Bernard Walter Balleine, PhD - US grants

DESCRIPTION (Adapted from applicant's abstract): The organization of goal-directed action is influenced significantly by the agent's ability to inhibit or gate responses to sensory, motor and cognitive information. Deficits in these central inhibitory mechanisms are manifest in a number of neuropsychiatric syndromes characterized by disorders of 'voluntary' movement, e.g., Parkinson's disease, and intrusive involuntary movement, e.g., Tourette's syndrome and Huntington's disease. These cases make it clear that the capacity for goal-directed action is highly adaptive, indeed it is this capacity that allows us and other animals to control the environment in the service of our needs and desires. Nevertheless, although research into the physiological systems that subserve learning processes in humans and other animals has been of ongoing concern to the neuroscience research community, the neural basis of instrumental action is very poorly understood. The broad, long term objective of the current project is, therefore, to understand the neural mechanisms that control the learning and performance of goal directed or instrumental actions. Over the last decade striking advances have been achieved in the PI's understanding of the behavioral determinants of instrumental conditioning in animals. Specifically, instrumental performance has been found to reflect the integration of (I) representations of the relations between an action and its consequences; with (ii) representations of the incentive value of those consequences. Elegant but powerful behavioral procedures will be used to focus on the role of cortico-striatal interactions and feedback to cortex via pallidal and limbic structures on processes involved in the representation of the relation between an action and its consequences. In other experiments, the role of parallel interactions between insular cortex and basal forebrain structures in the representation of the incentive or 'goal' value of the instrumental outcome will be assessed.

DESCRIPTION (provided by applicant): Considerable evidence suggests that a number of neurodegenerative disorders, particularly those that affect cortico-basal ganglia circuits, such as Huntingtons, Parkinsons, Alzheimers disease, obsessive-compulsive disorder and so on, have in common a range of deficits in planning and other executive functions associated with goal-directed action. Over the last decade or so we have been studying these deficits using a rodent model of goal-directed action, derived from manipulations of the instrumental conditioning paradigm, together with a battery of behavioral tests. Generally, human actions are sensitive to both the causal relation between the action and the goal as well as the current value of the goal. Likewise, rats can be trained to acquire new actions to gain access to rewarding events, e.g. learning to press a lever for sugar, and their tendency to select and initiate these responses is sensitive to changes in both the contingent relation between the action and outcome delivery and the current reward or incentive value of that outcome. Furthermore, just as in humans, choice of action is heavily influenced by extraneous information (advertising being the prime example), in rats a stimulus associated with a specific instrumental outcome can strongly alter the probability of performing actions associated with that outcome. This renewal application requests continued support for our investigation of the neural bases of instrumental conditioning focusing particularly on the neural systems that mediate (i) the representation of rewarding events and the effect that these events have on the performance of goal-directed actions;and (ii) the interaction of Pavlovian and instrumental conditioning through an assessment of the neural mechanisms that mediate the influence of cues that predict reward on the selection and initiation of instrumental actions. Considerable evidence suggests that a number of neurodegenerative disorders, particularly those that affect cortico-basal ganglia circuits such as Huntingtons, Parkinsons Alzheimers disease obsessive-compulsive disorder and so on, have in common a range of deficits in planning and other executive functions associated with goal-directed action. As these disorders make clear, the ability to acquire and exert control over specific actions is highly adaptive, allowing us and other animals to control the environment in the service of our basic needs and desires. Nevertheless, although research into the physiological systems that subserve learning processes generally has been of ongoing concern, the neural basis of goal- directed action remains poorly understood. The broad, long term objective of the current project is, therefore, to understand the neural mechanisms that control the learning and performance of goal directed or instrumental actions. Over the last decade striking advances have been achieved in our understanding of the behavioral determinants of instrumental conditioning in animals. Specifically, instrumental performance has been found to reflect the integration of (i) representations of the relations between an action and its consequences;with (ii) representations of the incentive value of those consequences. Powerful behavioral procedures will be used to focus on the role of cortico-striato-limbic interactions in processes involved in representing the reward value of the instrumental outcome and in the sensitivity of instrumental performance to reward-related cues.

DESCRIPTION (provided by applicant): During the development of addiction, the pursuit of drugs of abuse, such as alcohol, becomes progressively less goal-directed and progressively more habitual coming under the control of internal and external states and stimuli. Understandably, therefore, recent theory and research on alcoholism has started to focus on the habit learning process and its behavioral and neural bases. It is important, however, to distinguish habitual drug-seeking from other forms of habitual behavior. Under normal conditions, habit learning can be highly adaptive;habits allow us and other animals to relegate the control of routine behavioral responses to a system that uses few cognitive resources freeing up this limited capacity for tasks that need greater monitoring. Unlike goal-directed actions that are quickly acquired and flexibly deployed, habits are usually slowly acquired, stimulus-bound and inflexible. Nevertheless, their deployment can be rapidly suppressed when conditions change. Driving, cycling, even walking would be very dangerous activities if we couldn't quickly and reliably suppress these habits as and when circumstances change to navigate around an obstacle. In contrast, habitual drug seeking is pathological;drug exposure appears both to increase the rate of habit acquisition and the influence of drug associated contexts and cues on their performance. Furthermore, despite the heavy emphasis on habit processes in current research, a distinguishing feature of habitual drug seeking is the addicts'loss of executive and behavioral control over the habit;drug seeking persists even in the face of severe negative consequences. The compulsive pursuit of alcohol can be viewed, therefore, as the product of two interacting processes: (i) an alcohol-induced increment in the acquisition of habitual alcohol seeking and (ii) an alcohol-induced decrement in the addict's ability to exert control over the habit in the face of persistent, sometimes extreme negative feedback. It is important to recognize, however, that these effects of alcohol exposure extend beyond alcohol seeking and appear to have an effect on decision-making and adaptive behavioral control more generally. It is likely, therefore, that alcohol exposure produces extensive changes in the larger neural systems that control the acquisition and performance of goal-directed and habitual actions. Given these considerations, the broad objective of the current project is to assess the effect of alcohol exposure on the behavioral and neural determinants of (i) goal directed learning, (ii) habit learning and (iii) the processes that control the degree to which these learning processes are implemented in performance. PUBLIC HEALTH RELEVANCE: The transition from casual drinking to compulsive alcohol seeking may stem from alcohol's tendency to disrupt the cognitive and behavioral processes that guide action selection and decision making more generally. In instrumental conditioning, the behavioral processes, and the corresponding neural systems, responsible for goal-directed action selection and habitual performance have been relatively well characterized. The broad, long-term objective of the current project is, therefore, to investigate how exposure to alcohol affects the neural systems that control goal-directed and habitual instrumental learning processes.

DESCRIPTION (provided by applicant): Recent evidence suggests that the learning processes that underlie the acquisition of goal-directed actions and that support their transition into habits are encoded within distinct regions of the dorsal striatum and involve distinct cortio-striatal networks. Disorders of `voluntary' movement, e.g. Parkinson's disease, and involving intrusive involuntary movement, e.g. Tourette's syndrome, obsessive compulsive disorder and Huntingdon's disease, have also been found to involve damage to cortico-striatal networks and to result in severe cognitive deficits in choice, planning and executive processes generally. These cases make it clear that the capacity for goal-directed action is highly adaptive. Nevertheless, although research into the physiological systems that subserve learning processes in humans and other animals has been of ongoing concern to the neuroscience research community, the neural bases of both goal-directed and habit learning are still very poorly understood. The broad, long-term objective of the current project is, therefore, to understand the neural systems that control both goal-directed and habitual learning processes. In this project we will focus specifically on cortio-striatal networks involving the medial prefrontal cortex and its efferents to the dorsomedial striatum in goal-directed learning and sensorimotor cortex and its afferents to dorsolateral striatum in habit learning under three specific aims: (i) to examine the role of the dorsomedial striatum in goal-directed learning processes; (ii) to explore the role of cortico-dorsomedial striatal circuits in goal-directed learning; and (iii) to compare the role of dorsomedial and dorsolateral striatum in actions and habits. We plan to use behavioral manipulations and tests that allow direct assessment of the specific learning processes engaged under a number of circumstances and to establish the neural networks that support these learning processes using a series of molecular and cellular markers and interventions that, in recent years, have proven to be of value in studying neural circuits and systems. PUBLIC HEALTH RELEVANCE The learning processes that underlie the acquisition of goal-directed actions and that support their transition into habits are encoded within distinct regions of the dorsal striatum and involve distinct cortio-striatal networks. Disorders of `voluntary' movement, e.g. Parkinson's disease, and involving intrusive involuntary movement, e.g. Tourette's syndrome, obsessive compulsive disorder and Huntingdon's disease, have also been found to involve damage to cortico-striatal networks and to result in severe cognitive deficits in choice, planning and executive processes generally. These cases make it clear that the capacity for goal-directed action is highly adaptive. Nevertheless, the neural bases of both goal-directed and habit learning are still very poorly understood. The broad, long-term objective of the current project is, therefore, to understand the neural systems that control both goal-directed and habitual learning processes. In this project we will focus specifically on cortio-striatal networks involving the medial prefrontal cortex and the dorsomedial striatum in goal-directed learning and sensorimotor cortex and its afferents to dorsolateral striatum in habit learning. We plan to use behavioral manipulations and tests that allow direct assessment of the specific learning processes engaged under a number of circumstances and to establish the neural networks that support these learning processes using molecular and cellular approaches that have proven of value in studying neural circuits and systems.