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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurology B Subcommittee 2 (NEUB)
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Kitt, Cheryl A
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Saint Louis University
Anatomy/Cell Biology
Schools of Medicine
Saint Louis
United States
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Subramanian, Suriya; Reichard, Rhett A; Stevenson, Hunter S et al. (2018) Lateral preoptic and ventral pallidal roles in locomotion and other movements. Brain Struct Funct 223:2907-2924
Zahm, Daniel S; Root, David H (2017) Review of the cytology and connections of the lateral habenula, an avatar of adaptive behaving. Pharmacol Biochem Behav 162:3-21
Reichard, Rhett A; Subramanian, Suriya; Desta, Mikiyas T et al. (2017) Abundant collateralization of temporal lobe projections to the accumbens, bed nucleus of stria terminalis, central amygdala and lateral septum. Brain Struct Funct 222:1971-1988
Lavezzi, Heather N; Parsley, Kenneth P; Zahm, Daniel S (2015) Modulation of locomotor activation by the rostromedial tegmental nucleus. Neuropsychopharmacology 40:676-87
Yetnikoff, Leora; Cheng, Anita Y; Lavezzi, Heather N et al. (2015) Sources of input to the rostromedial tegmental nucleus, ventral tegmental area, and lateral habenula compared: A study in rat. J Comp Neurol 523:2426-56
Yetnikoff, L; Lavezzi, H N; Reichard, R A et al. (2014) An update on the connections of the ventral mesencephalic dopaminergic complex. Neuroscience 282:23-48
Zahm, Daniel S; Schwartz, Zachary M; Lavezzi, Heather N et al. (2014) Comparison of the locomotor-activating effects of bicuculline infusions into the preoptic area and ventral pallidum. Brain Struct Funct 219:511-26
Yetnikoff, Leora; Reichard, Rhett A; Schwartz, Zachary M et al. (2014) Protracted maturation of forebrain afferent connections of the ventral tegmental area in the rat. J Comp Neurol 522:1031-47
Uchoa, Ernane Torres; Zahm, Daniel S; de Carvalho Borges, Beatriz et al. (2013) Oxytocin projections to the nucleus of the solitary tract contribute to the increased meal-related satiety responses in primary adrenal insufficiency. Exp Physiol 98:1495-504
Zahm, Daniel S; Parsley, Kenneth P; Schwartz, Zachary M et al. (2013) On lateral septum-like characteristics of outputs from the accumbal hedonic ""hotspot"" of Pecina and Berridge with commentary on the transitional nature of basal forebrain ""boundaries"". J Comp Neurol 521:50-68

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