In the past few years, evidence from both experimental and clinical studies suggests a key role for the subthalamic nucleus in the pathogenesis of Parkinson's disease. As the principal excitatory pathway interconnecting basal ganglia nuclei, it is one of the most likely suspects as the origin of the synchronous rhythmic firing patterns in the globus pallidus that are associated with the motor symptoms of that disease. In slices of the subthalamic nucleus, the neurons spontaneously fire rhythmically at a rate approximating that seen in dopamine-denervated animals and in Parkinsonism in humans. The proposed experiments will determine the ionic mechanisms responsible for the rhythmic firing of subthalamic neurons seen in slices, and determine the degree to which rhythmic activity may become synchronized by recurrent excitatory interactions between subthalamic neurons. The experiments will employ infrared-visualized whole cell recording, imaging of calcium entry during spontaneous and evoke rhythmic firing, and intracellular staining of recurrent axonal connections. A possible role of extrinsic excitatory inputs in desynchronizing the cells of the nucleus, and in disrupting their rhythmic activity will be explored by micro-stimulation and cortico- subthalamic fibers in slices preserving a portion of that pathway. A knowledge of the mechanism underlying rhythmic and possibly synchronous activity in vitro may offer new pharmacological approaches to treatment of the motor symptoms of Parkinson's disease, and provide a more mechanistic explanation of stereotaxic surgical treatments currently in use.

Project Start
2001-05-01
Project End
2002-04-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
14
Fiscal Year
2001
Total Cost
$111,112
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Type
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Reiner, A; Medina, L; Haber, S N (1999) The distribution of dynorphinergic terminals in striatal target regions in comparison to the distribution of substance P-containing and enkephalinergic terminals in monkeys and humans. Neuroscience 88:775-93
Figueredo-Cardenas, G; Harris, C L; Anderson, K D et al. (1998) Relative resistance of striatal neurons containing calbindin or parvalbumin to quinolinic acid-mediated excitotoxicity compared to other striatal neuron types. Exp Neurol 149:356-72
Figueredo-Cardenas, G; Chen, Q; Reiner, A (1997) Age-dependent differences in survival of striatal somatostatin-NPY-NADPH-diaphorase-containing interneurons versus striatal projection neurons after intrastriatal injection of quinolinic acid in rats. Exp Neurol 146:444-57
Medina, L; Anderson, K D; Karle, E J et al. (1995) An ultrastructural double-label immunohistochemical study of the enkephalinergic input to dopaminergic neurons of the substantia nigra in pigeons. J Comp Neurol 357:408-32
Karle, E J; Anderson, K D; Reiner, A (1994) Dopaminergic terminals form synaptic contacts with enkephalinergic striatal neurons in pigeons: an electron microscopic study. Brain Res 646:149-56
Figueredo-Cardenas, G; Anderson, K D; Chen, Q et al. (1994) Relative survival of striatal projection neurons and interneurons after intrastriatal injection of quinolinic acid in rats. Exp Neurol 129:37-56
Anderson, K D; Karle, E J; Reiner, A (1994) A pre-embedding triple-label electron microscopic immunohistochemical method as applied to the study of multiple inputs to defined tegmental neurons. J Histochem Cytochem 42:49-56
Reiner, A; Anderson, K D (1993) Co-occurrence of gamma-aminobutyric acid, parvalbumin and the neurotensin-related neuropeptide LANT6 in pallidal, nigral and striatal neurons in pigeons and monkeys. Brain Res 624:317-25
Karle, E J; Anderson, K D; Reiner, A (1992) Ultrastructural double-labeling demonstrates synaptic contacts between dopaminergic terminals and substance P-containing striatal neurons in pigeons. Brain Res 572:303-9
Anderson, K D; Reiner, A (1991) Immunohistochemical localization of DARPP-32 in striatal projection neurons and striatal interneurons: implications for the localization of D1-like dopamine receptors on different types of striatal neurons. Brain Res 568:235-43

Showing the most recent 10 out of 12 publications