A direct projection from the subthalamic nucleus to the ventral thalamus in monkeys
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).
References (39)
- et al.
The functional anatomy of basal ganglia disorders
Trends Neurosci.
(1989) - et al.
Detection of two different mRNAs in a single section by dual in situ hybridization: a comparison between colorimetric and fluorescent detection
J. Neurosci. Meth.
(2007) Primate models of dyskinesia: the experimental approach to the study of basal ganglia-related involuntary movement disorders
Neuroscience
(1987)Primate models of movement disorders of basal ganglia origin
Trends Neurosci.
(1990)- et al.
Update on models of basal ganglia function and dysfunction
Parkin. Rel. Disord.
(2009) - et al.
Subthalamic nucleus efferent projection to the cerebral cortex
Neuroscience
(1981) - et al.
The search for a role of the caudal intralaminar nuclei in the pathophysiology of Parkinson's disease
Brain Res. Bull.
(2009) Motor cortex dysfunction revealed by cortical excitability studies in Parkinson's disease: influence of antiparkinsonian treatment and cortical stimulation
Clin. Neurophysiol.
(2005)The basal ganglia: focused selection and inhibition of competing motor programs
Prog. Neurobiol.
(1996)A new dynamic model of the cortico-basal ganglia loop
Prog. Brain Res.
(2004)
Functional significance of the cortico-subthalamo-pallidal ‘hyperdirect’ pathway
Neurosci. Res.
Pathophysiology of the basal ganglia in Parkinson's disease
Trends Neurosci.
‘Functional’ neuroanatomical tract-tracing: analysis of changes in gene expression of brain circuits of interest
Brain Res.
Initial clinical manifestations of Parkinson's disease: features and pathophysiological mechanisms
Lancet Neurol.
Two separate neuronal populations of the rat subthalamic nucleus project to the basal ganglia and pedunculopontine tegmental region
Brain Res.
Thalamic innervation of the direct and indirect basal ganglia pathways in the rat: ipsi- and contralateral projections
J. Comp. Neurol.
Evidence for a direct subthalamo-cortical loop circuit in the rat
Eur. J. Neurosci.
Roles of GABA, glutamate, acetylcholine and STN stimulation on thalamic VM in rats
NeuroReport
Cited by (37)
Brain structure and connectivity mapping for deep brain stimulation using ultrahigh field (7 T) MRI
2018, Engineering in Medicine: Advances and ChallengesL-DOPA-treatment in primates disrupts the expression of A<inf>2A</inf> adenosine-CB<inf>1</inf> cannabinoid-D<inf>2</inf> dopamine receptor heteromers in the caudate nucleus
2014, NeuropharmacologyCitation Excerpt :The experimental design was approved by the Ethical Committee for Animal Testing of the University of Navarra (ref: 018/2008) as well as by the Department of Health from the Government of Navarra (ref: NA-UNAV-04-08). Of the 21 animals devoted to perform binding assays in freshly isolated tissue, 11 were naïve and 10 monkeys were treated with systemic delivery of the dopaminergic neurotoxin MPTP (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine from Sigma, Madrid, Spain) to induce a bilateral parkinsonian syndrome (Rico et al., 2010). Animals received a weekly injection of MPTP (0.2 mg/kg i/v; accumulated doses ranging from 5 to 7 mg/kg) until reaching a non-reversible parkinsonian syndrome.
The distributed somatotopy of tremor: A window into the motor system
2013, Experimental Neurology