The proposed work aims to extend the high resolution of single neuron analysis with combined anatomical and immunocytochemical techniques for a more precise description of cellular, electrical membrane and ionic currents; neurotransmitter and neuromodulator action; and circuits of neuronal elements in the basal ganglia. Moreover, at the same time, the proposed work aims to provide a more meaningful interpretation of various nuclear functions of the basal ganglia than can be obtained by conventional single or multiple unit recording or by conventional anatomical technique. The areas of interest will be addressed with intensive usage of the well established methodology in our laboratory, whereby, intracellular recording and intracellular labeling with biocytin and other labeling materials are combined with subsequent light and electron microscopic analysis. In addition, histochemical methods, including retrograde and anterograde transport techniques, will be employed. This convergent multidisciplinary analysis will be directed to in vitro slice preparation and cultured and acutely dissociated neuron preparation obtained from rat neostriatum globus pallidus, entopeduncular nucleus, substantia nigra, and subthalamus to three sets of aims: The first set will characterize the membrane properties (including ionic conductances such as K, Na, Ca, etc.) of the neuron by the use of whole-cell (voltage) clamp technique in acutely dissociated or cultured neurons or by an intracellular current clamp recording in slice preparation. The second set will delineate the action of putative neurotransmitters or neuromodulators by monitoring changes in ionic conductances produced by the drugs or their agonists and antagonists. The transmitters to be studied are dopamine (DA), glutamate, and acetylcholine (ACh), which are the major known neurotransmitters and modulators involved in these nuclear operation. We will identify the transmitter and morphological phenotypes of the neurons under study by anatomical techniques by combined techniques of immunocytochemistry. The third set is to re-examine functional circuits involved among these nuclei (e.g., subthalamo-pallidal, striato-nigral, etc.) by trigger-averaging techniques with simultaneous recordings from the projection and its target neurons. Disequilibria of cholinergic, dopaminergic, glutaminergic, and GABAergic systems in the basal ganglia are believed involved in the pathophysiology of basal ganglia disease. The search for more specific treatments will be facilitated by a clearer understanding of the specific nature of the basal ganglia anatomy, physiology, pharmacology, and subsequent imbalance of extra-pyramidal operation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS020702-10
Application #
3401249
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1983-08-01
Project End
1998-11-30
Budget Start
1991-12-15
Budget End
1992-11-30
Support Year
10
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
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Ramanathan, Sankari; Tkatch, Tatiana; Atherton, Jeremy F et al. (2008) D2-like dopamine receptors modulate SKCa channel function in subthalamic nucleus neurons through inhibition of Cav2.2 channels. J Neurophysiol 99:442-59
Baufreton, Jerome; Bevan, Mark D (2008) D2-like dopamine receptor-mediated modulation of activity-dependent plasticity at GABAergic synapses in the subthalamic nucleus. J Physiol 586:2121-42
Blythe, Sarah N; Atherton, Jeremy F; Bevan, Mark D (2007) Synaptic activation of dendritic AMPA and NMDA receptors generates transient high-frequency firing in substantia nigra dopamine neurons in vitro. J Neurophysiol 97:2837-50
Bevan, Mark D; Atherton, Jeremy F; Baufreton, Jerome (2006) Cellular principles underlying normal and pathological activity in the subthalamic nucleus. Curr Opin Neurobiol 16:621-8
Atherton, Jeremy F; Bevan, Mark D (2005) Ionic mechanisms underlying autonomous action potential generation in the somata and dendrites of GABAergic substantia nigra pars reticulata neurons in vitro. J Neurosci 25:8272-81
Wang, Lie; Kitai, Stephen T; Xiang, Zixiu (2005) Modulation of excitatory synaptic transmission by endogenous glutamate acting on presynaptic group II mGluRs in rat substantia nigra compacta. J Neurosci Res 82:778-87
Cragg, Stephanie J; Baufreton, Jerome; Xue, Yi et al. (2004) Synaptic release of dopamine in the subthalamic nucleus. Eur J Neurosci 20:1788-802
Hallworth, Nicholas E; Wilson, Charles J; Bevan, Mark D (2003) Apamin-sensitive small conductance calcium-activated potassium channels, through their selective coupling to voltage-gated calcium channels, are critical determinants of the precision, pace, and pattern of action potential generation in rat subthalamic nu J Neurosci 23:7525-42
Scroggs, R S; Cardenas, C G; Whittaker, J A et al. (2001) Muscarine reduces calcium-dependent electrical activity in substantia nigra dopaminergic neurons. J Neurophysiol 86:2966-72

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