The thalamostriatal system has generated significant interest recently because of clinical data showing that deep brain stimulation (DBS) of the centromedian/parafascicular (CM/PF) complex, the main sources of thalamic inputs to the striatum, alleviates symptoms associated with Tourette syndrome and Parkinson's disease (PD). However, the mechanisms underlying the effects of DBS and the involvement of CM/PF in movement disorders are not understood, due to lack of knowledge on the functional organization of the thalamostriatal system. One of the principal targets of synaptic innervation from the CM is the group of striatal cholinergic interneurons (likely corresponding to tonically active neurons [TANs] in electrophysiological studies). The activity of these neurons has been shown to be modulated in rewarded tasks under normal conditions, and it has been shown that the task-related activity is abolished by CM inactivation. Abnormal TANs activity may also be a feature of movement disorders, such as dystonia and PD. Recent findings from our laboratory and previous rodent studies have demonstrated that electrical activation of the glutamatergic CM efferents to the striatum frequently results in inhibitory TAN responses. The mechanisms involved in translating the excitatory inputs into inhibitory responses remain unknown, but it is likely that intrastriatal GABAergic processing is involved. To delineate the neuronal microcircuits involved in mediating the responses of striatal cholinergic interneurons to CM stimulation in nonhuman primates, two specific aims are proposed: (1) To determine the role of GABAergic transmission intrinsic to the striatum in regulating the spontaneous and CM-stimulation induced neuronal activity in TANs in the primate putamen and (2) To define the microcircuitry and chemical phenotype of GABAergic synaptic inputs along the somatodendritic domain of striatal cholinergic interneurons in monkeys. In the first set of studies, the responses of TANs to electrical CM stimulation will be recorded electrophysiologically in monkeys, before and after microinjections of GABA receptor antagonists in the vicinity of the striatal recording sites to determine if local GABAergic networks are modulating the responses of TANs to CM activation. In the second set of studies, a quantitative ultrastructural analysis of the GABAergic synaptic innervation of individual striatal cholinergic interneurons will be performed, providing insights into the substrate that underlies the GABAergic modulation of TAN activity. The findings from these studies will help us to dissect the neuronal networks that are involved in the thalamic regulation of the activity of striatal cholinergic interneurons in primates. The results will also be relevant for our understanding of the mechanisms underlying the therapeutic effects of CM/PF DBS in movement disorders.

Public Health Relevance

The interaction between the thalamus and the striatum has been implicated in disturbances of basal ganglia function such as Parkinson's disease, Tourette syndrome, and pain. Deep brain stimulation (DBS) of the thalamic caudal intralaminar complex, the centromedian/parafascicular nuclei (CM/PF), is effective in relieving motor symptoms associated with these conditions;however, the current application of CM/PF DBS is limited and the interpretation of its therapeutic effects is hampered by the minimal amount of information about the function of the thalamostriatal system. This study aims to examine in detail the anatomical and functional relationship between the CM/PF complex and the striatum in nonhuman primates, in order to gain a better understanding of the involvement of the thalamostriatal system in basal ganglia dysfunction and movement disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-ETTN-G (29))
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Sieber, Beth-Anne
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Emory University
Other Domestic Higher Education
United States
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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