The dorsal and ventral tiers

The distinction of the midbrain dopaminergic system into a dorsal and a ventral tier is based on the main cellular features mentioned above, as well as on distinct neurochemical features and pattern of connectivity, which will be presented in the following sections but are summarized here. 

In the rat, the dorsal tier includes cells of the dorsal parts of the VTA and SNc and cells of the RRA innervating the limbic portion of the striatum and limbic cortical fields, as well as the ventral basal forebrain structures, such as the olfactory tubercle and the amygdala. Neurons of the dorsal tier are mostly fusiform, with dendrites oriented horizontally in the mediolateral plane of the SNc. From the neurochemical point of view, neurons of the dorsal tier contain relatively low levels of TH mRNA and dopamine transporter (DAT) mRNA, and the calcium binding protein calbindin is colocalized with DA in most dorsal tier neurons (Gerfen, 1985) (Figs. 4D 13C,D). 

The ventral tier includes in the rat cells of the ventral parts of the VTA and SNc which innervate the neostriatum and dorsal structures of the basal forebrain such as the septum. Ventral tier neurons include the columns of dopaminergic neurons which pierce the SNr and project to the striatum (Figs. 12, 13A). The ventral tier neurons express high levels of DAT mRNA and do not exhibit calbindin immunoreactivity (Gerfen, 1985). 

At rostral levels (Fig. 4), the dorsal and the ventral tiers of the SNc are both located dorsal to the SNr, where they are distributed in two sheets of neurons one on top of the other. Proceeding caudally, the ventral tier of the SNc splits into two parts, one subjacent to the cells of the dorsal tier and the other comprising the dopaminergic neurons located within the SNr. These caudal dopaminergic neurons are also well evident in the mouse (Fig. 8). 

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Dopaminergic cells (identified with TH immunoreactivity) of the VTA, SNc, SN1, and of the caudal portion of the SNr contain calretinin (Rogers, 1992 Isaacs and Jacobowitz, 1994). In the rat, about 50% of midbrain dopaminergic neurons exhibit calretinin immunoreactivity. It is interesting to note that, in contrast to calbindin, calretinin is found in neurons of both the dorsal and ventral tiers. 

The reversal dorsoventral axis on the basis of which the ventral sheet of SNc and VTA cells project dorsally in the forebrain and the dorsal sheet project ventrally in the forebrain (Fig. 17), which led to the subdivision of the dopaminergic cells into dorsal and ventral tiers, has already been dealt with in Section 2.4. 

Prensa L, Parent A (2001) The nigrostriatal pathway in the rat A single-axon study of the relationship between dorsal and ventral tier nigral neurons and the striosome/matrix striatal compartments. J Neurosci 27 7247-7260. 

Fig. 3. Schematic illustration of proposed dopamine pathways in the human forebrain originating from the dorsal tier (DT) and ventral tier (VT) mesencephalic cell populations. A, anterior thalamus BF, basal forebrain BL, basolateral amygdala Ce, central amygdala DS, dorsal striatum (includes the caudate nucleus and putamen) Ec, entorhinal cortex F, frontal cortex Hipp, hippocampus MD, mediodorsal thalamus O, occipital cortex P, parietal cortex T, temporal cortex VS, ventral striatum.

In the rat, calbindin was detected in a high proportion of dopaminergic VTA cells and RRA cells, whereas in the SN1 calbindin was mainly found in nondopaminergic neurons (Gerfen et al., 1985). In particular, as mentioned earlier (see Section 2.4), calbindin immunoreactivity (Figs. 4D 13C,D) represents a distinctive chemoarchitectonic feature for the subdivision of dopaminergic midbrain neurons into dorsal (calbindin-positive) and ventral (calbindin-negative) tiers. 

Fig. 2. Tyrosine hydroxylase (TH), dopamine transporter (DAT), and dopamine D2 mRNA expression in the human mesencephalon. The dorsal tier cell group (dorsal part of the substantia nigra pars compacta, ventral tegmental area (paranigral and parabrachial pigmented nuclei), and retrobural area) are characterized by low mRNA expression levels of TH, DAT and D2, whereas the ventral tier (ventral part of the substantia nigra pars compacta that includes the densocellular region dorsal to the pars reticulata and the cell columns that extend into the reticulata) is characterized by high mRNA expression levels of these dopaminergic markers.

Ikemoto et al., 1995 Meredith et al., 1996). The shell subregion of the primate nucleus accumbens is innervated almost exclusively by the ventral tegmental area of the dorsal tier mesencephalic cell group (Haber et al., 2000 Fig. 5). The core of the nucleus accumbens as well as the adjacent rostral ventral putamen and ventromedial caudate nucleus also receives innervation from the dorsal tier as well as input from the densocellular part of the ventral tier mesencephalic neurons. 

Overall, as predicted by anatomical organization and connectivity, the ventral tier nigrostriatal dopaminergic system is primarily associated with basal ganglia function related to motor behavior, whereas the dorsal tier mesocorticolimbic system is more linked to the neural structures involved in reinforcement, motivation, emotion and cognitive function. 

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