Demonstrating the ability of GABAergic cells in the zona incerta to modulate motivation.

Motivation to engage in goal-directed actions is crucial for survival and well-being. Dopaminergic and serotonergic systems have been the focus of efforts to understand neurobiological etiologies of normative and disrupted motivation. Understanding how the brain incorporates salient sensory cues into motivational drive outside of these neuromodulatory systems is less appreciated. We posited that given their afferent and efferent connections, GABAergic cells in the zona incerta (ZI) are ideally positioned to perform this function. Combining behavioral tasks in mice with chemogenetics we show that GABAergic ZI neurons are capable of modulating effort-based motivation and that chemogenetic activation of this cell population can rescue motivational deficits induced by chronic stress - without affecting attention, memory, locomotion, or appetite. Next, using fiber photometry we report that GABAergic cells in the ZI robustly respond to sensory cues and their response to a cue increases as reward-predictive associations are formed. Inhibiting GABAergic cells in the ZI did not abolish cue-associated motivational behavior while cue-locked optogenetic activation of these cells robustly enhanced cue-associated motivated behavior demonstrating that these cells are not necessary but sufficient to allow for sensory cues to influence action selection. These findings establish GABAergic cells in the ZI as modulators of motivation and afford us a neuroanatomical hub that could be targeted to potentially remedy treatment-resistant deficits in motivation.