Striatal Axons Research Articles

Basal ganglia dopamine loss due to defect in purine recycling

Several rare inherited disorders have provided valuable experiments of nature highlighting specific biological processes of particular importance to the survival or function of midbrain dopamine neurons. In both humans and mice, deficiency of hypoxanthine-guanine phosphoribosyl transferase (HPRT) is associated with profound loss of striatal dopamine, with relative preservation of other neurotransmitters. In the current studies of knockout mice, no morphological signs of abnormal development or degeneration were found in an exhaustive battery that included stereological and morphometric measures of midbrain dopamine neurons, electron microscopic studies of striatal axons and terminals, and stains for degeneration or gliosis. A novel culture model involving HPRT-deficient dopaminergic neurons also exhibited significant loss of dopamine without a morphological correlate. These results suggest that dopamine loss in HPRT deficiency has a biochemical rather than anatomical basis and imply that purine recycling to be a biochemical process of particular importance to the function of dopaminergic neurons.

Selective enrichment of DJ‐1 protein in primate striatal neuronal processes: Implications for Parkinson's disease

Mutations in DJ-1 cause autosomal recessive, early-onset Parkinson's disease (PD). The precise function and distribution of DJ-1 in the central nervous system remain unclear. In this study, we performed a comprehensive analysis of DJ-1 expression in human, monkey, and rat brains with antibodies that recognize distinct, evolutionarily conserved epitopes of DJ-1. We found that DJ-1 displays region-specific neuronal and glial labeling in human and nonhuman primate brain, sharply contrasting with the primarily neuronal expression pattern observed throughout rat brain. Further immunohistochemical analysis of DJ-1 expression in human and nonhuman primate brains showed that DJ-1 protein is expressed in neurons within the substantia nigra pars compacta and striatum, two regions critically involved in PD pathogenesis. Moreover, immunoelectron microscopic analysis revealed a selective enrichment of DJ-1 within primate striatal axons, presynaptic terminals, and dendritic spines with respect to the DJ-1 expression in prefrontal cortex. Together, these findings indicate neuronal and synaptic expression of DJ-1 in primate subcortical brain regions and suggest a physiological role for DJ-1 in the survival and/or function of nigral-striatal neurons.

Differentiation and transcription factor gene therapy in experimental parkinson's disease: sonic hedgehog and gli-1, but not Nurr-1, protect nigrostriatal cell bodies from 6-OHDA-induced neurodegeneration

We tested the activity of the dopaminergic neuron differentiation factor sonic hedgehog, its downstream transcription factor target Gli-1, and an orphan nuclear receptor, Nurr-1, necessary for the induction of the dopaminergic phenotype of nigrostriatal neurons, in an in vivo model of nigrostriatal neurodegeneration. Our preliminary experiments demonstrated that all three constructs expressed the proper molecules and that these had the predicted biological activities in vitro. We expressed the N-terminal of sonic hedgehog (ShhN) and the Gli-1 and Nurr-1 entire coding regions from highly purified, and quality controlled, replication-defective adenoviral vectors injected into the brains of rats and used the dopaminergic growth factor GDNF as a positive control. The neurotoxin 6-hydroxydopamine was used to lesion the nigrostriatal dopaminergic innervation; RAd-ShhN and RAd-Gli-1 protected dopaminergic neuronal cell bodies in the substantia nigra, but not axonal terminals in the striatum, from 6-OHDA-induced cell death, while RAd-Nurr-1 was ineffective in protecting either cell bodies or axons. RAd-GDNF was able to protect both the dopaminergic cell bodies and the striatal axon terminals. Our results establish for the first time, to the best of our knowledge, that gene transfer of ShhN and one of its target transcription factors can selectively protect dopaminergic nigrostriatal neuronal cell bodies from a specific neurotoxic insult. Selective protection of nigrostriatal dopaminergic cell bodies by the differentiation factor ShhN and the transcription factor Gli-1 was achieved in a neurotoxic model that eliminates more than 70% of the nigral neurons under consideration. Differentiation and transcription factors can thus be used for the treatment of neurodegeneration by gene therapy.

Age-dependent synuclein pathology following traumatic brain injury in mice

Synucleins (Syn), a family of synaptic proteins, includes α-Syn, which plays a pivotal role in Parkinson’s disease and related neurodegenerative diseases (synucleinopathies) by forming distinct brain pathologies (Lewy bodies and neurites). Since traumatic brain injury (TBI) is a poorly understood risk factor for Parkinson’s disease, we examined the effects of TBI in the young and aged mouse brain on α-, β-, and γ-Syn. Immunohistochemical analysis showed that brains from sham-injured young and aged mice had normal α- and β-Syn immunoreactivity (IR) in neuropil of cortex, striatum, and hippocampus with little or no γ-Syn IR. At 1 week post TBI, the aged mouse brain showed a transient increase of α- and β-Syn IR in the neuropil as well as an induction of γ-Syn IR in subcortical axons. This was associated with strong labeling of striatal axon bundles by antibodies to altered or nitrated epitopes in α-Syn as well as by antibodies to inducible nitric oxide synthase. However, these TBI-induced changes disappeared by 16 weeks post TBI, and altered Syn IR was not seen in young mice subjected to TBI nor in α-Syn knockout mice while Western blots confirmed that TBI induced transient alterations of α-Syn in the mouse brains. This model of age-dependent TBI-induced transient alterations in α-Syn provides an opportunity to examine possible links between TBI and mechanisms of disease in synucleinopathies.

Effects of dynorphin on rat entopeduncular nucleus neurons in vitro

The entopeduncular nucleus (EP) receives dense neostriatal afferent axons that contain dynorphin (DYN, an endogenous κ-receptor agonist), in addition to GABA and substance P. To examine the role of DYN in the EP, whole-cell recordings were performed in rat brain slice preparations. Based on the physiological and morphological characteristics, all the neurons recorded were similar to the Type-I EP neuron described in a previous study. The κ-receptor agonist dynorphin A (1-13) (DYN13) hyperpolarized and decreased the input resistance of approximately one-quarter of the EP neurons examined. The hyperpolarization was due to an increase in potassium conductance since current–voltage relationship curves obtained before and after DYN13 application crossed at the potassium equilibrium potential. In the presence of the glutamate blocker 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide and 3-(2-carboxypiperzin-4-yl)-propyl-1-phosphonic acid in artificial cerebrospinal fluid, stimulation of the globus pallidus evoked bicuculline-sensitive multi-component GABAergic responses in EP neurons. Application of DYN13 equally reduced the amplitudes of the short-latency response, conceivably evoked by pallido-EP axons, and the medium-latency response, conceivably evoked by striato-EP axons. These effects were reversed by bath application of a non-selective opioid antagonist naloxone or by a κ-opioid receptor-selective antagonist nor-binaltorphimine dihydrochloride (nor-BNI), but not by the ∂-antagonist naltrindole or the μ-antagonist D-Phe-Cys-Tyr- D-Trp-Orn-Thr-Pen-Thr-NH 2. DYN13 also reduced the frequency of tetrodotoxin-insensitive miniature-inhibitory postsynaptic potential (mIPSPs) without changing their amplitude distributions. The decrease of the frequency of mIPSPs was reversible upon washing and was also completely blocked by nor-BNI. The results of the present study on the EP indicated that DYN released from striatal axons might exert at least three different effects on these target nuclei. Firstly, DYN might provide negative feedback regulation of striatal GABAergic outputs at their termination sites. Secondly, DYN released from the striatal terminals might diffuse to the pallidal terminals, regulating their GABA release. Thirdly, DYN might exert a direct inhibition of EP neurons. Thus, DYN released from striatal axons might control the activity of EP neurons by reducing the GABAergic transmission and also by hyperpolarizing postsynaptic membrane.

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

Axons from dorsal/ventral tiers of substantia nigra pars compacta (SNc), ventral tegmental area (VTA), and retrorubral field (RRF) were traced after injecting their cell body with biotinylated dextran amine. Fifty-three single axons were reconstructed from serial sagittal sections with a camera lucida, and mu-opiate receptor immunostaining served to differentiate the striosome/matrix striatal compartments. Most dorsal tier SNc axons terminate within the matrix of the dorsal striatum, but their patterns of arborization vary markedly; some axons innervate one specific matriceal area, whereas others arborize in multiple discontinuous loci. Some dorsal tier SNc axons also project to both striosomes and matrix. Other dorsal tier SNc axons, as well as VTA axons, innervate the ventral striatum and send collaterals to striosomes lying ventrally in the dorsal striatum or to the ventral sector of the subcallosal streak (SS). Ventral tier SNc axons arborize principally in striosomes, but some ramify in both compartments or in striosomes and the SS. Ventral tier neurons that form deep clusters in substantia nigra pars reticulata innervate principally the matrix and the SS. The amygdala and ventral pallidum receive secondary collaterals from striatal axons of dorsal/ventral tier neurons or RRF neurons. The subthalamic nucleus receives collaterals from striatal axons of SNc clustered neurons, whereas the globus pallidus gets collaterals from striatal axons of dorsal/ventral tier SNc neurons. These findings reveal that the nigrostriatal pathway is composed of several neuronal subsystems, each endowed with a widely distributed axonal arborization that allows them to exert a multifaceted influence on striatal and/or extrastriatal structures.

5-HT1B receptors modulate release of [3H]dopamine from rat striatal synaptosomes.

The effect of the selective r5-HT1B agonist 3-(1,2,5,6-tetrahydro)-4-pyridil-5-pyrrolo [3,2-b] pyril-5-one (CP93,129) on the K(+)-evoked overflow of [3H]dopamine was studied in rat striatal synaptosomes loaded with [3H]dopamine. The aim of the study was to investigate the participation of 5-HT1B receptors in the serotonergic modulation of striatal dopaminergic transmission. The Ca2(+)-dependent, tetrodotoxin-resistant K(+)-evoked overflow of [3H]dopamine was inhibited by CP93,129 (0.01-100 microM) in a concentration-dependent manner (IC50=1.8 microM; maximal inhibition by 35.5% of control). [+/-]8-OH-DPAT, a 5-HT(1A) receptor agonist, [+/-]DOI, a 5-HT2 receptor agonist, and 2-methyl-5-hydroxytryptamine, a 5-HT3 receptor agonist, at concentrations ranging from 0.01 microM to 100 microM did not show any significant effect. Neither ketanserin (1 microM and 5 microM), a selective 5-HT2/5-HT1D receptor antagonist, nor ondansetron (1 microM), a 5-HT3 receptor antagonist, changed the inhibitory effect of CP93,129. SB224289, GR55562, GR127935, isamoltane and metergoline, selective and non-selective 5-HT1B receptor antagonists, in contrast, used at a concentration of 1 microM, antagonized the inhibitory effect of CP93,129 (3 microM and 10 microM). SB224289, a selective 5-HT1B receptor antagonist, inhibited the effect of CP93,129 in a concentration-dependent manner; the calculated K(i) value was 1.8 nM. Our results indicate that in rat striatal axon terminals the K(+)-evoked release of dopamine is regulated by the presynaptic 5-HT1B heteroreceptors.

Vesicular monoamine transporter‐2: Immunogold localization in striatal axons and terminals

The vesicular monoamine transporter-2 (VMAT2) mediates the reserpinesensitive neuronal uptake of monoamines into vesicles and other intracellular organelles. Accordingly, this transporter is expressed at high levels in regions that contain a dense monoamine innervation, such as the rat dorsolateral striatum. We used ultrastructural immunocytochemistry in this region to show that immunogold labeling for VMAT2 is present in varicose axonal processes, many of which also contain the catecholamine-synthesizing enzyme tyrosine-hydroxylase. Within these mainly dopaminergic processes, VMAT2 was associated with small synaptic vesicles (SSVs) and more rarely with large dense-core vesicles or tubulovesicles. These findings suggest that SSVs are the major organelles involved in the storage and release of dopamine in the dorsolateral striatum. Synapse 26:194–198, 1997. © 1997 Wiley-Liss, Inc.

Vesicular monoamine transporter-2: immunogold localization in striatal axons and terminals.

The vesicular monoamine transporter-2 (VMAT2) mediates the reserpine-sensitive neuronal uptake of monoamines into vesicles and other intracellular organelles. Accordingly, this transporter is expressed at high levels in regions that contain a dense monoamine innervation, such as the rat dorsolateral striatum. We used ultrastructural immunocytochemistry in this region to show that immunogold labeling for VMAT2 is present in varicose axonal processes, many of which also contain the catecholamine-synthesizing enzyme tyrosine-hydroxylase. Within these mainly dopaminergic processes, VMAT2 was associated with small synaptic vesicles (SSVs) and more rarely with large dense-core vesicles or tubulovesicles. These findings suggest that SSVs are the major organelles involved in the storage and release of dopamine in the dorsolateral striatum.

A spatial and quantitative study of the striatopallidal connection in the monkey.

The striatopallidal connection was quantitatively analysed after three-dimensional reconstruction of biocytin-labelled striatal axons. A small striatal region gave rise to one or two elongated bands in each of the pallidal nuclei. Each band consisted of dense axonal plexuses and short axonal arborizations with few branches. Individual axons generally terminated in one band, giving a low density of varicosities on dendrites (10 per 100 microns length). This suggests that the striatopallidal connection can distribute the same striatal information to different remote pallidal regions which can in turn integrate information from different remote striatal regions. Corticostriatal information could thus be preserved or completely transformed according to the size and location of the striatal region activated.

Host striatal projections into fetal ventral mesencephalic tissue grafted to the striatum of immature or adult rat.

We have previously reported that few striatal axons from adult host brain innervate intrastriatal grafts of fetal ventral mesencephalic tissue. To see whether the immature rat brain would favor striatal innervation of the graft, unilateral implantation of fetal ventral mesencephalic tissue was carried out at 7 (P7), 14 (P14), or 60 (adults) days of age in neonatally dopamine-(DA)-lesioned and nonlesioned rats. Immunocytochemistry for tyrosine hydroxylase (TH), and/or dopamine- and adenosine 3',5'-monophosphate-regulated phosphoprotein-32 (DARPP-32) was performed 2-6 months later. In the great majority of immature and in all adult recipients, the resulting graft consisted of a distinct intrastriatal mass of tissue surrounded by the host parenchyma. Most TH-immunopositive neurons were found within the confines of such grafts, although some were lying at short distances into the host striatal tissue, particularly in immature recipients. In a few immature recipients, there was, however, extensive intermingling of TH-positive neurons with the adjacent host brain tissue. In all recipients grafted at P7, P14, or as adults, the distinct, intraparenchymal grafts contained moderate numbers of DARPP-32-positive processes, mainly at their periphery. These results indicate that the limited capacity of host striatal neurons to grow axons into transplanted fetal ventral mesencephalic tissue is not markedly different in young versus adult rats. A better integration of the ventral mesencephalic graft into the striatal circuitry of immature--as opposed to adult--recipients should therefore rely more on the higher tendency of DA neurons to become located into the host tissue following transplantation in young rats.

Chapter 10 Chemical signalling and striatal interneurones

Publisher Summary The majority of neostriatal neurones are mediumsized spiny neurones, which have diameters between 10 and 20 pm. These cells were originally believed to be interneurones; however, retrograde transport studies established them as projection neurones. Parallel studies showed that GABA inhibition (or more strictly disinhibition) controls the majority of the functional activity in the basal ganglia. In addition to the medium-sized spiny cells, the larger aspiny cells, 20–60 pm diameters, constitute some 4%– 5 % of all striatal neurones, and these are now known to be short axoned interneurones, although there are occasional reports of aspiny projection neurones. These interneurones integrate activity between output pathways through the striatum providing feed forward and feedback loops. In addition, interneurones may represent relatively specific targets for cortical or thalamic inputs. This chapter discusses some of the recent work exploring the phenotypes of striatal interneurones and present evidence indicating that nitric oxide may be a novel intercellular messenger in the striatum modulating the effects of glutamate on N-methyl-D-aspartate (NMDA) receptors expressed by striatal neurones. Stimulation of NMDA receptors in vivo activates local acetylcholine (ACh) release as does local application of substance P and substance P agonists. The exquisite sensitivity of cholinergic neurones to substance P and NMDA suggests that these neurones represent an important target both for local striatal axon collaterals containing substance P, and thalamic excitatory inputs releasing glutamate.

Interactions Between MPTP-Induced and Age-Related Neuronal Death in a Murine Model of Parkinson’s Disease

Abiotrophy is hypothesized to explain the onset and time course of deficits in Parkinson's disease (PD) Abiotrophy includes: 1) exposure to agent(s) causing the death of dopaminergic nigrostriatal neurons (DNSns), 2) gradual death of DNSns with age, 3) summation of 1) and 2) until DNSn numbers fall below a threshold for detectable neurological deficits. Murine DNSn death following methyl-phenyl-tetrahydropyridine (MPTP) exposure occurs according to an exponential relationship while age-related death of DNSns occurs according to a second exponential relationship. Summing the two exponential losses overestimates experimental DNSn death showing a simple abiotrophic model is not sufficient. Aged murine DNSns greatly increase their dopamine synthesis and the density of their striatal axon terminals which may explain the above threshold. Murine DNSns die gradually after MPTP exposure and L-deprenyl treatment rescues MPTP-damaged DNSns by a previously undiscovered action, altering the abiotrophic interactions and possibly explaining the slowed progression of PD found with deprenyl treatment.

Time course of MPTP-induced degeneration of the nigrostriatal dopamine system in C57 BL/6 mice

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a parkinsonism-inducing dopamine (DA) neurotoxin most effective in primates MPTP also causes a degeneration of both perikarya and axon terminals of the nigrostriatal DA neurons in C57 BL/6 mice. The time courses of the changes in tyrosine hydroxylase immunoreactive objects, endogeneous DA concentrations and specifically bound 3H-mazindol as markers of the integrity of DA neurons were studied in substantia nigra and striatum of adult C57 BL/6 mice, after systemic treatment with MPTP or intranigral injections of the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA). A rapid decrease in the three parameters studied was found in the substantia nigra during the first 2 days after MPTP-treatment while the MPTP-induced effects in the striatum were more protracted and maximal reduction was observed 7 days after MPTP. A basically similar pattern was found when studying the 6-OHDA-induced anterograde degeneration of the nigrostriatal system. These results indicate that in C57 BL/6 mice, MPTP primarily destroys the DAergic perikarya with a subsequent anterograde degeneration of the striatal axon terminals, although a limited rapid destruction of some striatal terminals cannot be excluded.

Striatal axons to the globus pallidus, entopeduncular nucleus and substantia nigra come mainly from separate cell populations in cat

The extent to which individual striatal neurons send collaterals to the globus pallidus, entopeduncular nucleus and substantia nigra in the cat brain was determined by double-retrograde tracing with rhodamine fluorescent latex microspheres in combination with either horseradish peroxidase or the fluorescent nuclear dye Diamidino Yellow. In each case, two of the three target nuclei were injected, each with a different tracer, until all three possible combinations of two had been obtained several times. In all cases in which the tracer encroaches upon a striatal target, there are cells labeled in the striatum of a size and shape that is consistent with the observation that they mainly belong to the category of medium striatal cells. Since the striatal projections to the globus pallidus, entopeduncular nucleus and substantia nigra are each topographically organized, the zones of cell-labeling within the striatum vary depending upon the portion of the target nucleus involved by the deposit. Thus, in many cases the fields of striatal cells containing one label overlap only slightly with those in which cells containing the other label occur. In other cases, however, there is extensive overlap of the striatal zones containing cells marked with either tracer. In all cases, very few double-labeled cells can be found, even where hundreds of cells labeled with either tracer are freshly intermingled. Doubly labeled cells occur somewhat more frequently in those cases where the tracers are placed in the entopeduncular nucleus and substantia nigra than in those with the other two combinations, suggesting that striatal axons branch more often to the entopeduncular nucleus and substantia nigra than to the globus pallidus and nigra or globus pallidus and entopeduncular nucleus These findings confirm, that, in the cat as in the primate, the striatal axons to the substantia nigra arise from cells that are largely separate from the striatopallidal population, and further show that the axons to the globus pallidus and entopenduncular nucleus also emanate mainly from different cells.

Evidence for the presynaptic localization of opiate binding sites on striatal efferent fibers

Using quantitative receptor autoradiography, [ 3H] d-Ala- d-Leu-enkephalin (DADL) and [ 3H]naloxone binding were studied in rat striatum and striatal projection areas (globus pallidus (GP) and substantia nigra pars reticulata (SN r)) after unilateral striatal kainic acid lesions. [ 3H]DADL and [ 3H]naloxone binding were each examined by two methods. Initially, [ 3H]DADL binding was performed in 50 mM Tris-HCl (pH 7.4), 30 mM NaCl, 3 mM manganese acetate and 2 μM GTP; [ 3H]naloxone binding was carried out in 50 mM Tris-HCl (pH 7.4) and 100 mM NaCl. Subsequent studies were carried out in 150 mM Tris-HCl (pH 7.4) and either [ 3H]DADL plus 500 nM morphiceptin (to block [ 3H]DADL binding to mu receptors) or [ 3H]naloxone plus 10 nM delta receptor peptide (to block [ 3H]naloxone binding to delta receptors). At one and eight weeks in the lesioned striatum, [ 3H]DADL binding was reduced by 70% and 82%, respectively, when compared to the control side. [ 3H]Naloxone binding was reduced by 35% and 20%. In GP and SN r, [ 3H]DADL binding was reduced by 31% and 41%, respectively, at one week and 27% and 26% at eight weekds. [ 3H]Nalaxone binding was reduced 19% in GP at eight weeks. A parsimonious explanation of these results is that opiate binding sites are located on presynaptic terminals of striatal efferent fibers to globus pallidus and substantia nigra pars reticulata as well as on local striatal axon collaterals. Since opiate peptides have recently been found to coexist with GABA in some striatal neurons, opiate peptides may play a role in striatal function by controlling GABA release from striatal efferent fibers. It is possible that pallidal and nigral opiate binding could be utilized as a marker for striatal terminals.

A Golgi analysis of the primate globus pallidus. II. Quantitative morphology and spatial orientation of dendritic arborizations

The morphology of pallidal neurons was analyzed quantitatively in Golgi-impregnated brains of men and macaques (Macaca irus). Selected neurons were drawn with a camera lucida and reconstructed from serial sections. Dendritic arborizations were analyzed in three dimensions using a video computer microscope (Yelnik et al., '81). Morphological (topological and metrical) parameters were computed, and the overall geometry of arborizations was studied in three dimensions with the aid of principal component analysis (Yelnik et al., '83). Statistical tests were used in order to compare human with simian large neurons and the lateral with the medial pallidum. All neurons were found to belong to a single neuronal population. Particular neurites may be added randomly onto pallidal dendrites, mainly in the lateral pallidum. Large pallidal neurons are characterized by sparsely branched dendritic arborizations (4 stems, 13 tips) with thick, smooth, and long dendrites (longest dendrite = 1,000 micron, total dendritic length = 7,600 micron). All arborizations are discoidal in shape with mean dimensions of 1,500 X 1,000 X 250 micron. Pallidal discs are always parallel to the lateral border of each pallidal nucleus and thus perpendicular to striatal axons to which they present their greatest extent. They may be traversed by a large number of these axons. The existence of other pallidal neuronal groups, "intermediate" and "local circuit" neurons, identified in their fine morphological features by François et al. ('84), was confirmed quantitatively in the present study.

A Golgi analysis of the primate globus pallidus. III. Spatial organization of the striato-pallidal complex.

An atlas of transverse sections of the globus pallidus and striatum was established in macaque with reference to ventricular coordinates. The three-dimensional geometry of the striato-pallidal complex was investigated by means of sagittal and horizontal reconstructions. Both a personal case studied with autoradiography and data from literature were used to analyze the distribution of cortical axons into the striatum. One may distinguish two striatal territories: one, somatotopically arranged, sensorimotor territory extending over the major part of the putamen; and the other, an associative territory, comprising the caudate nucleus and antero-medial and postero-inferior parts of the putamen. The striato-pallido-nigral bundle was studied using Golgi, Perls, and Fink-Heimer techniques. The bundle is described in four parts: prepallidal (subdivided into caudato-pallidal and putamino-pallidal subparts), transpallidal, pallido-nigral, and nigral. The tracing of the limit between the caudate (associative) and putaminal (essentially sensorimotor) territories shows that the two components are of roughly the same size in the pallidum. The data were compared with geometry and orientation of the dendritic arborizations of large pallidal neurons analyzed in Yelnik et al. ('84). Each pallidal dendritic disc is able to receive axons from a wide region of the striatum. This leads to a convergence on pallidal neurons of striatal axons from different striatal somatotopic strips and from the sensorimotor and associative territories. This is an indication that the globus pallidus may have an integrative role.

Intrinsic hazard of breech presentation

Axons from dorsal/ventral tiers of substantia nigra pars compacta (SNc), ventral tegmental area (VTA), and retrorubral field (RRF) were traced after injecting their cell body with biotinylated dextran amine. Fifty-three single axons were reconstructed from serial sagittal sections with a camera lucida, and μ-opiate receptor immunostaining served to differentiate the striosome/matrix striatal compartments. Most dorsal tier SNc axons terminate within the matrix of the dorsal striatum, but their patterns of arborization vary markedly; some axons innervate one specific matriceal area, whereas others arborize in multiple discontinuous loci. Some dorsal tier SNc axons also project to both striosomes and matrix. Other dorsal tier SNc axons, as well as VTA axons, innervate the ventral striatum and send collaterals to striosomes lying ventrally in the dorsal striatum or to the ventral sector of the subcallosal streak (SS). Ventral tier SNc axons arborize principally in striosomes, but some ramify in both compartments or in striosomes and the SS. Ventral tier neurons that form deep clusters in substantia nigra pars reticulata innervate principally the matrix and the SS. The amygdala and ventral pallidum receive secondary collaterals from striatal axons of dorsal/ventral tier neurons or RRF neurons. The subthalamic nucleus receives collaterals from striatal axons of SNc clustered neurons, whereas the globus pallidus gets collaterals from striatal axons of dorsal/ventral tier SNc neurons. These findings reveal that the nigrostriatal pathway is composed of several neuronal subsystems, each endowed with a widely distributed axonal arborization that allows them to exert a multifaceted influence on striatal and/or extrastriatal structures.