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Fusé, T., Forsyth, J. P., Marx, B., Gallup, G. G. & Weaver, S. J. Anxiety Disord. 21, 265–283 (2007). 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 We also offer a waffle tray recycling service which can save you money in addition to being kind to the environment. Bolton, A.D., Haesemeyer, M., Jordi, J., Schaechtle, U., Saad, F.A., Mansinghka, V.K., Tenenbaum, J.B., and Engert, F. (2019). Elements of a stochastic 3D prediction engine in larval zebrafish prey capture. eLife 8, e51975.

Salience memories formed by value, novelty and aversiveness

In a Bayesian, decision-theoretic account, depression entails pessimistic expectations about the value of future rewards and possible actions ( Huys et al., 2015), an observation well supported by evidence ( Cooper et al., 2021). As noted above, Panksepp emphasized the role of the SEEKING system in anticipation of positive outcomes rather than in ongoing hedonic experience, and he viewed hypoactivity of the system as a determinant of depression ( Panksepp and Yovell, 2014). That view seems well aligned with the notions of pessimistic expectations and decisional anhedonia. Huys et al. (2015) argue that alterations in model-based, rather than model-free, learning are the most likely route to pessimistic expectations. Definitive isolation of model-based learning in rodents from other forms of learning is not easy to achieve, but it has been demonstrated convincingly ( van der Meer et al., 2012; Redish, 2016; Miller et al., 2017). The experimental paradigms in question should be amenable to assessing the effect of MFB stimulation on reward expectations. Gréco, B., Edwards, D.A., Michael, R.P., and Clancy, A.N. (1996). Androgen receptor immunoreactivity and mating-induced Fos expression in forebrain and midbrain structures in the male rat. Neuroscience 75, 161–171. Benarroch, E.E. (2010). Neural control of the bladder: recent advances and neurologic implications. Neurology 75, 1839–1846. Isa, T., and Sasaki, S. (2002). Brainstem control of head movements during orienting; organization of the premotor circuits. Prog Neurobiol 66, 205–241.Allison, S., and Timmerman, G.M. (2007). Anatomy of a binge: food environment and characteristics of nonpurge binge episodes. Eat Behav 8, 31–38. Consoli, D., Contarino, A., Tabarin, A., and Drago, F. (2009). Binge-like eating in mice. Int J Eat Disord 42, 402–408. 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

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Dai, B., Sun, F., Kuang, A., Li, Y., and Lin, D. (2021). Dopamine release in nucleus accumbens core during social behaviors in mice. bioRxiv doi: https://doi.org/10.1101/2021.06.22.449478.

Implications for Research on the Antidepressant Effect of Deep-Brain Stimulation

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. Grinevich, V., and Stoop, R. (2018). Interplay between oxytocin and sensory systems in the orchestration of socio-emotional behaviors. Neuron 99, 887–904.

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Irwin, D.E., Milsom, I., Kopp, Z., Abrams, P., and Cardozo, L. (2006). Impact of overactive bladder symptoms on employment, social interactions and emotional well-being in six European countries. BJU Int 97, 96–100. Mukhopadhyay, S., and Stowers, L. (2020). Choosing to urinate. Circuits and mechanisms underlying voluntary urination. Curr Opin Neurobiol 60, 129–135. Barker, A.J., and Baier, H. (2013). SINs and SOMs: neural microcircuits for size tuning in the zebrafish and mouse visual pathway. Front Neural Circuits 7, 89. Han, W., Tellez, L.A., Rangel Jr, M.J., Motta, S.C., Zhang, X., Perez, I.O., Canteras, N.S., Shammah-Lagnado, S.J., van den Pol, A.N., and de Araujo, I.E. (2017). Integrated control of predatory hunting by the central nucleus of the amygdala. Cell 168, 311–324.e18.

Munz, M., Brecht, M., and Wolfe, J. (2010). Active touch during shrew prey capture. Front Behav Neurosci 4, 191. Folgueira, C., Beiroa, D., Porteiro, B., Duquenne, M., Puighermanal, E., Fondevila, M.F., Barja-Fernández, S., Gallego, R., Hernández-Bautista, R., Castelao, C., et al. (2019). Hypothalamic dopamine signalling regulates brown fat thermogenesis. Nat Metab 1, 811–829.

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dos Santos, L.M., Boschen, S.L., Bortolanza, M., de Oliveira, W.F., Furigo, I.C., Mota-Ortiz, S.R., Da Cunha, C., and Canteras, N.S. (2012). The role of the ventrolateral caudoputamen in predatory hunting. Physiol Behav 105, 893–898.

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Hu, R.K., Zuo, Y., Ly, T., Wang, J., Meera, P., Wu, Y.E., and Hong, W. (2021). An amygdala-to-hypothalamus circuit for social reward. Nat Neurosci 24, 831–842. Klaus, A., Alves da Silva, J., and Costa, R.M. (2019). What, if, and when to move: basal ganglia circuits and self-paced action initiation. Annu Rev Neurosci 42, 459–483. Dean, P., Mitchell, I.J., and Redgrave, P. (1988). Contralateral head movements produced by microinjection of glutamate into superior colliculus of rats: evidence for mediation by multiple output pathways. Neuroscience 24, 491–500. It would clearly be of great interest to determine which anhedonia constructs are impacted by MFB stimulation in patients with treatment-resistant depression. Might this be done by comparing appropriate behavioral measures acquired prior to and after the onset of stimulation or a patient-initiated pause ( Kilian et al., 2019)? Behavioral Activation