We live in an uncertain world in which events and outcomes are often unpredictable. Being able to flexibly modify our behavior based on our uncertainty about important future outcomes, such as rewards, is critical for survival. Many studies have reported that reward uncertainty modulates behavioral and emotional states, and that improper evaluation of uncertainty is associated with maladaptive behaviors, such as risk-seeking, anxiety, and addiction. Recent evidence suggests that within the brain there are populations of neurons devoted to signaling uncertainty. But how this signal is broadcast and utilized is unknown. We will test the hypothesis that the basal forebrain (BF) plays a major role in broadcasting this signal. We will further test the idea that medial and dorsal-lateral subregions of BF differentially contribute to the regulation of behavior in uncertain contexts.
In Aim 1, we will test whether and how different subregions of the primate BF signal and combine information about uncertainty and value. The medial BF is thought to be crucial for learning and monitoring of important events, and dorsal-lateral portions of the BF, known as the ventral pallidum or the ventral-rostral globus pallidus, are thought to regulate motivation. If this is true, then it seems likely that these two BF subregions might represent uncertainty in very different ways. Next, we propose to examine how the differential representations of uncertainty and value in different regions of the BF contribute to behavior. If dorsal-lateral BF regulates motivation, then it is possible that uncertainty-signals there modulate uncertainty-related behaviors, such as risk-seeking. To test this hypothesis, we will study BF activity while monkeys choose between certain and uncertain rewards. Preliminary data support the hypothesis that dorsal-lateral BF's uncertainty representation is correlated with risky-choices, while medial BF's uncertainty signals emerge after the risky choice, while the subject awaits the choice-outcome. Finally, we will transiently inactivate different subregions of BF to causally test how the differential neuronal encoding of uncertainty in those regions contributes to choice behavior.
In Aim 2 we will test whether a major input to the dorsal-lateral BF, the striatum, is a source of the uncertainty signal we observed there. Based on data gathered during preliminary experiments, we hypothesize that uncertainty coding neurons clustered in the internal capsule bordering region of the striatum could be the source of uncertainty modulation observed in dorsal-lateral BF. To causally test this hypothesis, the last experiment in Aim 2 will assess whether inactivation of this striatal area reduces the uncertainty sensitivity of neurons in the BF. Uncertainty about rewards modulates motivation and decision making. Our proposed experiments will provide crucial information about the neuronal mechanisms of behavioral modulation by uncertainty. Understanding these mechanisms in primates provides a crucial linkage to understanding human neuropsychiatric diseases.

Public Health Relevance

We live in an uncertain world in which events are often unpredictable. Being able to appropriately modify our behavior relative to our own uncertainty regarding future rewards is crucial for survival. Malfunctions of behavior and emotion in uncertain contexts are associated with psychiatric disorders and maladaptive behavioral states, such as anxiety, persistent risk- seeking, and drug-addiction. To date, the neuronal mechanisms of uncertainty-related behaviors are poorly understood. We will test if the basal forebrain, a widely projecting region in the middle of the brain, helps to support and regulate motivation and behavior in uncertain contexts.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Rossi, Andrew
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Washington University
Schools of Medicine
Saint Louis
United States
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Turchi, Janita; Chang, Catie; Ye, Frank Q et al. (2018) The Basal Forebrain Regulates Global Resting-State fMRI Fluctuations. Neuron 97:940-952.e4
Charpentier, Caroline J; Bromberg-Martin, Ethan S; Sharot, Tali (2018) Valuation of knowledge and ignorance in mesolimbic reward circuitry. Proc Natl Acad Sci U S A 115:E7255-E7264
Monosov, Ilya E (2017) Anterior cingulate is a source of valence-specific information about value and uncertainty. Nat Commun 8:134
White, J Kael; Monosov, Ilya E (2016) Neurons in the primate dorsal striatum signal the uncertainty of object-reward associations. Nat Commun 7:12735
Ledbetter, Noah M; Chen, Charles D; Monosov, Ilya E (2016) Multiple Mechanisms for Processing Reward Uncertainty in the Primate Basal Forebrain. J Neurosci 36:7852-64