Kate Wassum - US grants

DESCRIPTION (provided by applicant): Drug addiction is a chronic, relapsing disorder characterized by poorly managed motivated behavior. The formation of rational and effective pharmacotherapies for addictions necessitates an understanding of the neurobiological underpinnings of reward hedonia and the representation of reward value. Previous research has implicated the endogenous opioid systems as a potential mediator of the affective properties of reward. Moreover, endogenous opioids have been shown to modulate glutamate transmission in the brain reward circuitry. Interestingly, glutamate transmission in these basal forebrain regions is highly implicated in motivated behavior, particularly towards abused substances. Therefore the specific aims of this proposal are to differentiate the role of the endogenous opioid systems in consummatory hedonia, reward value representation and general motivational arousal using a novel instrumental paradigm designed specifically to distinguish these components of goal-directed actions. We will also elucidate the anatomical substrates within basal forebrain curcuitry regulating reward hedonia/and or the representation of reward value, and test the hypothesis that endogenous opioids modulate reward value representation through changes in glutamate release in these structures. These aims will be accomplished by using central and peripheral manipulation of the endogenous LI opioid receptor system as well as electroenzymatic overoxidized polypyrrole and glutamate oxidase-coated platinum micro-array biosensors for real-time recordings of extrasynaptic glutamate during a heterogeneous sucrose seeking-taking chain with a consummatory palatibility analyssi. It has been established that performance on the seeking component of this chain reflects the reward's specific value. Therefore, these data will elucidate the opioid and glutamatergic modulation ofreward hedonia and the encoding of value. It is the long-term objective of this research proposal to gain an understanding of how the opioid system regulates reward value and motivation. This work will provide a basis for comprehending how the endogenous reward processes go awry during addictive behavior. The endogenous opioid and glutamate systems are implicated in the reinforcing and addictive properties of several classes of abused substances. We intend to understand how these systems mediate specific components of reward processing. Consequently, this research will inform not only our understanding of how the reward systems may be usurped by addictive drugs, but also research on potential pharmacotherapies.

DESCRIPTION (provided by applicant): Here we seek to understand the neurochemical signals and neurosystems underlying reward-related decision- making. Considerable evidence suggests the decision between actions leading to different rewards relies heavily on the anticipated value of each action's outcome. In addition to this, reward-related decisions are also biased by reward-paired environmental cues, such that a cue predicting a specific reward will bias one towards the action that obtains that reward, even if other, potentially better, options ar available. Regarding the circuitry of reward-related decisions, numerous interconnected structures, including the basolateral amygdala, orbitofrontal cortex and insula are all implicated, but how or if they interact to control decisions remains unclear. Neurochemically, glutamate signaling and neuromodulatory opioid peptides are also implicated in aspects of reward seeking, but how these signals are related to discrete aspects of behavior has not been elucidated. Here we will use a novel glutamate biosensor technology, which allowed us, for the first time, to monitor transient extracellular glutamate concentration changes in the basolateral amygdala of freely-behaving rats, to clarify the role of rapid basolateral amygdala glutamate signaling in both reward learning and decision- making. Moreover, we will explore the basolateral amygdala-cortical circuitry that controls reward-seeking decisions. Given the limited number of signaling molecules in the brain, interactions between them must occur in order to account for the vast number of human behaviors. To this end, we will also explore the regulation of decision-related basolateral amygdala glutamate release by the neuromodulatory opioid peptide systems. The long-term goals of this research trajectory are to characterize the specific neurochemical signals that underlie discrete aspects of decision-making. Importantly, this research aims to identify brain regions and neurochemical systems that interact to underlie decisions driven by reward value as well as those that are biased by environmental cues. Each of these forms of decision-making can be disrupted in addiction to drugs, alcohol or even highly palatable foods. Therefore, information gleaned from this research trajectory will provide the basic science necessary for the development of new pharmacotherapies to combat these specific deviations in addiction and compulsive over-eating. Importantly, the proposed research makes use of a new tool, not yet applied to these questions, in order to provide new information regarding the role of brain glutamate signaling in reward-related behaviors.

PROJECT SUMMARY Growing evidence suggests that the cognitive symptoms underlying many psychiatric disorders, including addiction, result from a failure to appropriately learn about and/or anticipate potential future events. Indeed, deficits in the prospective consideration of potential rewarding events have been detected in patients diagnosed with addiction, accounting for their inability to limit use despite deleterious consequences. Similar deficits have been identified in patients diagnosed with mental illnesses comorbid with addiction, such as depression, anxiety, and schizophrenia. These mental illnesses are major intractable public health problems in the US, accounting for hundreds of billions of dollars in costs associated with health care, crime, incarceration and law enforcement. Effective approaches to prevent and/or treat these conditions are, therefore, badly needed. The goal of this research is to expose the neural circuits required to learn predictive relationships and to use this information to generate expectations about the future, in order to gain insight into how pathological states arise and determine what can be done to combat them. Addictive substances are thought to hijack the brain systems that normally support adaptive decision making, resulting in maladaptive choices. Adaptive decision making requires accurate prospective consideration of possible future events. Prior encoding of specific stimulus-reward associative memories enables this prospective consideration by allowing the mental simulation (i.e., representation) of possible future rewarding events. Recent studies in rodents and humans have indicated that the basolateral amygdala (BLA) might be a brain region crucial for learning these associations, but precisely how and the neural circuitry through which it achives this function are unknown. The proposed research provides a critical, in-depth, and hypothesis-driven investigation of the contribution of the BLA and its reciprocal connections with the orbitofrontal cortex, a region implicated in decision making, to stimulus-reward encoding and subsequent retrieval of this information to guide adaptive behavior and choice. This will be achieved through a multi-faceted and integrative neural recording and manipulation approach. We will combine projection-specific activity monitoring, tag and capture techniques for manipulation of specific event-activated neuronal ensembles, and behavioral procedures with translational relevance to symptoms of human mental illness to uncover the function of amgydala-cortical loops in adaptive reward-guided behavior and decision making.

PROJECT SUMMARY Growing evidence suggests addiction and other diseases of behavioral control result from the development of maladaptive habits. Indeed, an overreliance on habit is associated with the compulsive phenotype found in patients diagnosed with addiction and alcoholism, and comorbid conditions including obsessive-compulsive disorder and schizophrenia. Addictive substances and stress are thought to hijack the brain systems that normally support habit learning, causing habits to form faster and more strongly influence behavior than normal. This results in behavior that is insensitive to its consequences, even when those consequences are negative. Our ultimate goal is to expose the epigenetic-genomic-physiological-functional conduit that allows stress and exposure to addictive substances to promote these maladaptive habits. To achieve this, our specific goal here is to expose the multi-layered biological architecture required for mechanistic understanding of adaptive and maladaptive habits. Thus, this work will provide insight into how pathological states arise and what can be done to combat them. The striatum has long been known to function in habit learning. Where information is lacking is on how each striatal projection pathway, the direct- and indirect-projections to basal ganglia output nuclei, contribute and how their function might differ depending on the anatomically and functionally distinct medial and lateral striatal subdivisions. We will use a multi-faceted and integrative approach to expose the physiological and molecular changes that occur in each striatal subcircuit during goal-directed and habit learning. Our preliminary investigations have indicated that one major epigenetic repressor, HDAC3, functions in the striatum as a negative regulator of habit formation. Our hypothesis is that dorsal striatal HDAC3 functions as a molecular gate over habit, being engaged at the promoters of key neuronal activity genes to slow the transition to habit and being removed when conditions are ripe for habits to dominate. Thus, chronic stress and exposure to addictive substances might open this gate, creating an epigenetic landscape that biases future behavioral strategy towards habit, even with this is not adaptive, producing the compulsivity that marks many mental illnesses. Our proposed research begins to test this by investigating the molecular and cellular mechanisms that allows HDAC3 to regulate habit. This will enable future investigations into how disruptions in these mechanisms promote maladaptive behavior.