Mapping the primate thalamus: systematic approach to analyze the distribution of subcortical neuromodulatory afferents.

Neuromodulatory afferents to thalamic nuclei are key for information transmission and thus play critical roles in sensory, motor, and limbic processes. Over the course of the last decades, diverse attempts have been made to map and describe subcortical neuromodulatory afferents to the primate thalamus, including axons using acetylcholine, serotonin, dopamine, noradrenaline, adrenaline, and histamine. Our group has been actively involved in this endeavor. The published descriptions on neuromodulatory afferents to the primate thalamus have been made in different laboratories and are not fully comparable due to methodological divergences (for example, fixation procedures, planes of cutting, techniques used to detect the afferents, different criteria for identification of thalamic nuclei…). Such variation affects the results obtained. Therefore, systematic methodological and analytical approaches are much needed. The present article proposes reproducible methodological and terminological frameworks for primate thalamic mapping. We suggest the use of standard stereotaxic planes to produce and present maps of the primate thalamus, as well as the use of the Anglo-American school terminology (vs. the German school terminology) for identification of thalamic nuclei. Finally, a public repository of the data collected under agreed-on frameworks would be a useful tool for looking up and comparing data on the structure and connections of primate thalamic nuclei. Important and agreed-on efforts are required to create, manage, and fund a unified and homogeneous resource of data on the primate thalamus. Likewise, a firm commitment of the institutions to preserve experimental brain material is much needed because neuroscience work with non-human primates is becoming increasingly rare, making earlier material still more valuable.

Mapping the primate thalamus: historical perspective and modern approaches for defining nuclei.

The primate thalamus has been subdivided into multiple nuclei and nuclear groups based on cytoarchitectonic, myeloarchitectonic, connectional, histochemical, and genoarchitectonic differences. Regarding parcellation and terminology, two main schools prevailed in the twentieth century: the German and the Anglo-American Schools, which proposed rather different schemes. The German parcellation and terminology has been mostly used for the human thalamus in neurosurgery atlases; the Anglo-American parcellation and terminology is the most used in experimental research on the primate thalamus. In this article, we review the historical development of terminological and parcellation schemes for the primate thalamus over the last 200 years. We trace the technological innovations and conceptual advances in thalamic research that underlie each parcellation, from the use of magnifying lenses to contemporary genoarchitectonic stains during ontogeny. We also discuss the advantages, disadvantages, and practical use of each parcellation.

Distribution of the Noradrenaline Innervation and Adrenoceptors in the Macaque Monkey Thalamus.

Noradrenaline (NA) in the thalamus has important roles in physiological, pharmacological, and pathological neuromodulation. In this work, a complete characterization of NA axons and Alpha adrenoceptors distributions is provided. NA axons, revealed by immunohistochemistry against the synthesizing enzyme and the NA transporter, are present in all thalamic nuclei. The most densely innervated ones are the midline nuclei, intralaminar nuclei (paracentral and parafascicular), and the medial sector of the mediodorsal nucleus (MDm). The ventral motor nuclei and most somatosensory relay nuclei receive a moderate NA innervation. The pulvinar complex receives a heterogeneous innervation. The lateral geniculate nucleus (GL) has the lowest NA innervation. Alpha adrenoceptors were analyzed by in vitro quantitative autoradiography. Alpha-1 receptor densities are higher than Alpha-2 densities. Overall, axonal densities and Alpha adrenoceptor densities coincide; although some mismatches were identified. The nuclei with the highest Alpha-1 values are MDm, the parvocellular part of the ventral posterior medial nucleus, medial pulvinar, and midline nuclei. The nucleus with the lowest Alpha-1 receptor density is GL. Alpha-2 receptor densities are highest in the lateral dorsal, centromedian, medial and inferior pulvinar, and midline nuclei. These results suggest a role for NA in modulating thalamic involvement in consciousness, limbic, cognitive, and executive functions.

Dopamine innervation in the thalamus: monkey versus rat.

We recently identified the thalamic dopaminergic system in the human and macaque monkey brains, and, based on earlier reports on the paucity of dopamine in the rat thalamus, hypothesized that this dopaminergic system was particularly developed in primates. Here we test this hypothesis using immunohistochemistry against the dopamine transporter (DAT) in adult macaque and rat brains. The extent and density of DAT-immunoreactive (-ir) axons were remarkably greater in the macaque dorsal thalamus, where the mediodorsal association nucleus and the ventral motor nuclei held the densest immunolabeling. In contrast, sparse DAT immunolabeling was present in the rat dorsal thalamus; it was mainly located in the mediodorsal, paraventricular, ventral medial, and ventral lateral nuclei. The reticular nucleus, zona incerta, and lateral habenular nucleus held numerous DAT-ir axons in both species. Ultrastructural analysis in the macaque mediodorsal nucleus revealed that thalamic interneurons are a main postsynaptic target of DAT-ir axons; this suggests that the marked expansion of the dopamine innervation in the primate in comparison to the rodent thalamus may be related to the presence of a sizable interneuron population in primates. We remark that it is important to be aware of brain species differences when using animal models of human brain disease.

Distribution of the dopamine innervation in the macaque and human thalamus.

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.

The primate thalamus is a key target for brain dopamine.

The thalamus relays information to the cerebral cortex from subcortical centers or other cortices; in addition, it projects to the striatum and amygdala. The thalamic relay function is subject to modulation, so the flow of information to the target regions may change depending on behavioral demands. Modulation of thalamic relay by dopamine is not currently acknowledged, perhaps because dopamine innervation is reportedly scant in the rodent thalamus. We show that dopaminergic axons profusely target the human and macaque monkey thalamus using immunolabeling with three markers of the dopaminergic phenotype (tyrosine hydroxylase, dopamine, and the dopamine transporter). The dopamine innervation is especially prominent in specific association, limbic, and motor thalamic nuclei, where the densities of dopaminergic axons are as high as or higher than in the cortical area with the densest dopamine innervation. We also identified the dopaminergic neurons projecting to the macaque thalamus using retrograde tract-tracing combined with immunohistochemistry. The origin of thalamic dopamine is multiple, and thus more complex, than in any other dopaminergic system defined to date: dopaminergic neurons of the hypothalamus, periaqueductal gray matter, ventral mesencephalon, and the lateral parabrachial nucleus project bilaterally to the monkey thalamus. We propose a novel dopaminergic system that targets the primate thalamus and is independent from the previously defined nigrostriatal, mesocortical, and mesolimbic dopaminergic systems. Investigating this "thalamic dopaminergic system" should further our understanding of higher brain functions and conditions such as Parkinson's disease, schizophrenia, and drug addiction.