The proposed work is focused on identifying the functional organization of cortico-basal ganglia loops. Such cortico-basal ganglia loops have been implicated in a wide range of human disorders, and in normal individuals, in decision-making that influences the choice of movements, thoughts and emotions. Imbalances in these loops are thought to contribute to the disorders by emphasizing too little or too much movement, or thought. The underlying mechanisms responsible for such selection functions of the basal ganglia are not yet understood. There is a pressing need for more knowledge of these mechanisms in order to develop better therapies for neurologic and neuropsychiatric disorders. There is evidence that these loops are part of a distributed valuation system in the brain that can attach high or low value to potential physical and mental actions. It is these valuation circuits that we propose to focus on in the proposed granting period. We have developed a cost-benefit decision-making task that has the special property of requiring subjects to either accept or avoid offered outcomes that are signaled to them by visual cues. Our initial work with this paradigm suggests that subjects develop expectations about the value of these simultaneously offered outcomes, so that they may accept the offer even though there is some cost, and reject it even though there is some benefit, depending on the relative balance of the cost and benefit. This kind of 'approach-avoidance'decision-making is common in everyday life (a typical example could be deciding whether to park a bit farther away and have to walk farther or to park closer but then to pay a steeper parking fee). But cost-benefit decisions can be enormously important and very difficult. In some disorders, this kind of decision-making is difficult and fraught with problems. Individuals may be overly pessimistic, as in depression, or overly optimistic, as in hypomanic states. Because of the central importance of the brain circuits underlying such decisions, we propose three Specific Aims in which we will record spike and field activity from many neurons in key cortical nodes of this circuitry (medial prefrontal cortex, anterior cingulate cortex) as well as in the striatum (caudate nucleus) during decision-making, and to apply state-of-the-art methods for analyzing the circuit dynamics of this network of regions during the decision-making process. Guided by our preliminary work, in which we were able to shift the decision-making toward pessimistic or optimistic choices, we will perturb the network at key sites and determine the changes in network activity and behavior. Finally, we will explicitly focus on identifying the pathways by which this cortico-basal ganglia circuitry controls the dopamine system of the midbrain, known to mediate positive and negative reward prediction errors and motivational aspects of behavior. This work has the goal of helping to establish a therapeutically useful, mechanistic understanding of cortico-basal ganglia loop functions, and specifically the functions of major cortico-basal ganglia loops whose dysfunction is directly implicated in human neurologic and neuropsychiatric disorders.
Parkinson's disease, Huntington's disease, some dystonias, as well as Tourette syndrome, obsessive- compulsive disorder, addiction and depression, all have been associated with dysfunction of the basal ganglia and the neural circuits that interact with the basal ganglia. In the work proposed, our goal is to understand core functions of these basal ganglia-related circuits by using state of the art experimental methods. Through this work, we will contribute directly to understanding the neural circuits that are critical in these disordes, and we will make a major effort to contribute to the development of therapies.
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