Elsevier

Neurobiology of Disease

Volume 39, Issue 3, September 2010, Pages 381-392
Neurobiology of Disease

A direct projection from the subthalamic nucleus to the ventral thalamus in monkeys

https://doi.org/10.1016/j.nbd.2010.05.004Get rights and content

Abstract

The current basal ganglia model considers the internal division of the globus pallidus and the substantia nigra pars reticulata as the sole sources of basal ganglia output to the thalamus. However, following the delivery of retrograde tracers into the ventral anterior/ventral lateral thalamic nuclei, a moderate number of labeled neurons were found within the subthalamic nucleus (STN) in control cases, MPTP-treated monkeys and animals with levodopa-induced dyskinesias. Furthermore, dual tracing experiments showed that subthalamo-thalamic and subthalamo-pallidal projections arise from different subpopulations of STN efferent neurons. Moreover, upregulated expression of the mRNA coding the vesicular glutamate transporter 2 (vGlut2) was found in retrogradely-labeled STN neurons in MPTP-treated monkeys. By contrast, there is a reduction in vGlut2 mRNA expression in subthalamo-thalamic neurons in dyskinetic monkeys. In conclusion, our findings support the presence of a direct projection from the STN to the ventral thalamus that appears to be functionally modulated by dopaminergic activity.

Introduction

The classic model of the basal ganglia (Albin et al., 1989, DeLong, 1990), considers the internal division of the globus pallidus (GPi) and the substantia nigra, pars reticulata (SNr) as the only basal ganglia output nuclei. Information processed within basal ganglia circuits converges in GPi/SNr neurons to be further funneled to the thalamus through the pallido- and nigrothalamic pathways. At the thalamic level, the ventral anterior (VA) and ventral lateral (VL) nuclei are known to be the major recipients of basal ganglia output in monkeys (Sidibé et al., 1997, Illinsky et al., 1997, Kultas-Illinsky et al., 1997). Under circumstances of dopaminergic depletion, basal ganglia output neurons become hyperactive, leading to excessive GABAergic outflow reaching thalamic targets, which impairs thalamo-cortical connectivity and leads to the appearance of the cardinal motor symptoms that characterize Parkinson's disease. Although it is widely accepted that GABA is the only neurotransmitter involved in basal ganglia output, the presence of sparse projections arising from the STN that reach the VA/VL thalamic nuclei has been reported in monkeys and cats (Nauta and Cole, 1978). Nevertheless, since these findings were not confirmed in later reports (Smith et al., 1990, Sato et al., 2000) they have since been neglected.

In recent years, certain anatomical evidence has appeared that has led to the reconsideration of the position of the STN nucleus within the basal ganglia indirect pathway. For instance, it is well known that STN efferents are highly branched and therefore most STN neurons collateralize to simultaneously innervate the GPe, GPi and SNr (Van der Kooy and Hattori, 1980, Kita et al., 1983, Kita and Kitai, 1987, Plenz and Kitai, 1999, Sato et al., 2000, Parent et al., 2000, Castle et al., 2005). Moreover, STN neurons are also known to receive strong glutamatergic innervation from the caudal intralaminar nuclei (reviewed in Lanciego et al., 2009) as well as from the cerebral cortex, the latter also known as the “hyperdirect” pathway (Nambu, 2004, Nambu et al., 2002). Finally, it is worth noting that a direct projection arising from the STN that reaches the cerebral cortex has also been reported (Jackson and Crossman, 1981, Degos et al., 2008).

In an attempt to better elucidate whether STN efferents gain direct access to the VA/VL ventral thalamic motor nuclei in monkeys, we have carried out single- and double-retrograde tract-tracing studies. Our findings confirm and expand earlier observations (Nauta and Cole, 1978) by showing that the STN nucleus is composed of at least two different subtypes of projection neurons, one subtype innervating the GPi; and the other involving a moderate number of neurons that directly project to the VA/VL nuclei, presumably providing an excitatory input to these thalamic targets.

Section snippets

Methods

A total of 8 adult male Macaca fascicularis monkeys (body weight ranging from 3.8 to 4.5 kg) were used in this study. At all times the animals were handled in accordance with the European Council Directive 86/609/EEC as well as in agreement with the Society for Neuroscience Policy on the Use of Animals in Neuroscience Research. The experimental design was approved by the Ethical Committee for Animal Testing of the University of Navarra (ref: 018/2008).

MPTP-induced dopaminergic lesion

All 4 monkeys intoxicated with MPTP developed a stable parkinsonian syndrome between 5 and 8 months after the initiation of MPTP administration, scoring 21 to 25 points in the accumulative Kurlan scale (Kurlan et al., 1991). The two monkeys showing the highest scores (24 and 25) received levodopa treatment and developed mild dyskinesias (LIDs' level 1) from the end of the first month under daily levodopa treatment. In both monkeys, the severity of LIDs increased to level 3 (overt dyskinetic

Discussion

The presence of a direct glutamatergic connection from the STN nucleus to the motor thalamus has not been considered either in the classic model of the basal ganglia (Crossman, 1987, Albin et al., 1989, DeLong, 1990) or in later updates of this model (Mink, 1996, Obeso et al., 2000, Wichmann and DeLong, 2003, DeLong and Wichmann, 2009). However, the data reported here confirm and expand earlier observations (Nauta and Cole, 1978) that (i) there is a subpopulation of efferent STN neurons that

Acknowledgments

This study was supported by Ministerio de Educación y Ciencia (BFU2006-06744 and BFU2009-08351), CIBERNED (CB06/05/0006), Departamento de Salud del Gobierno de Navarra and by the UTE-project/Foundation for Applied Medical Research (FIMA).

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