward-mountain method removes a key source of ambiguity inherent in curve-shift measurements. Response-rate-versus-pulse-frequency curves are displaced laterally either by altering reward strength or the effort required to press the lever. In contrast, the reward mountain is displaced in orthogonal directions by manipulation of the strength and cost variables. This disambiguation is crucial for interpreting displacement of the reward mountain by experimental variables. As we will describe shortly, application of the reward-mountain method has falsified the long-standing “series-circuit” model of brain reward circuitry and has inspired its replacement with a new candidate germane to interpreting the effects of deep-brain stimulation in humans: the convergence model. Mapping the Reward-Mountain Model Onto Stages of Neural Processing

ACTION CIRCUITS (U.K.) LIMITED people - Find and update ACTION CIRCUITS (U.K.) LIMITED people - Find and update

Nour, S., Svarer, C., Kristensen, J.K., Paulson, O.B., and Law, I. (2000). Cerebral activation during micturition in normal men. Brain 123, 781–789. Our procedures are based on the EIA JEDEC standard JESD22-A112, and International Standard STD020, which define six levels of moisture sensitiveness.Navarro, M., Olney, J.J., Burnham, N.W., Mazzone, C.M., Lowery-Gionta, E.G., Pleil, K.E., Kash, T.L., and Thiele, T.E. (2016). Lateral hypothalamus GABAergic neurons modulate consummatory behaviors regardless of the caloric content or biological relevance of the consumed stimuli. Neuropsychopharmacology 41, 1505–1512. 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. Anjum, F., Turni, H., Mulder, P.G.H., van der Burg, J., and Brecht, M. (2006). Tactile guidance of prey capture in Etruscan shrews. Proc Natl Acad Sci USA 103, 16544–16549. Dean, P., Redgrave, P., Sahibzada, N., and Tsuji, K. (1986). Head and body movements produced by electrical stimulation of superior colliculus in rats: effects of interruption of crossed tectoreticulospinal pathway. Neuroscience 19, 367–380 Griffiths, D. (2015). Neural control of micturition in humans: a working model. Nat Rev Urol 12, 695–705.

Contact | Action Circuits

Extension of the quantitative approach to rewarding effects produced by specific optogenetic activation of midbrain dopamine neurons has led to a new view of the circuitry underlying intracranial self-stimulation ( Trujillo-Pisanty et al., 2020). On that view, parallel processing channels convey to the behavioral final-common path signals arising in non-dopaminergic MFB fibers and in the ascending projections of midbrain dopamine neurons. We summarize that new view below and explore its potential implications for explaining the relief of treatment-resistant depression by MFB stimulation. Before doing so, we situate the study of intracranial self-stimulation within the context of animal models of depression, we review aspects of depression germane to the question of how MFB stimulation provides relief, and we discuss how research on the effects of such stimulation in rodents could provide insight into the mechanism underlying the antidepressant effect in humans. Animal Models of Depression Mandiyan, V.S., Coats, J.K., and Shah, N.M. (2005). Deficits in sexual and aggressive behaviors in Cnga2 mutant mice. Nat Neurosci 8, 1660–1662. Davidson, J.M. (1966). Activation of the male rat’s sexual behavior by intracerebral implantation of androgen. Endocrinology 79, 783–794. Merrill, L., Gonzalez, E.J., Girard, B.M., and Vizzard, M.A. (2016). Receptors, channels, and signalling in the urothelial sensory system in the bladder. Nat Rev Urol 13, 193–204.

Oteiza, P., Odstrcil, I., Lauder, G., Portugues, Carrillo, A., and McHenry, M.J. (2016). Zebrafish learn to forage in the dark. J Exp Biol 219, 582–589. The convergence model accommodates a number of prior findings that fit poorly with the series-circuit model. These include the results of studies employing radical ablation methods that eliminated most of the forebrain terminations of ascending dopamine neurons ( Huston and Borbély, 1973; Pritzel et al., 1983), a study of the effect of cytotoxic lesions of the nucleus-accumbens terminal field ( Johnson and Stellar, 1994), and a comparison between frequency following in midbrain dopamine neurons and the substrate for the rewarding effect of electrical MFB stimulation ( Cossette et al., 2016). The extraordinary zeal, vigor, and persistence shown by laboratory animals working for rewarding MFB stimulation provides a diametrically opposed image of the weakened motivation and goal seeking shown by patients with depression. In the throes of a depressive episode, even goals that normally loom as urgent can lose their incentive power. Could hypoactivity of conserved neural circuitry subserving electrical self-stimulation in laboratory animals account for the motivational deficit burdening depressed humans? If so, it seems plausible that chronic electrical stimulation of such pathways could provide relief and that a deep understanding of the neural mechanisms underlying electrical self-stimulation could contribute further to the development of novel, effective treatments. Contingency