The Subthalamic Nucleus Part I: Development, Cytology, Topography and Connections

This monograph on the subthalamic nucleus accentuates the gap between experimental animal and human information concerning subthalamic development, cytology, topography and connections.

This monograph gives an overview of the STN. It treats the position of the STN in hemiballism, based on older and recent data. The cytology encompasses the neuronal types present in the STN in nearly all studied species and focuses on interneurons and the extent of their dendrites. Ultrastructural features are described for cat and baboon (F1, F2, Sr, LR1, LR2 boutons and d.c.v. terminals, together with vesicle containing dendrites), the cytochemistry is focused on receptors (dopamine, cannabinoid, opioid, glutamate, GABA, serotonin, and cholinergic-, purinergic ones) and calcium binding proteins and calcium channels. The development of the subthalamic nucleus from the subthalamic cell cord is given together with its developing connections. The topography of rat, cat, baboon and man is worked out as to cytology, sagittal borders, surrounding nuclei and tracts, and aging of the human STN. The connections of the STN are extensively elaborated on: cortical-, subthalamo-cortical-, pallidosubthalamic-, pedunculopontine-, raphe-, thalamic-, central grey-, and nigral connections. Emphasis is put on human connections. Recent nigro-subthalamic studies showed a contralateral projection. The role of the STN in the basal ganglia circuitry is described as to the direct, indirect and hyperdirect pathway. The change the STN undergoes in Parkinson’s disease in neuronal firing rate and firing pattern is demonstrated together with the possible mechanisms of deep brain stimulation. The results of in vitro measurements on dissociated cultured subthalamic neurons are presented. The preliminary effects of application of acetylcholine and high frequency stimulation are described. This part is preceded with studies concerning spontaneous activity, depolarizing and hyperpolarizing inputs, synaptic inputs, high frequency stimulation, and burst activity of STN cells. The last extensive part concerns STN cell models and simulation of neuronal networks. Single cell models (model of Otsukaand Terman/Rubin) are compared and the multi-compartment model of Gillies and Willshaw is explored. The globus pallidus externus-STN network as proposed by Terman is briefly described. The monograph finishes with a series of interpretations of the results.

1 Introduction 1.1 Hemiballism Hemiballism or hemichorea is a rare neurological disorder, but the crucial invol- ment of the subthalamic nucleus (STN) in its pathophysiology has been app- ciated for decades (Jakob 1923; Martin 1927; Glees and Wall 1946; Whittier and Mettler 1949; Carpenter and Carpenter 1951; Crossman 1987). Only recently have serious doubts come forward. Postuma and Lang (2003) have described the STN as being involved in only a minority of cases, and indicated unrecognized causes such as non-ketotic hyperosmolar hyperglycaemia and complications of human immunodeficiency virus (HIV) infections. Moreover, the crucial involvement of a lesion of the STN is in doubt (Guridi and Obeso 2001; Postuma and Lang 2003). On the other hand, idiopathic Parkinson's disease (Battistin et al. 1996; Usunoff et al. 2002) is a common neurodegenerative disorder, but the key role of the STN in the pathophysiological origin of the parkinsonian state has become evident only recently (Miller and DeLong 1987; Mitchell et al. 1989; Bergman et al. 1990, 1994; Hollerman and Grace 1992; Guridi et al. 1993; Parent and Hazrati 1995b; Hassani et al. 1996; Levy et al. 1997, 2002; Blandini et al. 2000; Hirsch et al. 2000; Ni et al.