This is a competing renewal application that has been continuously funded for the last 11 years. The focus of the research program has been, and remains, the chemoanatomic and synaptic organization of the striatum. The applicant has become one of the leaders in the field of basal ganglia neuroanatomy. He has earned a well-deserved reputation for his detailed analyses of the sub-regional organization of the ventral striatum, particularly the nucleus accumbens. In the current funding period, the investigator and others developed and employed a novel pharmacological approach for unraveling the complexities of the striatum. Since dopamine is a dominant transmitter in this system, Dr. Zahm and others have used DA agonists and antagonists to D1 and D2 receptors to manipulate gene expression in specific populations of striatal neurons. This has led to the definition of identification subpopulations of neurons that, once revealed by their characteristic DA receptor-mediated gene responses, have subsequently been found to have common transmitters, morphologies and connections. This functional chemoanatomic approach has been a particularly useful strategy for identifying sub-regional organization in the striatum because the intrinsic organization of this system is so complex that it has been refractory to more 'static' classical anatomical approaches. In the present renewal application, the investigator will continue to employ these and similar sophisticated anatomical strategies to investigate the organization of the major, but poorly understood, role of neurotensin in striatal function. NT is a highly abundant neuroactive peptide present in multiple synaptic networks in the nigral-VTA- striatal system. NT has potent modulatory actions on striatal function and different populations of NT neurons have differential responses to activation of DA receptor subtypes, but little is known about the anatomical organization of different NT-ergic circuits. The present application will close these gaps.
Three specific aims are proposed. The connectional organization of the projections of ventromesencephalic NT neurons to specific target territories in the striatum will be delineated by a series of combined retrograde labeling, in situ hybridization and immunohistochemical labeling experiments. Ventromesencephalic DA containing areas (SN and VTA) also receive dense NT afferents but the neurons providing this input have not been identified or characterized. In this aim tract tracing will be combined with in situ and immunostaining to characterize the locations and neurochemical makeup of NT neurons afferent to ventromesencephalic DA neuron containing structures, In addition, a tract tracing-EM immunocytochemical approach will be used to identify and quantitate NT innervation of DA neurons in VTA and SN.
The third aim will use a complex set of pharmacologically-mediated changes in specific gene expression to distinguish among and characterize different populations of striatal NT neurons.
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