Elsevier

NeuroImage

Volume 34, Issue 3, 1 February 2007, Pages 965-984
NeuroImage

Distribution of the dopamine innervation in the macaque and human thalamus

https://doi.org/10.1016/j.neuroimage.2006.07.032Get rights and content

Abstract

We recently defined the thalamic dopaminergic system in primates; it arises from numerous dopaminergic cell groups and selectively targets numerous thalamic nuclei. Given the central position of the thalamus in subcortical and cortical interplay, and the functional relevance of dopamine neuromodulation in the brain, detailing dopamine distribution in the thalamus should supply important information. To this end we performed immunohistochemistry for dopamine and the dopamine transporter in the thalamus of macaque monkeys and humans to generate maps, in the stereotaxic coronal plane, of the distribution of dopaminergic axons. The dopamine innervation of the thalamus follows the same pattern in both species and is most dense in midline limbic nuclei, the mediodorsal and lateral posterior association nuclei, and in the ventral lateral and ventral anterior motor nuclei. This distribution suggests that thalamic dopamine has a prominent role in emotion, attention, cognition and complex somatosensory and visual processing, as well as in motor control. Most thalamic dopaminergic axons are thin and varicose and target both the neuropil and small blood vessels, suggesting that, besides neuronal modulation, thalamic dopamine may have a direct influence on microcirculation. The maps provided here should be a useful reference in future experimental and neuroimaging studies aiming at clarifying the role of the thalamic dopaminergic system in health and in conditions involving brain dopamine, including Parkinson’s disease, drug addiction and schizophrenia.

Introduction

The thalamus is made up of multiple nuclei relaying information from subcortical centers or from other cortices to the cerebral cortex (Sherman and Guillery, 2005), as well as the striatum, the nucleus accumbens and the amygdala (Steriade et al., 1997). In addition to specific subcortical and cortical afferents, the primate thalamus receives axons containing the neuromodulators acetylcholine (Heckers et al., 1992), histamine (Manning et al., 1996), serotonin (Morrison and Foote, 1986, Lavoie and Parent, 1991), and the catecholamines adrenaline (Rico and Cavada, 1998a), noradrenaline (Morrison and Foote, 1986, Ginsberg et al., 1993) and dopamine (Sánchez-González et al., 2005).

Until recently, the existence of significant dopamine innervation in the primate thalamus has been largely ignored, probably because dopamine innervation of the rodent thalamus is very scant (Groenewegen, 1988, Papadopoulos and Parnavelas, 1990). However, fragmentary data scattered through the literature endorse the presence of dopamine innervation in the primate thalamus. Postmortem biochemical studies showed the presence of dopamine in the thalamus of macaques (Brown et al., 1979, Goldman-Rakic and Brown, 1981, Pifl et al., 1990, Pifl et al., 1991) and human subjects (Oke and Adams, 1987). Later, receptor binding and in situ hybridization analyses detected the presence of dopamine D2-like (Joyce et al., 1991, Kessler et al., 1993, Hall et al., 1996, Langer et al., 1999, Rieck et al., 2004) and D3-like receptors (Gurevich and Joyce, 1999) in several human thalamic nuclei. Positron emission tomography (PET) radioligand studies have also demonstrated the presence of the dopamine transporter (DAT) (Wang et al., 1995, Halldin et al., 1996, Helfenbein et al., 1999, Brownell et al., 2003) and of D2-like receptors (Farde et al., 1997, Langer et al., 1999, Okubo et al., 1999, Brownell et al., 2003, Rieck et al., 2004) in the human and macaque thalamus. In the course of PET studies focusing on schizophrenia, D2- and D3-like radioligand binding was also found in the thalamus of control subjects (Talvik et al., 2003, Yasuno et al., 2004). Finally, an immunohistochemical study using anti-DAT antibodies detected the presence of dopaminergic axons in the mediodorsal nucleus (MD) of the macaque thalamus (Melchitzky and Lewis, 2001).

Our group has recently defined the primate thalamic dopaminergic system based on our findings of dopaminergic axons throughout the human and macaque monkey thalamus and of dopaminergic cell groups projecting to the macaque thalamus (Sánchez-González et al., 2005). Using retrograde tracing techniques in the macaque brain, we showed that dopamine thalamic innervation, unlike that of the striatum and the cerebral cortex, has a multiple origin in the hypothalamus, periaqueductal gray matter (PAG), mesencephalon, and the lateral parabrachial nucleus. In addition to their heterogeneous origin, we also observed an uneven distribution of the dopaminergic axons throughout the thalamus.

The purpose of the present study was to analyze in detail the distribution and morphology of dopaminergic axons in the macaque and human thalamus. Thus, here we provide detailed maps of the normal dopamine innervation of the primate thalamus using immunohistochemistry against dopamine (macaque thalamus) and DAT (macaque and human thalamus). Considering the growing interest in neuroimaging studies of the human thalamus (Niemann et al., 2000), we offer the maps in the stereotaxic coronal plane to facilitate their use in future experimental and clinical neuroimaging studies examining the thalamic distribution of dopamine, its receptors or DAT. Indeed, biochemical and PET radioligand studies have described thalamic abnormalities in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated parkinsonian macaque monkeys related to dopamine, DAT and D2-like receptors (Pifl et al., 1990, Pifl et al., 1991, Brownell et al., 2003). Moreover, biochemical and PET radioligand studies have also demonstrated alterations in the thalamus of schizophrenic patients related to dopamine and its receptors (Oke and Adams, 1987, Talvik et al., 2003, Yasuno et al., 2004).

Section snippets

Tissue preparation

The maps of the macaque brain were drawn from two young adult female macaques (Macaca nemestrina), weighing 4.6 kg and 5.6 kg. Additional tissue from the thalamus of another four macaques (one female and three males, M. nemestrina and Macaca mulatta) weighing between 4.7 kg and 7.2 kg was also studied. The macaque experiments were approved by the Bioethics Committee of the Universidad Autónoma de Madrid. Appropriate measures were taken to minimize animal pain or discomfort in accordance with

Control experiments

Anti-dopamine and anti-DAT antibodies revealed well-established dopaminergic neuronal groups (e.g., in the SNc and in the VTA) and terminal axonal fields (e.g., in the caudate nucleus and in the cerebral cortex). No immunolabeling of neuronal bodies or axons was observed in the brain stem, thalamus or other brain regions when the primary antibodies were not used in the immunostaining protocols.

Distribution of dopamine-ir and DAT-ir axons in the macaque monkey thalamus

Both dopamine and DAT immunolabeling were unevenly distributed in the macaque dorsal thalamus, with

Discussion

This study provides detailed coronal maps of the dopamine innervation of the macaque and human thalamus as revealed by dopamine and DAT immunolabeling. The maps show widespread and profuse dopamine innervation that is quite heterogeneous in density and nuclear distribution. In both species the most densely innervated thalamic nuclei are midline limbic nuclei, the association nuclei MD and LP, and the motor ventral nuclei (VLo, VLc and VPLo—monkey, VLa and VLp—human); in the human thalamus, the

Acknowledgments

This work was supported by Grants from the Ministerio de Ciencia y Tecnología and Ministerio de Educación of Spain (BFI2002-00513 and SAF2005-05380). B.R. and M.A.S.-G. were recipients of Fellowships from the Ministerio de Educación y Ciencia (B.R. and M.A.S.-G.) and from the Comunidad de Madrid (M.A.S.-G.). We are grateful to the Pathology Department of Hospital Universitario La Paz of Madrid, in particular to Dr. Manuel Gutiérrez and Dr. Carmen Morales, for their support and for giving us

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