Review
Dopamine neuron systems in the brain: an update

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The basic organization of the catecholamine-containing neuronal systems and their axonal projections in the brain was initially worked out using classical histofluorescence techniques during the 1960s and 1970s. The introduction of more versatile immunohistochemical methods, along with a range of highly sensitive tract-tracing techniques, has provided a progressively more detailed picture, making the dopamine system one of the best known, and most completely mapped, neurotransmitter systems in the brain. The purpose of the present review is to summarize our current knowledge of the diversity and neurochemical features of the nine dopamine-containing neuronal cell groups in the mammalian brain, their distinctive cellular properties, and their ability to regulate their dopaminergic transmitter machinery in response to altered functional demands and aging.

Introduction

The study of catecholamine (CA) neurons in the brain goes back to the early 1960s. Using the newly introduced formaldehyde histofluorescence method [1] (Box 1), Carlsson, Falck and Hillarp [2], were the first to identify the two primary CAs, noradrenaline (NA) and dopamine (DA), in discrete neuronal systems in the brain. Two years later, Dahlström and Fuxe [3] published the first detailed account of the distribution of CA and serotonin-containing neurons in the rat brain. They identified twelve groups of CA cells (designated A1–A12) distributed from the medulla oblongata to the hypothalamus. Five additional cell groups, A13–A17, located in the diencephalon, olfactory bulb and retina, as well as three adrenaline-containing cell groups, C1–C3, were added later [4]. This nomenclature has been retained and has proved advantageous for two reasons. First, the CA cell groups are in most cases not confined to single, defined anatomical structures. Second, the distribution of cell bodies within each cell group varies markedly between different mammalian species (e.g. between rodents, primates and human), and is even more variable between different vertebrates 5, 6. The use of the A1–A17 nomenclature is thus convenient when comparing data obtained in different animal species.

With the introduction of immunohistochemistry for the CA-synthesizing enzymes, tyrosine hydroxylase (TH), aromatic amino acid decarboxylase (AADC) and dopamine-β-hydroxylase (DBH) in the 1970s, it became possible to map the CA systems in greater detail, and these new tools made it possible to distinguish more accurately between different CAs. In Figure 1, the distribution of the nine major dopaminergic cell groups (excluding retina), as revealed by TH immunohistochemistry, is schematically illustrated in sagittal view of the rat brain, both in embryonic development (Figure 1a) and in adults (Figure 1b and Box 2). TH immunohistochemistry has largely confirmed the original mapping made with the histofluorescence technique, but with some notable discrepancies. In hypothalamus and adjacent areas of the basal forebrain, in particular, TH-positive cells far outnumber the DA-containing neurons detectable with the histofluorescence method. Additional systems of TH-immunoreactive neurons not containing detectable levels of DA or NA have been identified in the rostral hypothalamus and preoptic area (designated A15 by Hökfelt et al. [4]), and further abundant TH-positive cells were detected in primates and human in cortical and striatal areas 7, 8. The failure to detect the decarboxylating enzyme, AADC, or any CA in these cells raises the question as to whether all TH-expressing cells are indeed catecholaminergic, that is, do they use DA or NA as their neurotransmitter? Immunohistochemistry has also revealed – somewhat surprisingly – that some DA neurons, particularly in the basal hypothalamus and the olfactory bulb, coexpress DA and γ-aminobutyric acid (GABA) (or the GABA-synthesizing enzyme, glutamic acid decarboxylase, GAD), and might thus operate with more than one transmitter. In the hypothalamus, the DA neurons in the arcuate nucleus (group A12) have been shown to colocalize various neuropeptides, such as growth hormone-releasing hormone (GHRH), neurotensin, galanin, enkephalin and dynorphin, suggesting a broader neuroendocrine role of these neuron subtypes [9]. Moreover, in the mesencephalon, access to more refined tract-tracing techniques has gradually come to reveal a more complex picture of the anatomical organization and projection patterns of the DA neurons in the A8 (retrorubral area), A9 (substantia nigra, SN) and A10 (ventral tegmental area, VTA) cell groups than was originally conceived (see below).

Section snippets

Are all TH-positive cells catecholaminergic?

TH-positive cells that are undetectable with the histofluorescence technique occur in rodents in the hypothalamus (particularly in the rostral A15 cell group); in primates and human, they are abundant also in the basal forebrain, striatum and cortical areas. These neurons do not contain any detectable CA (DA or NA) and they also lack the decarboxylating enzyme, AADC, as well as the vesicular monoamine transporter, VMAT-2 10, 11, 12 (see Figure Ib in Box 2). The vast majority of these neurons

Do all DA neurons express TH?

The fact that the expression of TH is substantially increased in striatal interneurons in response to DA-denervating lesions shows that the cellular levels of TH enzyme can be dynamically regulated in response to deafferentation or functional changes. In the olfactory bulb, TH expression in the periglomerular DA interneurons is activity dependent and substantially downregulated in odor-deprived mice below the level of detection in many cells [32]. In the hypothalamic arcuate nucleus, both TH

Midbrain DA neurons and their projections

It is often presumed, as a convenient heuristic, that the mesencephalon contains two major DA neuron subtypes: the nigral A9 neurons projecting to the striatum along the nigrostriatal pathway and the A10 neurons of the VTA projecting to limbic and cortical areas along mesolimbic and mesocortical pathways. This has long been recognized as an oversimplification. The SN contains not only neurons projecting to the striatum, but also neurons that innervate cortical and limbic areas; in addition, the

Forebrain projections

Early histofluorescence studies suggested three distinct ascending DA projection systems from the SN–VTA complex, the nigrostriatal (or, more accurately, ‘mesostriatal’), mesolimbic and mesocortical pathways, with widespread projections to forebrain targets 47, 48, 49. Subsequent studies support the view that those three pathways are both anatomically and functionally distinct, but that their cells of origin in the SN–VTA complex are intermixed. Retrograde, double-labeling studies have shown

DA projections to downstream striatal targets

Interestingly, not only the caudate-putamen but also several other basal ganglia structures are innervated by midbrain DA neurons. This includes the external and internal segments of the globus pallidus (entopeduncular nucleus in rodents), parts of the ventral pallidum and the subthalamic nucleus 55, 56, 57, 58, 59. In the SN itself, DA is known to be released from a plexus of dendritic terminals that is derived from the DA neurons located in the ventral tier of the SNc, and extends throughout

Concluding remarks

Over the 50 years since their discovery, DA neurons have been among the most widely studied systems of the brain, in part owing to various tools available for their study and analysis. Yet, the more we have learned, the less clear-cut have the principles of their organization become. The defining feature of a CA neuron, that is, the expression of the essential synthetic enzyme TH has been complicated by the discovery of neuronal systems (above all in hypothalamus, striatum and cortex) that

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