Sean Bjorn Ostlund - US grants

DESCRIPTION (provided by applicant): There is growing interest in the possibility that drugs of abuse subvert normal learning and decision- making processes, leading to the development of compulsive, pathological drug-seeking behavior. Chronic exposure to psychostimulants, like cocaine, results in sensitization of nigrostriatal and mesolimbic dopamine pathways, which are critically involved in the acquisition of habits (i.e., rigid, stimulus-bound responses) and the expression of incentive motivation (i.e., the capacity for a reward-related cue to facilitate appetitive behaviors, or induce 'wanting'). In this project, we will evaluate two distinct (but not mutually exclusive) theories of addiction: that drug exposure allows habits to dominate the control of action selection (at the expense of deliberative, goal-directed action selection), and that drug exposure potentiates the influence of reward-related environmental cues over performance. Our plan is to use a combination of carefully controlled behavioral procedures and well-established neurochemical detection techniques to answer the following questions: (i) Does dopamine release during instrumental training match the profile of the prediction error-based reinforcement signal assumed to be responsible for governing habit formation? (ii) What are the effects of cocaine pre-exposure on the acquisition and expression of habitual performance and on reinforcement-related dopamine signaling? (iii) Does mesolimbic dopamine efflux mediate the incentive motivational processes that guide cue-based action selection? (iv) and, What are the effects of repeated cocaine exposure on cue-based action selection and on the mesolimbic dopamine response to reward-related cues? Recent studies have shown that response-contingent cocaine elicits stronger neurochemical effects and results in more dramatic and longer-lasting changes in the circuitry underlying dopamine release than noncontingent cocaine. Such findings raise questions about the validity of studies assessing the effects of experimenter-administered drugs on learning, behavioral control, and brain chemistry. Therefore, a secondary objective of the current application is to determine whether the behavioral and neurochemical effects of repeated cocaine exposure depend on the mode of drug delivery. PUBLIC HEALTH RELEVANCE: Repeated exposure to drugs of abuse, including psychostimulants like cocaine, can significantly alter the neurocircuitry that supports learning and decision-making. Modern theories of addiction propose that these alterations lead to the compulsive, pathological drug-seeking behavior displayed by addicts. The current application combines well-established behavioral tests with neurochemical analysis to investigate how taking cocaine influences the way organisms acquire and select actions.

DESCRIPTION (provided by applicant): Obesity has reached a crisis point in the Western world, especially in the US where one third of the population is obese, and many more are classified as overweight. A major cause of obesity is overeating, the majority of which is targeted to energy-dense, highly palatable foods. Feeding is the product of a complex interaction between humoral, metabolic, physiological and psychological processes. Regarding the latter, advances in the neurobiology of motivated behavior and addiction demonstrate that endogenous opioid peptides and dopamine are central to affective processing of rewarding stimuli, especially food, and to learning about rewards and the relevance of reward-related stimuli, making them logical suspects for focused investigation in the etiology of obesity. In the first part of this project, we will test the hypothesis that chronic consumption of energy-dense highly palatable foods disrupts opioid-dependent instrumental incentive learning processes, resulting in discordance between the pleasurable experience of palatable food consumption and the incentive value assigned to the food that guides food-seeking behavior, leading ultimately to compulsive food-seeking. The hypothesized role of disruption in endogenous opioid transmission in the basolateral amygdala will be tested using a combination of pharmacological and genetic interventions and by measurement of enkephalin release. As environmental stimuli, such as carefully engineered advertising, packaging and product placement can potently influence feeding, the second part of the project will test the hypothesis that chronic consumption of highly palatable foods accentuates cue-induced food-seeking, and that this process involves plasticity in central dopamine and/or opioid transmission. Thus, we will combine a preclinical model of diet-induced obesity with a combination of advanced behavioral, neurochemical and genetic methodologies to yield data that promise to have important implications for guiding public policy and treating overeating and obesity.

DESCRIPTION (provided by applicant): The decision to engage in an action leading to a rewarding outcome is governed by several factors that may vary with age. Primary among these is the value placed on the reward at the time of the decision, which is continually updated on the basis of previous emotional experience with the reward. Cues associated with reward experience also impact decision-making through a Pavlovian incentive motivation process. Endogenous opioids play a major role in mediating emotional responsiveness to palatable food rewards through actions in the nucleus accumbens/ventral pallidum, and independently facilitate instrumental incentive learning via mu opioid receptors in the basolateral amygdala. Dopamine transmission in the nucleus accumbens is essential for the invigorating effects of reward-associated cues. The goal of this proposal is to examine whether developmental transitions in endogenous opioid and dopamine transmission in these brain regions manifest as shifts in the manner in which adolescent, middle-aged, and aged rodents react to changes in experienced reward value and to environmental cues predictive of reward. We will use licking architecture during consumption of sweet solutions to assess how emotional experience of reward (palatability) changes over the lifespan and an instrumental incentive learning task to parse the effects of aging on how the emotional impact of a reward is translated into a goal value used in the decision-making process. The Pavlovian-to- instrumental transfer test will assess the ability of reward-paired cues to initiate and invigorate reward-seeking actions and how this process changes over the lifespan. The role of developmental shifts in opioid and dopamine transmission in the shifting influence of these factors across ages will be determined using central pharmacological manipulations, viral-mediated gene transfer, in vivo measures of enkephalin and dopamine release, and mice with targeted conditional manipulation of pro-enkephalin expression. Understanding how aging impacts cue-evoked incentive motivation, reward palatability, and incentive learning may inform development of targeted cognitive-behavioral and pharmacological therapies for age-dependent decision- making impairments and behavioral control disorders.

? DESCRIPTION (provided by applicant): Environmental cues can serve as triggers for various pathological behaviors, including drug seeking and compulsive overeating. Indeed, there is growing evidence that the behavioral influence of drug-paired cues becomes dysregulated in addiction, accounting for the progressive nature of this disorder. Obesity and drug addiction 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 disorders are therefore badly needed. The long-term goal of this research proposal is to advance our understanding of the basic neural substrates of cue-triggered reward seeking to gain insight into how such pathological states arise and determine what can be done to combat them. Addictive substances are thought to hijack the normal role of reward-predictive stimuli in adaptive decision making. Research has identified two distinct functions of such cues. First, they provide a nonspecific motivational function, indiscriminately invigorating reward-seeking behaviors. This motivational function is gated by physiological need, such that, for instance, shifting an organism from hunger-to-satiety will suppress the motivational impact of a food-associated cue. Second, reward-predictive cues can bias decision processes to favor actions with which they share a common outcome. Recent studies in rodents and humans have established that these processes are mediated by distinct corticostriatal circuits including the nucleus accumbens core (NAc), which supports the general motivational process, and the dorsomedial striatum (DMS), which supports the outcome-specific, action biasing process. However, much remains unknown regarding the specific neurochemical underpinnings of these aspects of cue-motivated behavior. Here we provide an in-depth and hypothesis-driven investigation of the involvement of dopamine and acetylcholine, the two main striatal neuromodulators. While it is known that cue-motivated behavior is accompanied by phasic striatal dopamine signaling, the proposed research will provide critical tests of whether these events are causally linked. The contributions of acetylcholine to motivated behavior are even less well understood, though there is evidence that striatal acetylcholine is involved in the homeostatic regulation of feeding behavior. Importantly, recent in vitro studies have shown that acetylcholine plays an important, but complex, role in modulating striatal dopamine release through its actions at nicotinic acetylcholine receptors on dopamine terminals. While this work has been crucial in characterizing the neuromodulatory relationship, its ultimate behavioral significance is not known. The current proposal will apply a highly integrative approach to investigate the potentially region- and function-specific roles of dopamine and acetylcholine and their interaction in cue-motivated behavior by combining sophisticated behavioral analysis with pharmacological and optogenetic manipulations, and in vivo neurochemical analysis of striatal acetylcholine and dopamine systems.

Summary Apathy, defined as ?lack of motivation? or a ?quantitative reduction in goal-directed behavior? is a major and prevalent (up to 72%) debilitating symptom of Alzheimer's disease and related dementias. It is also associated with poor outcome, and is the primary cause of caregiver distress. Remarkably, however, very few studies have probed for disrupted reward processing and goal-directed decision-making underlying the apathy domain using rodent models of Alzheimer's disease. Apathy may result from dysfunction of one or more of the behavioral processes necessary to achieve goal-directed behavior, including internal and external determinants that motivate behavior, selection of goals, elaboration of a plan of action, initiation, execution, evaluation of goals achieved and feedback control of the behavioral response. We will employ a battery of behavioral tasks, used routinely in our labs to probe reward and decision making deficits in rats related to normal aging and addiction, to examine such processes in a double- transgenic rat model of Alzheimer's disease (TgF344-AD). This model expresses a single `Swedish mutation' human amyloid precursor protein (APPsw) gene plus a delta exon 9 mutant human presenilin-1 (PS1deltaE9) gene and manifests age-dependent cerebral amyloidosis, including an abundance of soluble amyloid-beta, that precedes tauopathy, gliosis, apoptopic loss of neurons in the cortex and hippocampus, and cognitive deficits. We will perform in-depth microstructural analysis of licking behavior during reward consumption as a measure of experienced hedonia; instrumental incentive learning to determine how experienced reward value is used to guide reward-seeking actions; Pavlovian-to-instrumental transfer to evaluate the motivational impact of reward-paired cues; and progressive ratio instrumental testing as a catch-all motivational assay of willingness to work for rewards, to test the hypothesis that these core emotional and motivational processes are disrupted in the TgF344-AD rat. In addition to probing for an apathy phenotype at a late stage of development when neuropathology is profound (18 months), we will also probe prior to presentation of overt neuropathology (3 months) and at an early stage of progression (6 months), to test the hypothesis that such deficits precede cognitive impairments in this model and that individual variability in motivation at early stages predicts severity of cognitive deficits and neuropathology assessed later in the animals' life. Apathy is a core behavioral symptom of Alzheimer's disease. Identifying the neurobehavioral basis for apathy in an animal model of the disease will provide targets for behavioral and pharmacological therapeutic intervention. Further, demonstration that emotional and/or motivational deficits precede and predict cognitive decline and overt neuropathology in an animal model will inform the development of tools for using measures of apathy (and their neural correlates) as biobehavioral markers of disease risk and onset in humans, allowing for the implementation of interventions that can be tailored to the unique needs of individual patients.

Abstract Our health and well being depend on our ability to make adaptive decisions that take into account information about the expected value and availability of potential behavioral goals. It is believed that dysfunction within the neural systems that support goal-directed decision making can result in maladaptive reward-seeking behavior that is either exaggerated and difficult to control, such as with compulsive drug seeking and overeating, or becomes weakened to an unhealthy degree, such as with the apathy apparent in various psychiatric and neurodegenerative disorders (e.g., Alzheimer's disease and schizophrenia). Advances in our understanding of the neural systems that support adaptive decision making are needed so that we are better able to pinpoint the specific aberrations in neural function that give rise to pathological forms of reward seeking. The current project will use an integrative approach to provide novel tests of the decision-making functions of anatomically distinct pathways connecting the medial (MOFC) and lateral (LOFC) orbitofrontal cortices to each other and to the mediodorsal thalamus (MDTHAL). Our behavioral approach will make use of well-validated assays of cue- and value-based decision making in rats. The influence of reward-predictive cues on action selection will be probed using the outcome-specific Pavlovian-to-instrumental transfer task, in which noncontingent presentations of a cue that signals the availability of a specific reward outcome (e.g., sucrose solution) biases rats to selectively pursue that outcome instead of a different but equally valuable outcome (e.g., grain pellets). To probe value- based decision making, we will use outcome-specific reward devaluation tasks, in which rats demonstrate their capacity to flexibly suppress their performance of instrumental actions or Pavlovian conditioned approach responses when an expected reward is devalued through specific satiety. In Aim 1 we will virally express hM4Di, a Gi-coupled DREADD (Designer Receptors Exclusively Activated by Designer Drugs), in the MOFC, LOFC, or MDTHAL, allowing us to determine how inhibiting neurons in these areas (via systemic hM4Di activation) or specific pathways connecting these areas (via local hM4Di activation) impacts cue-based decision making (Pavlovian-instrumental transfer). In Aim 2 we will use the same basic chemogenetic approach to investigate the neural circuitry required for value-based decision making (instrumental and Pavlovian reward devaluation). Together these experiments will provide rigorous tests of innovative hypotheses regarding the behavioral functions of these understudied pathways within the broader orbitothalamic network. Given evidence that dysfunction within these pathways contributes to aberrations in reward-motivated behavior, we believe that this work will have a broad scientific impact, and will lay the groundwork for our own future research investigating neural mechanisms of maladaptive decisions.