Striatopallidal Projection Neurons Research Articles

Expression of a dopamine D2 receptor-activated K+ channel on identified striatopallidal and striatonigral neurons.

One view of the efferent circuitry of the basal ganglia holds that dopamine D1 and D2 receptors are segregated to striatonigral and striatopallidal neurons, respectively. The present studies investigated whether functional D2-like receptors are, in fact, restricted to striatopallidal neurons. Single, freshly dissociated cells from rat striatum were identified as either striatonigral or striatopallidal projection neurons by fluorescence retrograde labeling. By using cell-attached patch-clamp recordings, neurons of each efferent group were evaluated for the presence of a D2-like receptor-activated 85-pS K+ channel as a measure of receptor function. We now report the presence of this D2 receptor-mediated response on both striatal efferent populations, but we observed an approximately 2-fold higher likelihood of encountering the channel on pallidal- versus nigral-projecting neurons. The channel's conductance properties appeared identical in both groups of neurons, but there was a significantly greater open probability for channels detected on striatopallidal neurons. These results indicate that functional D2 receptors are not segregated to striatopallidal neurons, but may be expressed in a higher proportion of, or at a higher density and/or efficiency of coupling on, pallidal- versus nigral-projecting striatal efferents.

Localization of mGluR1a-like immunoreactivity and mGluR5-like immunoreactivity in identified populations of striatal neurons

Metabotropic glutamate receptors are important mediators of excitatory amino acid neurotransmission in the striatum. Two-color immunofluorescence histochemistry and immunohistochemistry in combination with retrograde tract-tracing techniques were used to examine the distribution of metabotropic glutamate receptor subtypes 1a and 5 (mGluR1a and mGluR5) among identified subpopulations of striatal projection neurons and interneurons. The majority of striatopallidal and striatonigral neurons were double-labeled for both mGluR1a or mGluR5. Approximately 60% to 70% of either striatonigral or striatopallidal neurons expressed mGluR1a- or mGluR5-like immunoreactivity. The percentage of double-labeled striatopallidal or striatonigral projection neurons did not differ among striatal quadrants. Striatal interneurons expressing parvalbumin or somatostatin or choline acetyltransferase exhibited varying degrees of expression of mGluR1a or mGluR5. Virtually all (94%) parvalbumin-immunoreactive striatal neurons expressed mGluR1a-like immunoreactivity with a majority (79%) of these neurons expressing mGluR5-like immunoreactivity. A high percentage (89%) of striatal choline acetyltransferase-immunoreactive neurons were double-labeled for mGluR1a-like immunoreactivity. Approximately 65% of striatal choline acetyltransferase-immunoreactive neurons expressed mGluR5-like immunoreactivity. A majority (65%) of somatostatin-immunoreactive striatal interneurons expressed mGluR1a-like immunoreactivity with a slightly lower percentage (55%) expressing mGluR5-like immunoreactivity. These findings indicate considerable heterogeneity among striatal projection and interneurons with respect to mGluR1a and mGluR5 expression. There may be subpopulations of striatonigral and striatopallidal projection neurons. These results are consistent as well with prior data indicating subpopulations of the different classes of striatal interneurons.

Neural information transferred from the putamen to the globus pallidus during learned movement in the monkey.

1. We studied the physiology of the neuronal projection from the striatum to the external and internal segments of the globus pallidus (GPe and GPi, respectively) in macaque monkeys. The objective of the study was to answer the following specific questions. 1) Which classes of the electrophysiologically identified striate neurons project to GPe and GPi? 2) What kind of information is transferred from the striatum to GPe and GPi during learned movement? 3) What are the physiological actions of striate projection neurons on target neurons in GPe and GPi? 4) What is the spatial pattern of the striatopallidal projections? 2. Sequential arm and orofacial movements were used as behavioral tasks. Visual stimuli triggered a sequence of three flexions-extensions of the elbow joint across the target, and the click of a solenoid valve triggered repetitive licking movements. 3. Striatopallidal projection neurons were electrophysiologically identified by antidromic activation after focal stimulation of either GPe or GPi. Of two classes of striate neurons, tonically active neurons (TANs) with tonic spontaneous discharges (2-8 imp/s) and broad action potentials, and phasically active neurons (PANs) with a very low spontaneous discharge rate (< 0.5 imp/ s) and high-frequency discharges in relation to behavioral tasks, PANs were identified as the projection neurons to either GPe or GPi. In 325 TANs examined by stimulation of GPe or GPi, no neuron was activated antidromically, even in the case of TANs located in the close vicinity of PANs that were identified as striatopallidal projection neurons. 4. The physiologically identified projection neurons (52 cells) in the striatum exhibited either discharges related to movement (30 cells) or discharges related to preparation for movement (4 cells) during performance of learned motor tasks. The activities of the remaining 17 striatopallidal neurons either were not related to the behavioral tasks used or could not be characterized sufficiently in the tasks. However, all of the unidentified striatopallidal neurons were PANs, on the basis of the spontaneous discharge rate and the shape of the action potential. 5. PANs with movement-related activity and those with preparation for movement-related activity were antidromically activated from the globus pallidus (GP). Not only the PANs that show burst discharges specifically at the beginning of a sequence of movement but also PANs that show phasic discharges time-locked to each movement of a sequence were identified as putaminopallidal projection neurons. On the other hand, no neurons that showed responses to sensory stimulus were identified as putaminopallidal neurons. 6. The conduction velocities of the putaminopallidal axons were estimated at approximately 1 m/s on the basis of the latency of antidromic activation and conduction distance. The PANs with activity only at the beginning of a sequential movement were more frequently found to project to GPi than to GPe, whereas the PANs with burst activity at each movement were more frequently found to project to GPe than to GPi. Among the GPi-projecting PANs, neurons with initial activity only showed a tendency to have longer latencies of activation from GPi than neurons with activity time-locked to each movement. 7. The physiological action of the striatopallidal projection was examined by switching from recording to microstimulation after identification of striatopallidal projection neurons in the putamen while recording evoked field potentials or spike discharges of single GP neurons located where the electrical stimulation evoked antidromic activation of the striate neurons with the lowest threshold. A small majority of GP neurons that exhibited increase of discharges during motor tasks received facilitatory putaminopallidal influences, whereas the vast majority of GP neurons that exhibited decrease of discharges during motor tasks received suppressive putaminopallidal influences.

Human striatum: Chemoarchitecture of the caudate nucleus, putamen and ventral striatum in health and Alzheimer's disease

The morphology and distribution of perikarya positive for choline acetyltransferase, somatostatin, calcium binding protein (calbindin D 28K) and nicotinamide adenine dinucleotide phosphate diaphorase were surveyed in the human striatum. Choline acetyltransferase and somatostatin antibodies labeled separate populations of large striatal interneurons. Somatostatin immunoreactivity and nicotinamide adenine dinucleotide phosphate diaphorase (nitric oxide synthase) activity were completely co-localized. Calbindin antibody identified two distinct groups of striatal neurons: (1) numerous medium-sized, lightly stained neurons, probably analogous to striatopallidal projection neurons in the rat, and (2) much less numerous, large, darkly stained neurons. Half of the latter group, but none of the former, were also nicotinamide adenine dinucleotide phosphate diaphorase-positive. Somatostatin-positive and medium-sized, calbindin-positive neurons were more numerous in the caudate nucleus than in the putamen or ventral striatum. By contrast, large calbindin-immunoreactive neurons were more frequently encountered in the putamen. Choline acetyltransferase-positive neurons were evenly distributed across striatal components. In aged control subjects, the size of large, darkly stained calbindin-positive neurons was reduced relative to young subjects. Aging had no effect on somatostatin-, medium-sized calbindin-, or choline acetyltrans-ferase-positive neurons. However, in histologically confimed cases of Alzheimer's disease, there was a selective, 75% loss of choline acetyltransferase-immunoreactive perikarya from the ventral striatum, but not from the dorsal striatum, compared to aged controls. Furthermore, the remaining cholinergic neurons in the ventral striatum of Alzheimer's disease cases were significantly smaller than similar neurons in controls. These results indicate that various striatal components which have been shown to differ in their anatomical connectivity and functional specialization, also differ in their neurochemical signatures. The specific and marked loss of choline acetyltransferase-positive neurons from the ventral striatum in Alzheimer's disease is consistent with the characteristic cholinergic and ‘limbic’ pathology in this disease.

Differential Effects of Suicide Transport Lesions of the Striatonigral or Striatopallidal Pathways on Subsets of Striatal Neurons

In the basal ganglia, centrally active suicide transport agents produce apparently selective lesions of the striatopallidal and striatonigral pathways based on receptor binding and neuropeptide mRNA studies. In the present study we sought to determine the selectivity of suicide transport lesions for specific subsets of striatal neurons. Using immunohistochemical methods, the neostriata of adult rats were examined 10 days after an injection of volkensin into the substantia nigra or an injection of OX7-saporin into the globus pallidus, Ricin, a suicide transport agent active in the peripheral but not the central nervous system, was injected into each target as a control. Adjacent sections were processed for (1) Nissl stain to assess neuronal density, both overall and for large interneurons. (2) NADPH-diaphorase (NADPH-d) histochemistry, to mark medium-sized aspiny interneurons, (3) eukephalin immunocytochemistry, to label striatopallidal neurons, or (4) substance P immunocythochemistry, to label striatonigral neurons. Ricin injections produced no change in the densities of these subsets of striatal cells. In animals receiving volkensin or OX7-saporin injections, analyses of Nissl material revealed that the striata ipsilateral to the toxin injections appeared normal and did not exhibit shrinkage or gliosis; however, a quantitation analysis revealed a moderate decrease in cell density (12-16% loss, P < 0.01). The densities of both large and NADPH-d-containing striatal interneurons were unchanged after lesions in either target. Following nigral injections with volkensin, the density of striatal substance P-labeled cells decreased (26% loss, P < 0.01), while the density of enkephalin-labeled cells did not decrease significantly (11% decrease, P > 0.1). After pallidal injections with OX7-saporin, the density of striatal enkephalin-labeled cells decreased (20% loss, P < 0.01), while that of substance P-labeled cells remained unchanged. These data show that nigral volkensin and pallidal OX7-saporin injections differentially lesion striatonigral and striatopallidal projection neurons and spare striatal interneurons. This study provides further evidence for the selectivity, specificity, and utility of suicide transport agents to study brain structure and function.

Output architecture of the primate putamen

The basal ganglia act through direct and indirect striatopallidal output pathways that have different effects on cortical activity. This division has been proposed to underlie the fundamental distinction between hyperkinetic and hypokinetic movement disorders such as Parkinson's disease and Huntington's disease. Evidence to date does not favor a relationship between this dual organization and the division of the striatum into striosome and matrix compartments. However, the possibility has been raised that the division of striatopallidal output paths reflects a compartmentalization of the matrix itself into clusters of different striatopallidal projection neurons. We directly tested this hypothesis in squirrel monkeys by comparing the distributions of striatal output neurons retrogradely labeled from the two pallidal segments. Striatopallidal neurons labeled by small injections confined to either the external pallidum (GPe) or the internal pallidum (GPi) formed small clusters ("matrisomes") in the matrix compartment of the putamen. However, contrary to previous predictions, labeled matrisomes projecting to GPe were not systematically separated from those projecting to GPi. They could overlap extensively, and within individual matrisomes GPe-projecting neurons and GPi-projecting neurons were extensively intermixed. Double-retrograde labeling analysis in single sections demonstrated that only 2.1 +/- 2.7% of labeled striatal neurons were doubly labeled from both GPe and GPi--a number not significantly different from zero. GPe-projecting and GPi-projecting neurons in the putamen also differed sharply in their expression of enkephalin-like immunoreactivity: 71.3 +/- 7.6% of the neurons labeled by GPe injections were enkephalin positive, in contrast to 10.0 +/- 3.6% of the neurons labeled by GPi injections. These results suggest that in the primate, populations of striatopallidal output neurons are grouped in clusters in the matrix, but that individual neurons in any given cluster project either to GPe or to GPi. Matrisomal clustering may thus coordinate signals sent into the direct and indirect pathways of the basal ganglia from distributed populations of projection neurons in the striatum.

Cocaine self-administration differentially alters mRNA expression of striatal peptides

The influence of cocaine self-administration on the expression of messenger RNAs for dynorphin, enkephalin and substance P was analyzed in the rat striatum with in situ hybridization histochemistry. Cocaine, an indirect dopamine agonist, was found to differentially affect the levels of mRNA encoding these neuropeptides in different subregions of the striatum. Following a 7 day period of variable free access to cocaine, dynorphin and substance P mRNA levels were elevated throughout the striatum, but the increases were substantially greater in the dorsal striatum than in the nucleus accumbens. Enkephalin mRNA was not significantly altered in the dorsal striatum but was slightly elevated in the nucleus accumbens. These results suggest that cocaine self-administration has differential effects on striatonigral and striatopallidal projection neurons, and that these effects vary in subregions of the striatum.

Immunohistochemical localization of DARPP-32 in striatal projection neurons and striatal interneurons: implications for the localization of D 1-like dopamine receptors on different types of striatal neurons

Immunohistochemical double-label techniques were used to study the localization of DARPP-32, a phosphoprotein that is enriched in neurons possessing members of the D 1 subfamily of dopamine receptors, in several different types of striatal neurons in the rat basal ganglia. The vast majority (94.1%) of striatonigral projection neurons (the vast majority of which contain substance P), identified by retrograde labeling with fluorogold, were observed to contain DARPP-32. Similarly, the vast majority of striatopallidal projection neurons (87.7%), identified by immunofluorescence labeling for enkephalin (ENK), were found to label for DARPP-32. In contrast, cholinergic and neuropeptide Y-containing striatal interneurons were never observed to contain DARPP-32. These results suggest that essentially all major types of striatal medium spiny projection neurons may possess members of the D 1 subfamily of dopamine receptors, but that striatal local circuit neurons do not possess members of the D 1 subfamily of receptors.

Modular organization of projection neurons in the matrix compartment of the primate striatum

It is well known that the striatum has a chemical architecture dividing it into striosomes and matrix, and that these compartments have different input-output connections. However, striatal afferent-fiber systems also form vividly patchy terminal fields in the matrix, and studies in the past year have uncovered instances of nonstriosomal clustering of striatal output neurons. In the experiments reported here, we systematically investigated this output-neuron clustering in the primate, using the striatopallidal system as a model. Our goals were to determine whether the modular organization is a general characteristic of projection neurons in the striatal matrix, whether the modularity occurs independent of striosomal boundaries, and whether the output modules are systematically organized. We studied the distribution of striatopallidal projection neurons in 9 adult squirrel monkeys by centering deposits of the retrograde tracer HRP-WGA in either the external segment or the internal segment of the globus pallidus. Following injections of each type, many retrogradely labeled neurons appeared in the striatal matrix in clusters and bands having cross-sectional diameters of 0.2-0.8 mm. Comparisons with adjoining sections stained to demonstrate striosomes established that the local groups of striatal output neurons sometimes abutted striosomes but often did not. The retrogradely labeled clusters and bands appeared both in the caudate nucleus and in the putamen. Their arrangements were regular and often periodic. These findings suggest that the large matrix compartment of the primate striatum, which is the primary site of origin of striatal outputs to the pallidum and the reticular part of the substantia nigra, contains systematic mosaics of projection neurons. We propose that this output-neuron modularity of the striatal matrix in the primate could serve as the template for redistribution of the massive afferent-fiber systems of the striatum into specialized striatopallidal output channels.

Extensive co‐occurrence of substance P and dynorphin in striatal projection neurons: An evolutionarily conserved feature of basal ganglia organization

A number of different neuroactive substances have been found in striatal projection neurons and in fibers and terminals in their target areas, including substance P (SP), enkephalin (ENK), and dynorphin (DYN). In a preliminary report on birds and reptiles, we have suggested that SP and DYN are to a large extent found in the same striatal projection neurons and that ENK is found in a separate population of striatal projection neurons. In the present study, we have examined this issue in more detail in pigeons and turtles. Further, we have also explored this issue in rats to determine whether this is a phylogenetically conserved feature of basal ganglia organization. Simultaneous immunofluorescence double-labeling procedures were employed to explore the colocalization of SP and DYN, SP and ENK, and ENK and DYN in striatal neurons and in striatal, nigral, and pallidal fibers in pigeons, turtles, and rats. To guard against possible cross-reactivity of DYN and ENK antisera with each others' antigens, separate double-label studies were carried out with several different antisera that were specific for DYN peptides (e.g., dynorphin A 1-17, dynorphin B, leumorphin) or ENK peptides (leucine-enkephalin, metenkephalin-arg6-gly7-leu8, methionine-enkephalin-arg6-phe7). The results showed that SP and DYN co-occur extensively in specific populations of striatal projection neurons, whereas ENK typically is present in different populations of striatal projection neurons. In pigeons, 95-99% of all striatal neurons containing DYN were found to contain SP and vice versa. In contrast, only 1-3% of the SP+ striatal neurons and no DYN neurons contained ENK. Similarly, in turtles, greater than 75% of the SP+ neurons were DYN+ and vice versa, whereas ENK was observed in fewer than 5% of the SP+ neurons and 2% of the DYN+ neurons. Finally, in rats, more than 70% of the SP+ neurons contained DYN and vice versa, but ENK was found in only 5% of the SP+ neurons and in none of the DYN+ perikarya. Fiber double-labeling in the striatum and its target areas (the pallidum and substantia nigra) was also consonant with these observations in pigeons, turtles, and rats. These results, in conjunction with studies in cats by M.-J. Besson, A.M. Graybiel, and B. Quinn (1986; Soc Neurosci. Abs. 12:876) strongly indicate that the co-occurrence of SP and DYN in large numbers of striatonigral and striatopallidal projection neurons in a phylogenetically widespread, and therefore evolutionarily conserved, feature of basal ganglia organization.(ABSTRACT TRUNCATED AT 400 WORDS)

Compartmental origins of the striatopallidal projection in the primate

The organization of striatopallidal projection neurons in the primate was studied by injecting horseradish peroxidase conjugated with wheat germ agglutinin and fluorescent markers (latex microspheres, Fluorogold, Diamidino Yellow or Nuclear Yellow) into the globus pallidus of 20 adult squirrel monkeys ( Saimiri sciureus). Single injections of horseradish peroxidase conjugated with wheat germ agglutinin were placed so as to involve predominantly either one or both pallidal segments. In the double-tracer experiments, fluorescent tracer injections were centered in the external pallidum and deposits of horseradish peroxidase conjugated with wheat germ agglutinin were made in the internal pallidum. In control cases, injections were made in nearby parts of the internal capsule or striatum. Distributions of retrogradely labeled neurons in the striatum were analysed in relation to its striosomal architecture as demonstrated by histochemistry and immunohistochemistry. Three principal findings emerged. (1) Both the external and the internal segments of the primate pallidum receive input from both the caudate nucleus and the putamen, but different sets of striatal cells within these nuclei project to the two segments. (2) The striatopallidal projection in the primate orginates mainly in the extrastriosomal matrix, although striosomes in the fields of labeling almost always contain some labeled neurons. (3) Heterogeneous groupings of striatopallidal projection neurons exist in the matrix and appear to be parts of three-dimensional projection-neuron arrays. We conclude that in the primate, separate lines of conduction lead from the striatum to the external and the internal pallidal segments and raise the possibility that the cells of origin of these pathways form a mosaic in the extrastriosomal matrix.