Modulation of NAc-DA signaling by learning, motivational state and peptides

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DESCRIPTION (provided by applicant): Appropriate behavioral responses to affective stimuli promote health and reduce the chance of harm. However, we often fail to respond appropriately. Obesity results, in part, from the overconsumption of nutrients where our motivation for pleasurable food overrides our homeostatic signals. Exposure to drugs of abuse leads some individuals to consume non-nutritive substances and ignore homeostatic signals. Both diseases involve individuals seeking reward and ignoring negative, aversive consequences. Affective stimuli gain access to motor circuitry by interfacing at the nucleus accumbens (Mogenson et al. 1980). The nucleus accumbens (NAc) and its afferent and efferent connections are critical for behavior directed at rewards. Primary rewarding stimuli evoke changes in neural activity and dopamine (DA) release in the NAc and changes in neural and neurochemical activity in the nucleus accumbens predict behavior directed at reward consumption. Furthermore, pharmacological manipulations of the NAc alter hedonic responses to rewarding stimuli and promote consumption even in the face of negative homeostatic signals. These findings have led some to suggest that the nucleus accumbens is essential for approach behavior and behavior directed at rewarding stimuli. If this is the case, then the NAc and its associated circuitry should behave very differently in response to negative affective stimuli and aversion. Far less is known about how aversive stimuli are processed by these neural elements. Aversive stimuli do seem to alter activity in these regions but in an entirely different manner than aversive stimuli. Behavior is obviously plastic and reflects changes the hedonic valence of affective stimuli through learning and motivational state. We do not know, though, how nucleus accumbens responses are altered when affective stimuli change sign. That is, stimuli can either be devalued or increase in value depending on learned associations and changes in motivational state. This proposal will determine the mechanisms by which the NAc and DA differentially signal reward and aversion. In addition, the proposal will determine plastic changes in neurophysiological and neurochemical signaling within the NAc when the value of affective stimulus changes. This proposal will utilize real-time recordings of NAc activity made during the delivery of positive and negative affective stimuli. The studies proposed here will give valuable insight into normal neural processes underlying changes in value of a given stimulus and thus, shed light on the aberrant signaling underlying disorders of motivational circuitry such as obesity and drug addiction. Aberrant signaling of the mesolimbic system underlie disorders of motivation such as obesity and drug addiction. The major goal of this project is to determine the mechanisms governing mesolimbic signaling in affect and how that signaling is altered by learning and motivational state changes. These studies have the potential for identifying new targets in the treatment of affective disorders.