The basal ganglia and thalamus are interconnected through a series of loops that process and convey basal ganglia outflow to either frontal cortical regions via the ventral motor nuclei or back to the striatum via the caudal intralaminar group, namely the centre median (CM) and parafascicular (Pf) nuclei. Although the existence of a thalamostriatal system has long been established, the role of these projections in the functional circuitry of the basal ganglia remains enigmatic. For the first four years of this grant, we focused our interest on the sources and chemical nature of basal ganglia and brainstem synaptic inputs that control the activity of thalamostriatal neurons. Both the internal globus pallidus (GPi) and the substantia nigra pays reticulata (SNr) provide GABAergic afferents to specific regions of CM/Pf. In addition, the pedunculopontine tegmental nucleus (PPN) is the source of highly heterogeneous chemical inputs to CM/Pf, some of them co-localize GABA and acetylcholine. In addition, neurons in CM/Pf, as in most thalamic nuclei, are endowed with intrinsic GABAergic influences from the reticular nucleus and local interneurons. Electrophysiological data show that GABA plays a crucial role in regulating thalamic activity. However, the exact mechanisms by which GABA mediates its effects on thalamic neurons are complex and still matter of speculation. In order to further characterize this issue, we propose to use state-of- the-art immunocytochemical procedures at the electron microscopic level to elucidate the subsynaptic and subcellular localization of GABA-A and GABA-B receptors in the basal ganglia-receiving territories of the ventral motor thalamic nuclei and CM/PF in monkeys. Abnormal increased GABAergic outflow from the basal ganglia to the thalamus is a cardinal feature of Parkinson's disease pathophysiology. Such increased activity likely results in downregulation of postsynaptic GABA receptors in basal ganglia receiving thalamic nuclei. In order to elucidate this issue, another goal of this project is to compare the pattern of subsynaptic localization of GABA-A and GABA-B receptors in CM/Pf and ventral motor nuclei of normal monkeys and animal models of Parkinson's disease. This series of studies should provide a comprehensive analysis of GABA receptors localization at specific synaptic sites in basal ganglia-receiving thalamic nuclei in primates. Such information is critical for the interpretation of functional studies and a better understanding of the pathophysiological changes generated at pallidothalamic and nigrothalamic synapses in Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037948-07
Application #
6726022
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Talley, Edmund M
Project Start
1998-07-01
Project End
2006-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
7
Fiscal Year
2004
Total Cost
$190,000
Indirect Cost
Name
Emory University
Department
Neurology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Iskhakova, Liliya; Smith, Yoland (2016) mGluR4-containing corticostriatal terminals: synaptic interactions with direct and indirect pathway neurons in mice. Brain Struct Funct 221:4589-4599
Gonzales, Kalynda K; Smith, Yoland (2015) Cholinergic interneurons in the dorsal and ventral striatum: anatomical and functional considerations in normal and diseased conditions. Ann N Y Acad Sci 1349:1-45
Zhu, Dan; Li, Chenchen; Swanson, Andrew M et al. (2015) BAI1 regulates spatial learning and synaptic plasticity in the hippocampus. J Clin Invest 125:1497-508
Smith, Yoland; Wichmann, Thomas (2015) The cortico-pallidal projection: an additional route for cortical regulation of the basal ganglia circuitry. Mov Disord 30:293-5
Mathai, Abraham; Ma, Yuxian; Paré, Jean-Francois et al. (2015) Reduced cortical innervation of the subthalamic nucleus in MPTP-treated parkinsonian monkeys. Brain 138:946-62
Smith, Yoland; Wichmann, Thomas; DeLong, Mahlon R (2014) Corticostriatal and mesocortical dopamine systems: do species differences matter? Nat Rev Neurosci 15:63
Villalba, R M; Wichmann, T; Smith, Y (2014) Neuronal loss in the caudal intralaminar thalamic nuclei in a primate model of Parkinson's disease. Brain Struct Funct 219:381-94
Smith, Y; Villalba, R M (2013) Dendrite spines plasticity in brain disorders. Neuroscience 251:1
Villalba, R M; Smith, Y (2013) Differential striatal spine pathology in Parkinson's disease and cocaine addiction: a key role of dopamine? Neuroscience 251:2-20
Gonzales, Kalynda Kari; Pare, Jean-Francois; Wichmann, Thomas et al. (2013) GABAergic inputs from direct and indirect striatal projection neurons onto cholinergic interneurons in the primate putamen. J Comp Neurol 521:2502-22

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