ilya e. monosov - US grants

Project Summary 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.  

Project Summary. The brain systems that control our motivation, emotions, and decisions rely at their most fundamental level on predicting the future: learning what rewards and punishments to expect, when they will arrive, and how valuable they will be. It is only natural that we are strongly motivated to seek information that will reduce our uncertainty about future events. Indeed, not only do humans and other animals choose to observe cues that inform them about future motivational outcomes, they are willing to pay for the privilege ? and remarkably, they pay for information even when they cannot use it to influence the outcome, effectively treating the knowledge itself as a reward. Despite its importance in everyday decision making and clinical settings, little is known about how this information seeking behavior is generated and governed ? how the brain anticipates information, endows it with value, and sends it to motivational circuits to drive behavior. We identified set of anatomically connected cortical and subcortical brain areas, including the anterior cingulate cortex and specific subregions of the basal ganglia (BG), that encode the quantitative level of reward uncertainty. Does this set of brain areas mediate the drive to seek advance information to reduce uncertainty, and if so, how? Aim 1 will first test whether and how uncertainty-selective neurons in the cortico-BG network anticipate the arrival of information about future rewards and punishments. Preliminary data suggest that the cortico-BG network anticipates information that resolves reward uncertainty (as dissociated from simple anticipation of valuable and/or uncertain rewards). Next, aim 1 will transiently disrupt specific uncertainty- sensitive subregions in the cortico-BG network to assess their contributions to information seeking, and to neuronal activity in other subregions of the network. Preliminary data suggest that the information-anticipation signals in the BG play an active role in mediating information seeking. Aim 2 will use a carefully designed decision-making paradigm in which primates pay to obtain information under different levels of reward uncertainty, combined with computational modelling, to quantitatively determine how information, uncertainty, and value signals in the cortico-BG network contribute to motivated decision making, including the evaluation of information, risk, and value. Next, aim 2 will use the same paradigm to elucidate information and reward value processing in the lateral habenula (LHb), a key structure for the control of motivation. Preliminary data indicate that BG information signals track the subjective value of obtaining information and that the LHb is a prime candidate for receiving these signals and generating information-seeking behavior. The Aims represent crucial steps for our understanding of the neurobiology of motivated behavior, will broaden our understanding of the mechanisms of information seeking and uncertainty reduction, and will shed light on how brain areas known to be crucially involved in human psychiatric disorders, but that have not been commonly studied in the primate, contribute to our decisions and actions.

PROJECT SUMMARY/ABSTRACT Critical advances in the treatment of human brain disorders are hindered by our inability to specifically target dysfunctional circuitry in a safe and noninvasive manner. Existing noninvasive techniques (e.g., transcranial magnetic, electrical, and ultrasound neuromodulation) activate many brain circuit components within the targeted region, and their efficacies are difficult to control. Genetic approaches (e.g., optogenetics and chemogenetics) modulate defined neural populations, but commonly require invasive surgical procedures for intracranial injection of viral vectors encoding stimulus-sensitive ion channels and/or implantation of long-term hardware for stimulus delivery. The objective of this application is to develop and validate a next-generation neuromodulation tool, incisionless sonogenetics (iSonogenetics), for noninvasive and cell-type-specific manipulation of neuronal activity in non-human primate (NHP) brains. Our ultimate goal is to use iSonogenetics for the modulation of the NHP and human brain to identify the neuronal bases of cognitive behavior and to progress toward the targeted treatment of human brain disorders. iSonogenetics involves a dual approach. (1) Sonodelivery uses focused ultrasound (FUS) to noninvasively deliver intranasally administered adeno-associated viruses (AAVs) encoding a thermosensitive ion channel, transient receptor potential vanilloid 1 (TRPV1), to genetically defined populations of neurons. (2) Sonoactivation uses FUS to induce mild warming, which opens TRPV1 channels and thereby activates the AAV-transduced neurons. Guided by strong preliminary data obtained in rodents, our objective will be accomplished by pursuing three specific aims: (1) Develop sonodelivery for noninvasive and efficient AAV delivery to a targeted brain region with minimal systemic exposure in anesthetized NHPs; (2) Develop sonoactivation for safe and reliable activation of AAV-transduced neurons in anesthetized NHPs; (3) Validate iSonogenetics in awake NHPs by conducting behavior testing. The proposed iSonogenetics is innovative because it can achieve noninvasive and cell-type-specific neuromodulation at deep brain targets with a high spatiotemporal resolution. The proposed research is significant because it directly addresses the central goal of RFA-MH-19-135 by providing the neuroscience community with a first-in-class neuromodulation tool that has the potential to transform our approaches for probing cell-specific processes and uncover new ways to understand and treat human brain disorders.