The basal ganglia may be viewed in a larger context as components of segregated cortico-subcortical reentrant circuits that also involve the thalamus. One of these circuits, the ~motor~ circuit, is critically involved in the development of Parkinsonian motor signs. Degeneration of nigrostriatal dopaminergic neurons leads to increased activity in the basal ganglia output nuclei. The neuronal activity in the motor portion of one of these output nuclei, the internal segment of the globus pallidus (GP), has been characterized in detail in intact and Parkinsonian animals. This together with other studies, eventually lead to the reintroduction of GPi lesions as treatment for Parkinson~s disease in humans, with very promising results. The neuronal activity in the motor circuit portion in the second major basal ganglia output nucleus, the substantial nigra pars reticulata (SNr), has received far less attention. In the proposed experiments, we will test the hypotheses that: (1) there is a distinct segregated motor area in the SNr of primates, (2) that abnormal neuronal discharge in this area contributes to motor signs in Parkinsonism, (3) that inactivation of the SNr motor area can alleviate some Parkinsonian motor signs, and (4) that combined lesions of SNr and GPi are more effective that lesions of GPi alone. Responses of SNr neurons to somatosensory examination will be studied with electrophysiologic extracellular recordings, using closely spaced microelectrode penetrations in primates (Specific Aim [S.A.] 1). Anatomic and physiologic studies suggest that neurons with responses to somatosensory examination will be found in centro-lateral regions of SNr. The degree of convergence between motor and non-motor circuits will be explored by assessing the responses of SNr neurons to electrical stimulation at striatal motor and non-motor sites (S.A. 1). Similar recordings will be done after rendering the animals Parkinsonian by injections of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP;S.A.2). It is expected that phasic and tonic activity in SNR is increased after MPTP. The behavioral effects of transient or permanent inactivation of the SNr motor area will be studied with local injections of the GABA-receptor agonist muscimol or the neurotoxin ibotenic acid, respectively (S.A. 3), and effects of combined GPi/SNr lesions will be compared with those of GPi lesions along (S.A. 4). With the hypothesis that abnormal discharge in SNr contributes to Parkinsonian motor signs, it is expected that inactivation of SNr will ameliorate the motor disturbances, and that effects of GPi and SNr lesions will be additive.
| Wichmann, Thomas; Kliem, Michele Ann (2004) Neuronal activity in the primate substantia nigra pars reticulata during the performance of simple and memory-guided elbow movements. J Neurophysiol 91:815-27 |
| Wichmann, T; Kliem, M A; DeLong, M R (2001) Antiparkinsonian and behavioral effects of inactivation of the substantia nigra pars reticulata in hemiparkinsonian primates. Exp Neurol 167:410-24 |
