A dysfunction of the brain circuitry mediating the translation of relevant environmental stimuli into adaptive motor responses is thought to have an etiologic or permissive role in many psychiatric disorders. Classic limbic structures provide emotional and cognitive context to environmental stimuli. The circuitry whereby this information is transferred to motor systems and the appropriate behavioral response initiated involves a series of nuclei possessing extensive reciprocal interconnectivity. This circuit is referred to as the 'motive circuit' and includes the ventral tegmental area, nucleus accumbens, ventral pallidum, mediodorsal thalamus, prefrontal cortex and pedunculopontine motor area. The goal of this continuation proposal is to functionally map the flow of information from limbic to motor nuclei through the motive circuit. This will be accomplished using three convergent technologies, 1) retrograde labeling of neurons combined with in situ hybridization for mRNA of relevant transmitter-related proteins, 2) intracranial infusions of transmitter analogues into the circuit to map the connections mediating behavioral activation, and 3) microinjecting transmitter analogues into the circuit and measuring changes in extracellular transmitter concentrations with microdialysis. The proposal is based upon three general hypotheses. 1) A detailed topography exists which permits the transfer of information into discrete compartments within nuclei comprising the motive circuit. 2) The selective transfer of information is, to some extent, chemically coded such that different neurotransmitters route information through different efferent projections. 3) The routing of information is under environmental/genetic control. This latter hypothesis relies on recent observations that the intensity of the motor response elicited by rats in a novel environment is correlated with neurochemical alterations in subnuclei of the motive circuit. Thus, prior to beginning all experiments, rats will be behaviorally screened in a novel open field to permit correlations between their motor response to novelty and other subsequent measures. Many behavioral symptoms defining psychiatric illnesses involve inappropriate behavioral responses to environmental stimuli. The motive circuit is responsible for translating environmental stimuli into adaptive motor responses. By understanding the anatomical and chemical organization of the motive circuit it will be possible to pharmacologically modulate inappropriate behaviors with greater accuracy. Furthermore, the anatomical and functional mapping of the motive circuit will provide a basis for interpreting future imaging studies in humans where attempts are made to correlate changes in spatially discrete nuclei.
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