The substantia nigra and ventral tegmental dopaminergic neurons from development to degeneration

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The substantia nigra and ventral tegmental dopaminergic neurons from development to degeneration YuHong Fua,b , George Paxinosa,b , Charles Watsona , Glenda M. Hallidaya,b,* a b

Neuroscience Research Australia, Sydney, NSW 2031, Australia School of Medical Science, The University of New South Wales, Sydney, NSW 2052, Australia

A R T I C L E I N F O

A B S T R A C T

Article history: Received 5 August 2015 Received in revised form 25 January 2016 Accepted 3 February 2016 Available online xxx

The pathology of Parkinson’s disease (PD) is characterised by the loss of neurons in the substantia nigra parcompacta (A9), which results in the insufficient release of dopamine, and the appearance of motor symptoms. Not all neurons in the A9 subregions degenerate in PD, and the dopaminergic (DA) neurons located in the neighboring ventral tegmental area (A10) are relatively resistant to PD pathogenesis. An increasing number of quantitative studies using human tissue samples of these brain regions have revealed important biological differences. In this review, we first describe current knowledge on the multi-segmental neuromere origin of these DA neurons. We then compare the continued transcription factor and protein expression profile and morphological differences distinguishing subregions within the A9 substantia nigra, and between A9 and A10 DA neurons. We conclude that the expression of three types of factors and proteins contributes to the diversity observed in these DA neurons and potentially to their differential vulnerability to PD. In particular, the specific axonal structure of A9 neurons and the way A9 neurons maintain their DA usage makes them easily exposed to energy deficits, calcium overload and oxidative stress, all contributing to their decreased survival in PD. We highlight knowledge gaps in our understanding of the cellular biomarkers for and their different functions in DA neurons, knowledge which may assist to identify underpinning disease mechansims that could be targeted for the treatment of any subregional dysfunction and loss of these DA neurons. ã 2016 Elsevier B.V. All rights reserved.

Keywords: Dopaminergic neurons Substantia nigra Ventral tegmental area Parkinson’s disease Quantification Cytoarchitecture

1. Introduction The cardinal neuropathological feature of Parkinson’s disease (PD) is the early consistent degeneration of dopaminergic (DA) neurons within the substantia nigra (SN) (Halliday et al., 1996; Braak et al., 2004; Hornykiewicz, 2006; Davie, 2008). Unlike other parkinsonian conditions, the DA cell loss is selective in PD and most severe in the ventral tier of the substantia nigra pars compacta (SNV) compared to the other subregions of the substantia nigra pars compacta (SNC) (Fearnley and Lees, 1991; Ma et al., 1995). Moreover, the neighboring regions of the ventral tegmental area (VTA) and retrorubral field are relatively resistant to degeneration in PD (McRitchie et al., 1997). The discrepant vulnerability of these DA neurons to PD indicates that there must be biological

* Corresponding author at: Neuroscience Research Australia, Barker St. and Hospital Rd., Randwick, Sydney, NSW 2031, Australia. Fax: +61 293991105. E-mail address: [email protected] (G.M. Halliday).

characteristics that determine the fate of these subtypes of DA neurons. The subgroups of SN and VTA DA neurons are developmentally, morphologically, and functionally different. Together with basic histological and pathological descriptions, quantitative assessments using either conventional single section based counting or stereological counting have provided an overview of the changes in DA neuronal number in both aging and PD. These quantitative data offer not only a better understanding on the difference between the aging process and PD-related changes, but also a picture of the different levels of cell loss in subregions of SNC and VTA. We review the biological characteristics of the subregions of SNC and VTA DA neurons and comment on potential links to their fate in PD. Mouse models of PD have been widely used in research, and the translation of data from mouse to human PD must be based on establishing anatomical homologies between these species. As the C57BL/6J mouse is the most commonly used strain for genetic engineering and PD models, the SN and VTA structures of this strain is briefly reviewed and compared with those of humans (Zaborszky and Vadasz, 2001; Fu et al., 2012; Reyes et al., 2012).

http://dx.doi.org/10.1016/j.jchemneu.2016.02.001 0891-0618/ ã 2016 Elsevier B.V. All rights reserved.

Please cite this article in press as: Y.H. Fu, et al., The substantia nigra and ventral tegmental dopaminergic neurons from development to degeneration, J. Chem. Neuroanat. (2016), http://dx.doi.org/10.1016/j.jchemneu.2016.02.001

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2. The human and mouse substantia nigra (SN) and ventral tegmental area (VTA) Before comparing the subgroups of SN and VTA DA neurons, we must briefly recall the anatomical organization of these two structures. In the nomenclature based on the numbering of catecholamine-containing neuron systems caudal to rostral, the DA neurons in the SNC are named A9 and those in the VTA are named A10 (Smeets and González, 2000; Björklund and Dunnett, 2007). In both humans and mice, the SN and VTA are located in the floor of the adult midbrain, with the SN ventral to the VTA (for a three dimensional view of human and mouse SN and VTA (see Halliday and Tork, 1986; McRitchie et al., 1995; Fu et al., 2012). Furthermore, the same subgroups of DA neurons can be identified in the SN and VTA in both species. The SNC forms the dorsal part of the SN and comprises the dorsal tier (SND), medial cluster (SNM), lateral cluster (SNL), and SNV. SNV DA neurons are embedded in the SNR, the latter being the ventral part of the SN that is harbored in the cerebral peduncle. Compared to the mouse, the human has an enlarged cerebral peduncle and a larger volume of SNV, while the VTA is forced to extend far more dorsally (Reyes et al., 2012). It must be noted that the VTA is the collective name for a number of distinct DA neuron groups, including the laterally placed parabrachial pigmented nucleus (PBP), three intermediate structures (paranigral nucleus (PN), parapeduncular nucleus (PaP), and rostral VTA (VTAR)), and three medial structures (interfascicular nucleus (IF), rostral linear nucleus of the raphe (RLi), and caudal linear nucleus of the raphe (CLi)) (McRitchie et al., 1996). 3. Heterogeneity of dopaminergic (DA) neurons in SN and VTA 3.1. Multi-segmental neuromeric origin While the midbrain location of DA neurons in the developing SN and VTA is well known, it is often not recognised these DA neurons are also located in the diencephalon and the isthmus (Marin et al., 2005; Puelles et al., 2007, 2013; Hebsgaard et al., 2009). Using the traditional biomarker tyrosine hydroxylase (TH, the rate-limiting enzyme for DA synthesis that catalyses the synthesis of L-3,4,dihydroxyphenylalanine (L-DOPA)), Aubert et al. (1997) described a series of development events of the SN and VTA DA neurons in human fetuses: (1) TH-immunoreactive signal first appears in mesencephalon at fetal week 12; (2) after this stage, THimmunoreactive precursors are still migrating from the ventricle; (3) SN is anatomically visible but the main subgroups of SN DA neurons become distinguishable at fetal week 16; (4) the SN displays an organisation resembling that of the adult SN at fetal week 19; and (5) also at this stage, neurons with morphology of those in the future VTA are visible. In a later study, Hebsgaard et al. (2009) confirmed that the DA neuron determinant, LMX1a, is expressed in the diencephalic and mesencephalic DA neuron domains during human development and that the progenitor cells are located in the ventricular zone of the floor plate region. In the chick the caudal SN arises from the isthmus (the most rostral segment of the hindbrain) instead of the mesencephalon, and the caudal VTA originates from rhombomere 1 of the hindbrain (Puelles et al., 2007). In the embryonic mouse, SNC and VTA DA neurons are located in the basal plate rostrocaudally from diencephalic prosomere 3 to the isthmus region (see review in Ang, 2006). Although the isthmus forms a complete segment of the brainstem between the mesencephalon and the rhombomeres of the hindbrain, it has been a region largely ignored when the origin of neuronal clusters has been considered (Puelles et al., 2013). The origin of DA neurons in the human isthmus has still to be confirmed by gene expression studies, but study of mice of a cre fgf8 lineage (fgf8 is the main organising molecule in the developing

isthmus (Martinez, 2001) and fate mapping could be used to examine isthmus-born DA neurons in mammals (Watson, 2010). If the avian multi-segmental neuromeric origin of the SN and VTA DA neurons is also true of humans, it may have implications for the pathogenesis of PD. It should be noted that there are rostrocaudal morphological differences in SN DA neurons in the mouse (Fu et al., 2012) which may have relevance to the increased rostrocaudal gradient of cell loss in PD patients (Damier et al., 1999). Anatomical landmarks revealing the developmental location of the DA cell groups should be considered in future pathological assessments. For instance, the medial terminal nucleus of the accessory optic tract is an exclusively diencephalic structure, the oculomotor nerve exits exclusively from the mesencephalon, and the rostal SN and VTA DA neurons are located in prosomeres 1, 2, and 3 of the diencephalon (Puelles et al., 2007). 3.2. Transcription factors for SN and VTA DA neurons Clearly, most studies to date have not considered the isthmic and diencephalic origin of many A9 and A10 neurons. However, DA neurons receive region-specific signals that lead them to develop into specific subsets distinguishable by their molecular and physiological parameters (Smidt and Burbach, 2007; Hegarty et al., 2013; Blaess and Ang, 2015). At embryonic stages, the SN and VTA DA precursor cells are under the regulation of different transcription factors (for recent reviews on molecular mechanisms that direct DA subset specification in development (see Hegarty et al., 2013; Veenvliet and Smidt, 2014; Blaess and Ang, 2015). Some of these transcription factors persist in their expression into adulthood, although remarkably little is known about their late functions in mature DA neurons. It is possible that some of these developmentally acting transcription factors are required throughout adulthood as key regulators of the axonal energy balance for different types of DA neurons (Doucet-Beaupré and Lévesque, 2013). This may contribute to their different vulnerability in PD, particularly through differences in mitochondrial dynamics (Zaltieri et al., 2015). PD-associated genes also directly or indirectly impinge on mitochondrial integrity, therefore linking the developmental regulation of DA neurons and the pathophysiological alterations observed in sporadic PD (see review in Winklhofer and Haass, 2010). Here we review reports on two types of such transcription factors. Most of their late functions have been revealed in mice, and these functions need to be confirmed in humans (Fig. 1): (1) transcription factors that differentiate SN and VTA DA progenitors and preserve a regional specific expression pattern into adulthood; (2) transcription factors that are expressed by DA progenitors and neurons in both embryonic and adult stages and function in cell survival and maintenance, but have no regional specific expression in the SN and VTA. 3.2.1. Transcription factors differentiating SN and VTA DA neurons Orthodenticle homeobox 2 (Otx2) is expressed in the midbrain as far caudal as the midbrain–hindbrain boundary and so identifies mesencephalic-derived DA neurons in developing mouse brain (Omodei et al., 2008; Di Giovanni et al., 2009). Otx2 targets genes that are nuclear-encoded mitochondrial mRNAs (Spatazza et al., 2013). It is known that neurons with high levels of glycosylated dopamine transporter have efficient dopamine reuptake and pronounced vulnerability to PD-related degeneration (Di Salvio et al., 2010a). Interestingly, Otx2 can suppress the expression of the glycosylated dopamine transporter (Di Salvio et al., 2010a), indicating its protective role. In adult mice, Otx2 controls the identity of subtypes of neurons by antagonizing molecular and functional features of the dorsal-lateral VTA, such as G-proteincoupled inwardly rectifying potassium channel subunit (GIRK2) and dopamine transporter (DAT) (Simeone et al., 2011).

Please cite this article in press as: Y.H. Fu, et al., The substantia nigra and ventral tegmental dopaminergic neurons from development to degeneration, J. Chem. Neuroanat. (2016), http://dx.doi.org/10.1016/j.jchemneu.2016.02.001

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Fig. 1. Transcription factors that maintain their expression in DA neurons of the adult mouse VTA and SN. The reported earliest expression day for each transcription factor (TF) is shown on the x-axis of age (Di Giovanni et al., 2009; Duan et al., 2013; Panman et al., 2014). The regional specific expression of transcription factors is expressed in the coronal plane of the adult mouse brain (Di Giovanni et al., 2009; Di Salvio et al., 2010b; Simeone et al., 2011; Reyes et al., 2013b), with blue for SNC-specific and green for VTAspecific distribution. The TFs without special regional distribution pattern are expressed in black font. Three key time points for the generation of DA precursors are indicated by red arrows inferior to the x-axis, which successively indicates the time when DA precursor cells appear (Smidt et al., 2003), the time when DA precursor cells start to express the rate-limiting enzyme (TH) (Duan et al., 2013), and the peak time of DA neurogenesis (Bayer et al., 1995). The TFs potentially involved in mitochondrial functions and oxidative stress are indicated by the light blue and red ovals, respectively (Burke et al., 2008; Surmeier, 2009; Doucet-Beaupré and Lévesque, 2013; Veenvliet and Smidt, 2014; Dragicevic et al., 2015; Glaab and Schneider, 2015). The hypothesised pathogenesis process in the SNC DA neurons relevant to the downstream functions of the TFs is illustrated in the black rectangular box (Hall et al., 2014; Subramaniam et al., 2014; Goldstein et al., 2015).

Otx2 expression in VTA DA neurons of aged mice is preserved, whereas no Otx2 immunoreactivity is detected in aged human SN and VTA DA neurons, although Otx2 gene expression occurs in young adulthood (Reyes et al., 2013b). This indicates that in humans Otx2 does not play a neuroprotective role following DA neuronal maturation. Transcription factors SRY (sex determining region Y)-box 6 (Sox6) and Nolz1 (also referred to as zinc finger protein 503) control the specification of SN and VTA DA neurons at the neural progenitor cell stage after they exit the cell cycle (Panman et al., 2014). Sox6 is selectively expressed in neurons belonging to the SNC, while Nolz1 is expressed in a subset of VTA neurons (Di Salvio et al., 2010a,b; Panman et al., 2014). In adult mice Sox6 expression in the SNC overlaps with GIRK2 and glycosylated DAT and partly with retinaldehyde dehydrogenase Aldh1a1 (also referred to Raldh1 or Ahd2), but not with the VTA-specific markers calbindin and Otx2 (Panman et al., 2014). Importantly, Panman and colleagues also show similar expression of Sox6 in human DA neurons, with diminished expression in neuromelanin-positive neurons of PD patients (Panman et al., 2014). Mice lacking Sox6 specifically in skeletal muscle have elevated muscle mitochondrial activity (Quiat et al., 2011), indicating that the downstream mitochondrial dysfunction is associated with Sox6 deficiency. However, the function of Sox6 in adult SNC DA neurons remains to be clarified, and further research is needed to determine if its loss in PD or aging brain is one of the contributing factors leading to DA neuron death. Interestingly, Nolz1 expression appears in VTA neurons and also in the developing ventral but not dorsal striatum around embryonic day (E) 11.5 (Ko et al., 2013). The expression of Nolz1 disappears at postnatal day 7, suggesting the early expression of this transcription factor may signal the development of striatal projection neurons (Ko et al., 2013). 3.2.2. Transcription factors essential for the survival and maintenance of SN and VTA DA neurons Essential signaling molecules, such as orphan nuclear receptor related 1 (Nurr1), need to be continuously expressed throughout adulthood to maintain SN DA neurons, whereas VTA DA neuronal survival is independent of Nurr1 expression (Kadkhodaei et al., 2009). Nurr1 modulates the expression of genes associated with mitochondrial function and oxidative phosphorylation (Decressac

et al., 2013). In a recent meta-analysis on jointly deregulated genes in aging and PD, Nurr1 was the most significantly differentially expressed gene with a high negative correlation with brain aging and in PD (Glaab and Schneider, 2015). Down-regulation of Nurr1 increases the transcriptional expression of a-synuclein (Yang and Latchman, 2008). In postmortem PD brain tissue, reduced Nurr1 expression occurs in neurons containing a-synuclein inclusions (Chu et al., 2006), and in rare cases of PD Nurr1 mutations and polymorphisms have been identified (Kadkhodaei et al., 2009; Decressac et al., 2013). Homeodomain transcription factor Pitx3 is pivotal to both SN and VTA DA neuron development. The loss of Pitx3 results in programming deficits in a rostrolateral subpopulation of SNC-DA neurons, while the VTA appears much less affected (Hwang et al., 2003; Van Den Munckhof et al., 2003). The different dependence of these DA neurons on Pitx3 has been associated with the downstream target gene Aldh1a1 (Jacobs et al., 2007), whose earliest expression is at E9.5 (Wallen et al., 1999). Consistent with Pitx3 expression in adult mice, Aldh1a1 mRNA expression is mostly located in the SNC with some expression in the medioventral VTA (http://developingmouse.brain-map.org; observation made on 30 April 2015). Aldh1a1 catalyzes the oxidation of retinaldehyde into retinoic acid and is involved in further metabolizing the toxic intra-neuronal production of dopamine, 3,4-dihydroxyphenylacetaldehyde (DOPAL) (Marchitti et al., 2007; Goldstein et al., 2013). Retinoic acid may either indirectly or directly regulate mitochondrial transcription (Everts and Berdanier, 2002) and it is proposed that the retinoid signal transduction may control DA neurotransmission, exert anti-apoptotic and antioxidant activities (Kitamura et al., 2002; Takeda et al., 2014). This may partly explain the protective role of Pitx3 in maintaining the survival of DA neurons. On the other hand, striatal uptake and retrograde axonal transport of glial cell line derived neurotrophic factor (GDNF) maintains the proper levels of both Pitx3 and brain derived neurotrophic factor (BDNF) expression in adult SNC DA neurons (Peng et al., 2011). Genetic variants coding for the transcription factors Pitx3 and Engrailed 1 (En1) have been suggested as risk factors for PD (Bergman et al., 2010; Haubenberger et al., 2011). Engrailed-1 and 2 (En1/2) proteins are important for adult DA neuron maintenance. It is thought that En1/2 participate in the

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local energetic metabolism of adult DA neurons by regulating the translation of nuclear-encoded subunits of mitochondrial complex I and the enzymatic activity of this complex (Alvarez-Fischer et al., 2011). More recent reports confirm that En1/2 mediate the expression of several nuclear-encoded mitochondrial genes as well as key genes implicated in mitochondrial metabolism (Doucet-Beaupré and Lévesque, 2013). The precise mechanism through which En1/2 takes a role in the survival and maintenance of SNC and VTA DA neurons remains elusive. LIM homeobox transcription factor 1 alpha (Lmx1a) and beta (Lmx1b) are key transcription factors required for the early specification of ventral midbrain DA neurons, while their continued function remains to be determined. A recent study using conditional ablation of these two transcription factors following DA neuron specification revealed that Lmx1b is required for normal performance of the autophagic-lysosomal pathway, the integrity of DA nerve terminals, and long-term DA neuronal survival (Laguna et al., 2015). Lmx1b expression is decreased in DA neurons in PD (Laguna et al., 2015). Forkhead box protein A 1 and 2 (Foxa1/2) are crucial for the development and differentiation of DA neurons (Sasaki and Hogan, 1994; Ferri et al., 2007), they remain expressed into adulthood (Besnard et al., 2004), and are required for DA neuronal maintenance (Stott et al., 2013). Although Foxa1/2 are expressed in DA neurons in adult mice, about 30% of mice heterozygous for Foxa2 develop asymmetric loss of DA neurons in the SNC late in life, with VTA DA neurons relatively spared (Kittappa et al., 2007). Specific conditional DA neuronal ablation of Foxa1/2 early in adulthood induces reduced Aldh1a1 expression, a decline in aromatic amino acid decarboxylase, and a complete loss of DAT in these neurons, leading to the reduction of SNC-DA neuron number in aged mice (Domanskyi et al., 2014). In summary, polymorphisms in Pitx3,En1, Nurr1, Lmx1a, and Lmx1b are associated with PD (Zheng et al., 2003; Bergman et al., 2009; Fuchs et al., 2009; Haubenberger et al., 2011). Further, by mining the available gene expression profile data, the expression levels of several transcription factors (Foxa1/2, Nurr1, and En1) and Aldh1a1 were found to be down-regulated in SNC in PD (Domanskyi et al., 2014; Glaab and Schneider, 2015). Nurr1 seems to be a priority gene to be investigated for its upstream and downstream pathway (Glaab and Schneider, 2015). Maungay and colleagues found that overexpressing human A53T a-synuclein did not affect the survival of VTA neurons, but led to profound cell loss in SN (Maingay et al., 2006). This selective susceptibility of SNC DA neurons to A53T a-synuclein may be associated with factor(s) involved in the handling of a-synuclein in SN but not critically in VTA neurons (Maingay et al., 2006). Discerning the factors contributing to the accumulation of a-synuclein in the SN may shed light on potential therapeutic strategies. 4. Biological characteristics of DA neurons in the SNC and VTA 4.1. Shape and number of DA neurons and the volume of the SNC Cresyl violet staining of human brain coronal sections reveals that the VTA and SNC neurons are polymorphous (Halliday and Tork, 1986). The same study also describes the dominant morphology of neurons in each subgroup of the DA regions; it showed that IF contains small round cells, PN had smaller, fusiform, and densely packed cells, and that the SNC contains cells that were variable in shape but specific in being heavily pigmented and darkly-Nissl staining. Some pigmented cells were also seen in all subgroups of the VTA (Halliday and Tork, 1986). Mouse DA neurons have been shown to have similar features, but TH immunohistochemistry is required as mice DA neurons do not contain neuromelanin (Fu et al., 2012).

Quantification shows that there are about 200,000– 420,000 TH-specific neurons bilaterally in the adult human SNC and about 60,000–65,000 TH-positive neurons in the adult human VTA (Halliday and Tork, 1986; Hirsch et al., 1988; Chu et al., 2002; Hardman et al., 2002; Marchitti et al., 2007). Early counting studies suggested that the number of human SN DA neurons gradually decreased with aging and that apoptosis could be observed (Fearnley and Lees, 1991; Anglade et al., 1997; Cabello et al., 2002; Stark and Pakkenberg, 2004; Rudow et al., 2008). However, this observation has not been consistently replicated using stereology methods and sometimes disagrees with findings in non-human primates, which show either no DA neuron loss or decreased THspecific neurons only in SNV (see review in Collier et al., 2011). It must be noted that there is a loss of DA phenotype with age (Chu et al., 2006) and in PD (McRitchie et al., 1997). It therefore seems that the presence of TH at detectable levels is not always a reliable marker for identifying DA neurons, particularly with aging. Adult C57BL/6 mice contain approximately 8000–12,000 THpositive neurons in each of the SNC and VTA bilaterally (German et al., 1996; Nelson et al., 1996; Brichta and Greengard, 2014), although the number of these neurons differs between mice strains (Baker et al., 1980; Zaborszky and Vadasz, 2001). As in humans, the expression of TH in SNC DA neurons appears to be variable and activity-dependent (Aumann et al., 2011). In humans, neuromelanin typically appears in greatest quantities in SNC DA neurons with the amount increasing with age. Perhaps surprisingly, neuromelanin is absent from the brains of many species, including the mouse (Zecca et al., 2001, 2003; Fedorow et al., 2005). The especial vulnerability of neuromelanincontaining neurons to cell death in PD may be related to the compromised ability of neuromelanin to interact with transition metals, especially iron, and to mediate intracellular oxidative mechanisms (Zecca et al., 2001; Fedorow et al., 2005; Sukhorukova et al., 2014). Recently, neuromelanin-sensitive MRI has been used to define the volume of the SNC in vivo, and as such can be used as a diagnostic method to differentiate PD cases from healthy persons and from cases of essential tremor (Castellanos et al., 2015; Reimao et al., 2015). Such MRI results show that the average bilateral volume of the SNC in healthy subjects is 248.2 mm3 and that there is a striking reduction of SNC volume in PD patients (idiopathic, LRRK2 or PARKIN mutation carriers) (Castellanos et al., 2015). 4.2. Differentially expressed proteins in DA neurons Unlike other parkinsonian conditions the demise of DA neurons in PD is regionally dependent, with VTA DA neurons largely resistant to PD (Fig. 2). This suggests an innate biological vulnerability potentially dependent on differentially expressed protein profiles. However, reports on the comparative expression of proteins between these two DA regions in human brain samples are remarkably rare, despite advances in techniques (laser-capture microdissection with gene expression profiling) (Brichta and Greengard, 2014). Based on current knowledge in both the limited human studies and also referring to rodent studies, three types of factors (level 1, 2 and 3) appear to be biologically relevant. Level 1 factors are those that are expressed more dominantly in the PDvulnerable DA subgroups within the SN. Level 2 factors are those that not exclusively expressed in PD-vulnerable DA neurons but who are changed in PD (e.g., dopamine phenotype). Level 3 factors are those that are expressed in the PD-resistant VTA DA neurons (i.e., potentially protective). Currently known relevant factors in these subgroups are identified below. Transcription factors are not discussed in this section. Level 1 factors—It is well known that SNV DA neurons are more vulnerable to PD than other DA neurons, even those in SND, so biomarkers that are dominantly expressed in SNV may be

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Fig. 2. Three types of factors and proteins that differentiate the subgroups of A9 and A10 neurons. Three types of factors and proteins that have been identified in different A9 and A10 neurons include those concentrating in SNV versus SND (1), those concentrating in SNC versus VTA (2), and those exclusively found in VTA (3) (A; references as shown in main text). An intermediate level of human midbrain, where the third nerve roots emerge (modified from McRitchie et al., 1996), is used for interpreting the distribution of representative proteins that are dominantly expressed in SNC or VTA (B; McRitchie et al., 1996; Liu et al., 2014; Panman et al., 2014). The percentage of pigmented cell loss reported from quantification studies as well as the pattern of cell loss in PD SNC (Fearnley and Lees, 1991; Halliday et al., 1996; Parkkinen et al., 2011) and VTA (McRitchie et al., 1997) are presented in (C). Abbreviations: 3n, the third nerve root; R: red nucleus; cp, cerebral peduncle.

particularly relevant to interpret the biological reason of the cellular vulnerability. ‘Deleted in colorectal cancer’ (DCC) is the receptor for the trophic factor netrin and it was considered to be a useful marker for the population of SNC DA neurons (Osborne et al., 2005). In humans, the mRNA content of DCC in SNC is higher than in the VTA and a larger proportion of SNV DA neurons contain high DCC expression compared to DA neurons of VTA and SND (Reyes et al., 2013b), suggesting that the DCC protein level may help distinguish DA populations with different vulnerability. Polymorphisms in the genes encoding netrin-1 and DCC are associated with a loss of function and increased susceptibility to develop PD (Lesnick et al., 2007; Lin et al., 2009). A loss of trophic factor function is likely to have a significant impact on neurons requiring high maintenance of axonal and dendritic structural integrity, like SNV neurons. Aldh1a1 is a protective factor that is strongly expressed in human SNV (Liu et al., 2014). In PD its expression is substantially reduced in DA neurons located in SNV (Liu et al., 2014) and Aldh activity is decreased by 70% in PD putamen (Goldstein et al., 2013). The physiological functions of Aldh1a1 include the metabolism of retinol to retinoic acid (Perlmann, 2002) and detoxifying DOPAL to DOPAC (Marchitti et al., 2007), indicating that in PD DOPAL detoxification by Aldh is compromised (Goldstein et al., 2013). Using stereological counting, the in vivo neurotoxicity of DOPAL has been confirmed in rats (Panneton et al., 2010) and retinoic acid-loaded polymeric nanoparticles are found to be neuroprotective in a PD mouse model (Esteves et al., 2015). Although meta-analysis has so far proved inconclusive, decreased blood levels of vitamin A may be associated with an increased risk of PD (Takeda et al., 2014). Taken together, the dominant expression of Aldha1a1 in the most vulnerable DA subregion may infer a pathway for the development of potential PD treatments. Moreover, quantitative RT-PCR mRNA measurements of peripheral blood samples from PD patients and controls have identified reduced Aldh1a1 expression as a promising peripheral biomarker for sporadic PD (Grünblatt et al., 2010). Level 2 factors—A number of DA factors are proposed to be involved in PD. a-Synuclein suppresses TH activity (and therefore DA production) via regulating its phosphorylation (Salvatore and Pruett, 2012; Tabrez et al., 2012; Zhu et al., 2012). In DA neurons requiring higher rates of DA production/usage, this is likely to have an effect. However, cellular deficiency in GTP cycloydrolase 1

(GTPCHI), an enzyme essential for the production of DA in SN, predisposes to nigrostriatal cell loss (Mencacci et al., 2014). GTPCH1 mRNA expression seems to be stronger in the dorsal part of SNC and VTA compared to the signal intensity in SNV (http:// mouse.brain-map.org/, observed on 16 May 2015; Lein et al., 2007), potentially providing a DA associated risk factor for more selective neurodegeneration in SNV. On the other hand, the SNV also contains the highest proportion of regional DA neurons expressing strong glycosylated DAT (mature and highly functional version of DAT) (Reyes et al., 2013a), suggesting that recycling of DA through DAT uptake may make up for any reduced cellular production of DA in SNV neurons compared to SND and VTA neurons. Imbalance in these mechanisms is likely to predispose initially to subregional dysfunction of SN neurons, and over time may have more detrimental consequences. SNC has disproportionately more DA neurons expressing strong D1/2 receptors and VMAT than VTA neurons (Reyes et al., 2013a). D2/3 receptors are primarily inhibitory autoreceptors on DA neuron (Jang et al., 2011), the activation of which inhibits self-firing of DA neurons and the release of DA. In PD, elevated mRNA levels of D2 receptor and GIRK2 were found (Dragicevic et al., 2014), indicating the remaining DA neurons are low producers. Somatodendritic D2 autoreceptors are coupled to GIRK2 channels to reduce activity and excitability of SN-DA neurons in response to extracellular DA (Gantz et al., 2013; Dragicevic et al., 2014; Ford, 2014). The first study to quantify the variability of GIRK2 expression in these human DA subgroups has shown the proportion of high expression of this channel in SNC is larger than that of the VTA (Reyes et al., 2012). Reduced extracellular DA may impact disproportionately on SNV DA neurons, as discussed above. SNC DA neurons of adult mice rely more on L-type Cav1.3 calcium channels to drive their rhythmic pace than those in juveniles, and blocking Cav1.3 induces a reversion to the juvenile form of pacemaking that relies on voltage-dependent sodium channels (Chan et al., 2007). Cav1.3 mediated pacemaking induces calcium influx and increases both DA production and oxidative stress, which collaboratively contribute to increased vulnerability of SNC DA neurons to degeneration (Surmeier, 2009). Cav1.3 in SN DA neurons may also function to modulate D2-autoreceptor responses (Dragicevic et al., 2014). There are no histological data that compare the distributional pattern and/or intensity of Cav1.3 in human SN and VTA DA neurons. In PD, there is a relative

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increase in Cav1.3 throughout the brain resulting in an altered average ratio of the subtypes of this ionic channel (Hurley et al., 2013). Level 3 factors—Calbindin-28KD is involved in calcium buffering and intraneuronal calcium homeostasis. A study in rats suggests that calbindin might control DA release (Pan and Ryan, 2012). Both aspects point to a protective role for calbindin in DA neurons. Although VTA neurons mainly rely on sodium rather than calcium channel regulation (Khaliq and Bean, 2010), the expression of calbindin in VTA DA neurons may provide additional protection. 4.3. Connections of the SNC and VTA DA neurons VTA DA neurons have been implicated in reward, aversion, salience, cognition, and several neuropsychiatric disorders (Lammel et al., 2015). Using TH-Cre transgenic mice, Ilango and colleagues found that the excitation and inhibition of SNC DA neurons elicit positive and negative affective effects, respectively, similar to those of VTA DA neurons (Ilango et al., 2014). This observation suggests that SNC DA neurons may be functionally busier in sending outputs than previously understood. It has been hypothesised that degenerating neurons, irrespective of the neurotransmitter type, are poorly myelinated, have long fine axons that connect different brain regions and have large axonal fields (Braak and Del Tredici, 2004). In rats, individual SNC DA neuron possess widely spread and highly dense axonal arborization in the neostriatum and exert strong influence over a large number of striatal neurons (Matsuda et al., 2009). SNC DA neurons are estimated to form larger axonal arbors and higher number of synapses than VTA DA neurons, therefore it is reasonable to speculate that SNC DA neurons have a higher energy demand and are likely more vulnerable to mitochondronial dysfunction (Prensa and Parent, 2001; Matsuda et al., 2009; Surmeier et al., 2010; Bolam and Pissadaki, 2012). In addition, SN DA neurons have a specific propensity to accumulate substantial amounts of mitochondrial DNA deletions, regardless of the underlying clinical phenotype (Bender et al., 2008). Although no firm conclusion can be drawn on whether mitochondrial gene deletions and smaller mitochondrial mass are two contributors to the SNC DA vulnerability to PD, the higher energy demand of the SNC DA neuronal axon arborization certainly makes these neurons easily affected by mitochondrial dysfunction or a shortage of energy supply. Healthy primary neurons secret a-synuclein, but this secretion is increased under stress conditions, such as mitochondrial dysfunction and oxidative stress (Jang et al., 2010; Lee et al., 2013). It was postulated that cells can recoginise misfolded or damaged a-synuclein that is prone to intracellular aggregation and selectively translocate them into vesicles (Lee et al., 2014). If SNC DA neurons are prone to more oxidative stress and mitochondronial dysfunction, they are likely to have a-synuclein accumulation. A comprehensive list of the brain areas that provide direct inputs to the SN and VTA has been reported in a mouse study that used Cre/LoxP system combined with rabies virus-based transsynaptic retrograde tracing (Watabe-Uchida et al., 2012). This study reveals that both SNC and VTA DA neurons receive a distinct set of inputs from a considerable number of brain areas. Further questions on whether these different inputs convey potential negative or positive signals to recipient neurons needs to be addressed to determine if connectivity is partly responsible for the different cell fate of the subpopulations of DA neurons in PD. 4.4. DA versus non-DA neurons in the SN The SNV is the subregion of SNC most severely affected early in PD. Interestingly, SNV DA neurons are embedded in the SNR which

is comprised of non-DA neurons, leading to the question of whether SNR neurons influence their vulnerability. In humans, caudal SNV DA neurons can be seen sending long dendritic extensions into the SNR neurons (McRitchie et al., 1996). The dendritic release of DA is likely to interact with D1 receptors on striato-nigral and pallido-nigral afferents innervating SNR neurons and therefore indirectly regulate their activity (Windels and Kiyatkin, 2006). Reciprocally SNR GABAergic neurons mediate the firing pattern of SN DA neurons to pallido-nigral afferents (Celada et al., 1999). Stereological counting has revealed no actual cell loss in the SNR in PD, although there is decreased parvalbuminimmunoreactivity by end stage disease (Hardman et al., 1996) indicating that SNR neurons change their activity pattern and calcium buffering capacity in PD. Compared to the SNC and VTA regions, SNR contains more densely packed microglia (our observations in aged mice and humans) which has been reported to increase degeneration to any toxin exposures (e.g., manganese) (Block et al., 2005; Verina et al., 2011). SNR is strongly immunopositive for substance P (McRitchie et al., 1996), and recently it was found that the mice lacking endogenous substance P were more resistant to inflammatoryrelated and toxin-induced PD pathological changes than their wild-type controls (Wang et al., 2014). In addition, microglial NADPH oxidase mediates the neuroinflammatory and DA neurodegenerative effects of the substance P (Wang et al., 2014). Clearly, SNR is a region busy with harboring inflammation activity-related signals. The SNV DA neurons that send long dendrites into the SNR may be more exposed to these detrimental signals, and more research on the interactions between SNR and SNC neurons is required. 5. SNC in aging and PD Aging research has shown that many people without evidence of significant functional deficits harbor age-related cellular changes in the brain. In fact a very small proportion of people in their early teens are now known to have cellular changes seen more commonly with age (Braak et al., 2011) and disease/ pathological concepts have progressed to identify people with age-related lesions as having prodromal or preclinical disease, rather than just normal aging (Dubois et al., 2014). Previous studies suggested a decrease in SNC DA neuronal number in aged human brains (Fearnley and Lees, 1991; Anglade et al., 1997; Ma et al., 1999; Cabello et al., 2002; Stark and Pakkenberg, 2004; Rudow et al., 2008; Reeve et al., 2014). The results of these studies now need to be revisited in this context, as it is highly likely that many aged cases assessed would now be considered to have preclinical aspects of age-related diseases. This also applies to recent metaanalysis of human brain transcriptomic data from cases not screened for prodromal disease effects (Glaab and Schneider, 2015). Such data suggest shared pathways and network alterations in aging and PD, implicating aging as a primary risk factor for developing idiopathic PD (Glaab and Schneider, 2015) and it may be that increasing age-associated prodromal disease may impact on the expression of PD in susceptible people. Glaab and Schneider pointed out that the observed changes in aging and PD include mitochondrial dysfunction, disruption of lysosomal function and apoptosis, neuroninflammation, metal ion homeostasis, affected synaptic vesicle endocytosis, and phosphatidylinositol metabolism (for their map of significant genes onto a cellular process map specific for aging and PD see their publicly available online link; (Glaab and Schneider, 2015; http://minerva.uni.lu/MapViewer/ map?id=pdmap-ageing). In contrast, some previous studies have shown that the number of neuromelanin containing SN neurons is generally stable with increasing age, but there is a loss of TH and Nurr1 protein expression, indicating a phenotypic change instead

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of a real age-associated SN neuron loss (Chu et al., 2002). SN DA neurons hypertrophy with age, whereas in PD SN DA neurons atrophy (Rudow et al., 2008). This suggests that normal aging SNC neurons increase cellular capacities for some but not all ageassociated changes, while in PD this cellular compensation does not occur. These data are more consistent with non-human primate studies of aging (see review in Collier et al., 2011). It remains to be determined how this aging phenotypic SN change influences the other cellular transcriptional changes identified in the SN (Glaab and Schneider, 2015). 6. Concluding remarks The studies of factors and proteins involved in the differentiation of both the structural architecture and biological characteristics of different populations of DA neurons have identified many candidates that perform survival and protective roles, and factors that could influence pathological processes such as PD. These factors can be influenced through pharmacological approaches that change their expression and strengthen the function of remaining SNC DA neurons under any toxic attack, energy deficiency, or other negative influence that would induce a pathological process. These biological differences are still poorly defined in human A9 and A10 neurons. With the accumulating knowledge obtained from studies on mice and the advance of new biological techniques to reveal gene profiles more efficiently, human studies will lead to more direct explanations to these underpinning mechanisms. Conflict of interest The authors declare that they have no conflict of interest. Acknowledgements GH and GP are National Health and Medical Research Council of Australia (NHMRC) Senior Principal Research Fellows (NHMRC APP1079679 and NHMRC APP1043626). This work was supported by the Australian Research Council Centre of Excellence for Integrative Brain Function (ARC Centre Grant CE140100007) and by NHMRC Project Grants (NHMRC APP1086643, APP1086083). References Alvarez-Fischer, D., Fuchs, J., Castagner, F., Stettler, O., Massiani-Beaudoin, O., et al., 2011. Engrailed protects mouse midbrain dopaminergic neurons against mitochondrial complex I insults. Nat. Neurosci. 14, 1260–1266. doi:http://dx. doi.org/10.1038/nn.2916. Ang, S.L., 2006. Transcriptional control of midbrain dopaminergic neuron development. Development 133, 3499–3506. doi:http://dx.doi.org/10.1242/ dev.02501. Anglade, P., Vyas, S., Hirsch, E.C., Agid, Y., 1997. Apoptosis in dopaminergic neurons of the human substantia nigra during normal aging. Histol. Histopathol. 12, 603–610. Aubert, I., Brana, C., Pellevoisin, C., Giros, B., Caille, I., et al., 1997. Molecular anatomy of the development of the human substantia nigra. J. Comp. Neurol. 379, 72–87. Aumann, T.D., Egan, K., Lim, J., Boon, W.C., Bye, C.R., et al., 2011. Neuronal activity regulates expression of tyrosine hydroxylase in adult mouse substantia nigra pars compacta neurons. J. Neurochem. 116, 646–658. doi:http://dx.doi.org/ 10.1111/j.1471-4159.2010.07151.x. Baker, H., Joh, T.H., Reis, D.J., 1980. Genetic control of number of midbrain dopaminergic neurons in inbred strains of mice: relationship to size and neuronal density of the striatum. Proc. Natl. Acad. Sci. U. S. A. 77, 4369–4373. Bayer, S.A., Wills, K.V., Triarhou, L.C., Ghetti, B., 1995. Time of neuron origin and gradients of neurogenesis in midbrain dopaminergic neurons in the mouse. Exp. Brain Res. 105, 191–199. Bender, A., Schwarzkopf, R.M., Mcmillan, A., Krishnan, K.J., Rieder, G., et al., 2008. Dopaminergic midbrain neurons are the prime target for mitochondrial DNA deletions. J. Neurol. 255, 1231–1235. doi:http://dx.doi.org/10.1007/s00415-0080892-9. Bergman, O., Hakansson, A., Westberg, L., Belin, A.C., Sydow, O., et al., 2009. Do polymorphisms in transcription factors LMX1A and LMX1B influence the risk

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