A Study of Lectin Affinity Differences Between Sensory Neurons and Autonomic Neurons

It has been reported that the different kinds of lectins selectively combined witch various types of neurons in spinal ganglia and that thiamine monophosphatase (TMPase)are characteristic enzymes of medium and small size neurons in the spinal ganglia, but so far, no observations and comparisons have been made in ganglia of different natures. We used the "HRP labeled lectins affinity method" and the "TMPase method" for the experiments on spinal     

Discovery and study on the structure and function of a new area in the mammalian striatum

In our previous study, we found a new subdivision, which is mainly composed of fusiform neurons, in the rat striatum. This new subdivision is located at the caudal border of the striatum surrounding the rostral edge of the globus pallidus. This area was named “marginal division” based on its location. The somatodendritic morphology in the marginal division revealed by Nissl staining and PHA-L label exhibits ovoid to fusiform somata with their long axes dorsoventrally parallel to the border between the striatum and the globus pallidus. The fusiform neurons have two spiny primary dendrites emerging from the two poles of the cell bodies.     

Effects of systemic 3-nitropropionic acid-induced lesions of the dorsal striatum on cannabinoid and µ-opioid receptor binding in the basal ganglia

Systemic administration of 3-nitropropionic acid (3NPA) in experimental animals produces bilateral striatal lesions similar to those seen in Huntington’s disease (HD) caudate and putamen. [³H]-CP55,940 binding to cannabinoid receptors in human basal ganglia nuclei has been shown to be highly susceptible to the earliest pathological changes in the HD brain. In this study, to assess further the suitability of 3NPA-induced striatal lesions as a model for HD neuropathology, we examined the effects of striatal lesions induced by the systemic administration of 3NPA on the binding of [³H]-CP55,940 to pre- and postsynaptic cannabinoid receptors in striatum, globus pallidus, entopeduncular nucleus and substantia nigra pars reticulata and also the effect of 3NPA-induced striatal lesions on the binding of [³H]-DAMGO to μ-opioid receptors in striatal striosomes. Systemic administration of 3NPA induced bilateral and symmetrical lesions in dorsolateral striatum. Within the lesion core, [³H]-CP55,940 and [³H]-DAMGO binding density was reduced to background levels. Beyond the immediate borders of the central core of the 3NPA-induced lesion, striatal binding density was not significantly different from that measured in unlesioned rats. [³H]-CP55,940 binding in globus pallidus, entopeduncular nucleus and substantia nigra in 3NPA-lesioned rats was significantly reduced compared to controls, and the individual decreases were similar for each site. However, these reductions were statistically marginal. These data suggest that, while producing striatal lesions which bear some similarity to those seen in HD, the consequences of 3NPA for striatopallidal and striatonigral efferent projections do not reflect the reported neurodegenerative changes seen in the HD brain. Received: 18 November 1998 / Accepted: 12 July 1999     

阿尔茨海默病中Aβ损伤线粒体的研究进展

The β-amyloid protein (Aβ) has long been considered to associate with Alzheimers disease (AD). In addition, groups of evidence show that the soluble intracellular Aβ plays an important role in the disease development. The mitochondrial dysfunction induced by Aβ accumulation is a main pathologic process in early stage of AD. Matured Aβ is imported into the mitochondria through an unclear route. Once inside the mitochondria, Aβ is able to interact with a number of targets, including amyloid-binding alcohol dehydrogenase (ABAD) and cyclophilin D (CypD), which is a component of the mitochondrial permeability transition pore. Interference with the normal functions of these proteins results in mitochondrial injury, such as energy dyshomeostasis, production of reactive oxygen species, membrane permeability alteration and so on. This review explores the Aβ generation and location in mitochondria. The mitochondrial injury induced by the interaction between Aβ and its targets are also discussed.     

骨髓间质干细胞诱导分化为神经元及其应用的研究进展

Mesenchymal stem cells (MSCs) are a population of muhipotent cells that can proliferate and differentiate into marrow and non - marrow cell types, such as adipocytes, chondrocytes, myocytes, and so on. In recent years, many researchers have studied whether MSCs are capable of differentiation into neurons in vivo and ex vivo. The result that MSCs - derived neurons express NSE and NF, but don‘t express GFAP suggests MSCs can differentiate into neurons, some researchers have achieved success in promoting functional recovery in Pakinsons and transactional spinal cord injury rat models by use of MSCs - derived neurons. Therefore, MSCs - derived neurons will play an important role in the therapy for a variety of diseases of the nervous system.     

THLAMO-CORTICAL SYSTEM OF NOCICEPTION IN ANIMALS

<正> Imaging studies in human subjects indicate that several different regions of the cerebral cortex are activated as a result of painful stimulation of the skin. Cortical processing occurs in the first and second somatosensory areas (SⅠ and SⅡ), the anterior cingulate gyrus and the insula. Nociceptive processing also occurs in subcortical structures, including the amygdala, basal ganglia and cerebellum. Sensory discrimination of pain appears to     

Glutamate and GABA modulate dopamine in the pedunculopontine tegmental nucleus

The pedunculopontine tegmental nucleus (PPTg) has an important anatomical position connecting basal ganglia and limbic systems with motor execution structures in the pons and spinal cord. It receives glutamatergic and GABAergic input and has additional reciprocal connections with mesencephalic dopaminergic neurons, suggesting that the PPTg plays a key role in frontostriatal information processing. In vivo microdialysis in freely moving rats, in combination with behavioral analysis, was used in this study to investigate whether the dopaminergic input can be modulated at the level of the PPTg via N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) or GABA_B receptors. Stimulation of the GABA_B receptor decreased dopamine release in the PPTg while that of the AMPA and NMDA receptors increased it. A time-related comparison of the effects of NMDA (0.75 and 1 mM) and AMPA (50 and 25 μM) revealed a more long-lasting effect after AMPA stimulation than after NMDA. However, only the infusion of the GABA_B receptor agonist baclofen (100 and 200 μM) stimulated stereotyped behavior (e.g. sniffing, digging or head movements) and contralateral circling. This study clearly demonstrates that GABAergic as well as glutamatergic terminals in the PPTg are critically involved in the modulation of the dopamine system. Moreover, a decrease in PPTg dopamine via GABA_B receptor stimulation seems to be behaviorally relevant. Electronic Publication     

A STUDY OF THE NERVE FIBERS ORIGINATED FROM INTRINSIC CARDIAC GANGLION CONNECT WITH STELLATE GANGLION IN THE RAT

There have been many reports about the intrinsic cardiac ganglion in recent years. Most of them are ultrastructural and immunohistochemical investgations, in which many neuropeptides have been localized in the nerve cells and fibers of the mammalian heart, such as vasoactive intestinal polypeptides, neuropeptide Y, neurotensin, substance P and so on. These reports suggested that the intrinsic cardiac ganglia are not only cholinergic but have also other properties. However, their function need to be studied further. Are there any sensory neurons and interneurons which transmit information from the heart to the intrinsic or extrinsic cardiac ganglia, as well as to the central nervous system, in these ganglia? Up to now, there have been no reports about this question. In the present study, CB-HRP was injected into the     

TEMPORAL FIRING PATTERNS AND RESPONSIVE SENSITIVITY IN THE INJURED DORSAL ROOT GANGLION NEURONS

<正> Temporal Firing Patterns of Spontaneous Activity For decades, temporal code has been considered as an important mode encoding neural information and evidence for temporal code in the cortex neurons and the receptors is growing. However, the basic temporal firing patterns that may constitute to the temporal coding mode and their generating mechanisms in the neurons     

The role of the human globus pallidus in Huntington's disease

Huntington's disease (HD) is characterized by pronounced pathology of the basal ganglia, with numerous studies documenting the pattern of striatal neurodegeneration in the human brain. However, a principle target of striatal outflow, the globus pallidus (GP), has received limited attention in comparison, despite being a core component of the basal ganglia. The external segment (GPe) is a major output of the dorsal striatum, connecting widely to other basal ganglia nuclei via the indirect motor pathway. The internal segment (GPi) is a final output station of both the direct and indirect motor pathways of the basal ganglia. The ventral pallidum (VP), in contrast, is a primary output of the limbic ventral striatum. Currently, there is a lack of consensus in the literature regarding the extent of GPe and GPi neurodegeneration in HD, with a conflict between pallidal neurons being preserved, and pallidal neurons being lost. In addition, no current evidence considers the fate of the VP in HD, despite it being a key structure involved in reward and motivation. Understanding the involvement of these structures in HD will help to determine their involvement in basal ganglia pathway dysfunction in the disease. A clear understanding of the impact of striatal projection loss on the main neurons that receive striatal input, the pallidal neurons, will aid in the understanding of disease pathogenesis. In addition, a clearer picture of pallidal involvement in HD may contribute to providing a morphological basis to the considerable variability in the types of motor, behavioral, and cognitive symptoms in HD. This review aims to highlight the importance of the globus pallidus, a critical component of the cortical‐basal ganglia circuits, and its role in the pathogenesis of HD. This review also summarizes the current literature relating to human studies of the globus pallidus in HD.     

Correlated multisecond oscillations in firing rate in the basal ganglia: modulation by dopamine and the subthalamic nucleus

Previous studies from this laboratory have shown that many neurons in the basal ganglia have multisecond (<0.5 Hz) periodicities in firing rate in awake rats. The frequency and regularity of these oscillations are significantly increased by systemically injected dopamine (DA) agonists. Because oscillatory activity should have greater functional impact if shared by many neurons, the level of correlation of multisecond oscillations was assessed by recording pairs of neurons in the globus pallidus and substantia nigra pars reticulata in the same hemisphere, or pairs of globus pallidus neurons in opposite hemispheres in awake, immobilized rats. Cross-correlation (90-180 s lags) and spectral analysis were used to characterize correlated oscillations. Thirty-eight percent of pairs recorded in baseline (n=50) demonstrated correlated multisecond oscillations. Phase relationships were near 0 or 180 degrees. DA agonist injection significantly increased the incidence of correlation (intra- and interhemispheric) to 94% (n=17). After DA agonist injection, phase relationships of globus pallidus/substantia nigra neuron pairs were exclusively concentrated near 180 degrees, and phases of interhemispheric pairs of globus pallidus neurons were concentrated near 0 degrees. After subthalamic nucleus lesion (n=8), the incidence of correlated multisecond oscillations (or of multisecond oscillations per se) was not changed, although the consistent phase relationship between the globus pallidus and substantia nigra pars reticulata was disrupted. Subthalamic lesion also blocked apomorphine-induced decreases in oscillatory period and increases in oscillation amplitude, and significantly attenuated apomorphine-induced changes in mean firing rate. The data demonstrate that multisecond oscillations in the basal ganglia can be correlated between nuclei, and that DA receptor activation increases the level of correlation and organizes internuclear phase relationships at these multisecond time scales. While the subthalamic nucleus is not necessary for generating or transmitting these slow oscillations, it is involved in DA agonist-induced modulation of mean firing rate, oscillatory period, and internuclear phase relationship. These data further support a role for DA in modulating coherent oscillatory activity in the basal ganglia, and for the subthalamic nucleus in shaping the effects of DA receptor stimulation on basal ganglia output.     

The role of the globus pallidus D2 subfamily of dopamine receptors in pallidal immediate early gene expression.

The globus pallidus plays an important role in basal ganglia circuitry, representing the first relay nucleus of the 'indirect pathway' of striatal efferents. In contrast to the well-characterized actions of dopamine on striatal neurons, the functional role of the dopamine innervation of globus pallidus is less well understood. Previous research showed that systemic administration of either a dopamine D2 receptor antagonist or combined dopamine D1 and D2 receptor agonists induces Fos, the protein product of the immediate early gene c-fos, in neurons of globus pallidus [Ruskin and Marshall (1997) Neuroscience 81, 79-92]. To determine whether the ability of the D2 receptor antagonist, sulpiride, to induce Fos in rat pallidal neurons is mediated by D2-like receptors in striatum or globus pallidus, intrastriatal or intrapallidal sulpiride infusions were conducted. The diffusion of intrastriatal sulpiride was estimated by measuring this antagonist's competition for N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)-induced D2 receptor inactivation. The phenotype of the striatal neurons expressing Fos after intrastriatal infusion was assessed by combining Fos immunocytochemistry with D2 receptor mRNA in situ hybridization. Intrastriatal infusions of (-)-sulpiride (10-200 ng) dose-dependently increased the number of striatal cells expressing Fos; and the Fos-immunoreactive striatal cells were D2 receptor mRNA-expressing, the same population in which systemic D2 receptor antagonists induce Fos. Intrastriatal infusions of high (5 microg), but not low (10-200 ng), (-)-sulpiride doses also induced Fos in globus pallidus cells but the sulpiride appeared to spread to the globus pallidus. Direct intrapallidal infusions of (-)-sulpiride (50-100 ng) dose-dependently induced Fos in globus pallidus with minimal influence on striatum or other basal ganglia structures. Using sensitive in situ hybridization conditions, prominent labeling of D2 receptor mRNA was evident in globus pallidus. D2 receptor mRNA was densest in a lateral 200 microm wide band that follows the curvature of the pallidal/striatal boundary. Cellular analysis revealed silver clusters associated with D2 receptor mRNA labeling over globus pallidus neurons that were immunoreactive for neuron-specific nuclear protein. These results strongly suggest that the dopaminergic innervation of globus pallidus, acting through D2-like receptors internal to this structure, can control gene expression in pallidal neurons.     

5-HT excites globus pallidus neurons by multiple receptor mechanisms

Anatomical and neurochemical studies indicated that the globus pallidus receives serotonergic innervation from raphe nuclei but the membrane effects of 5-HT on globus pallidus neurons are not entirely clear. We address this question by applying whole-cell patch-clamp recordings on globus pallidus neurons in immature rat brain slices. Under current-clamp recording, 5-HT depolarized globus pallidus neurons and increased their firing rate, an action blocked by both 5-HT(4) and 5-HT(7) receptor antagonists and attributable to an increase in cation conductance(s). Further experiments indicated that 5-HT enhanced the hyperpolarization-activated inward conductance which is blocked by 5-HT(7) receptor antagonist. To determine if 5-HT exerts any presynaptic effects on GABAergic and glutamatergic inputs, the actions of 5-HT on synaptic currents were studied. At 10 microM, 5-HT increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) but had no effect on both the frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs). However, 5-HT at a higher concentration (50 microM) decreased the frequency but not the amplitude of the mIPSCs, indicating an inhibition of GABA release from the presynaptic terminals. This effect was sensitive to 5-HT(1B) receptor antagonist. In addition to the presynaptic effects on GABAergic neurotransmission, 5-HT at 50 microM had no consistent effects on glutamatergic neurotransmission, significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs) in 4 of 11 neurons and decreased the frequency of mEPSCs in 3 of 11 neurons. In conclusion, we found that 5-HT could modulate the excitability of globus pallidus neurons by both pre- and post-synaptic mechanisms. In view of the extensive innervation by globus pallidus neurons on other basal ganglia nuclei, this action of 5-HT originated from the raphe may have a profound effect on the operation of the entire basal ganglia network.     

Synaptic organisation of the basal ganglia

The basal ganglia are a group of subcortical nuclei involved in a variety of processes including motor, cognitive and mnemonic functions. One of their major roles is to integrate sensorimotor, associative and limbic information in the production of context‐dependent behaviours. These roles are exemplified by the clinical manifestations of neurological disorders of the basal ganglia. Recent advances in many fields, including pharmacology, anatomy, physiology and pathophysiology have provided converging data that have led to unifying hypotheses concerning the functional organisation of the basal ganglia in health and disease. The major input to the basal ganglia is derived from the cerebral cortex. Virtually the whole of the cortical mantle projects in a topographic manner onto the striatum, this cortical information is ‘processed’ within the striatum and passed via the so‐called direct and indirect pathways to the output nuclei of the basal ganglia, the internal segment of the globus pallidus and the substantia nigra pars reticulata. The basal ganglia influence behaviour by the projections of these output nuclei to the thalamus and thence back to the cortex, or to subcortical ‘premotor’ regions. Recent studies have demonstrated that the organisation of these pathways is more complex than previously suggested. Thus the cortical input to the basal ganglia, in addition to innervating the spiny projection neurons, also innervates GABA interneurons, which in turn provide a feed‐forward inhibition of the spiny output neurons. Individual neurons of the globus pallidus innervate basal ganglia output nuclei as well as the subthalamic nucleus and substantia nigra pars compacta. About one quarter of them also innervate the striatum and are in a position to control the output of the striatum powerfully as they preferentially contact GABA interneurons. Neurons of the pallidal complex also provide an anatomical substrate, within the basal ganglia, for the synaptic integration of functionally diverse information derived from the cortex. It is concluded that the essential concept of the direct and indirect pathways of information flow through the basal ganglia remains intact but that the role of the indirect pathway is more complex than previously suggested and that neurons of the globus pallidus are in a position to control the activity of virtually the whole of the basal ganglia.     

Localization of cannabinoid receptor in the human developing and adult basal ganglia. Higher levels in the striatonigral neurons.

In the infant and adult human basal ganglia, the finding of mRNA exclusively in the striatal medium-sized neurons together with the detection of [3H]CP55,940 binding sites in the caudate-putamen, accumbens, substantia nigra pars reticulata and globus pallidus suggests cannabinoid receptor localization on the striatal intrinsic enkephalinergic and substance P-projecting neurons and on their nigral and pallidal terminals. However, the consistent finding of higher binding in the substantia nigra pars reticulata and medial part of the globus pallidus over its lateral segment suggests cannabinoid receptor enrichment on the striatal substance P neurons which express selectively the dopamine D1 receptor.     

The pattern of neurodegeneration in Huntington's disease: a comparative study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations in the human basal ganglia in Huntington's disease

In order to investigate the sequence and pattern of neurodegeneration in Huntington's disease, the distribution and density of cannabinoid CB(1), dopamine D(1) and D(2), adenosine A(2a) and GABA(A) receptor changes were studied in the basal ganglia in early (grade 0), intermediate (grades 1, 2) and advanced (grade 3) neuropathological grades of Huntington's disease. The results showed a sequential pattern of receptor changes in the basal ganglia with increasing neuropathological grades of Huntington's disease. First, the very early stages of the disease (grade 0) were characterized by a major loss of cannabinoid CB(1), dopamine D(2) and adenosine A(2a) receptor binding in the caudate nucleus, putamen and globus pallidus externus and an increase in GABA(A) receptor binding in the globus pallidus externus. Second, intermediate neuropathological grades (grades 1, 2) showed a further marked decrease of CB(1) receptor binding in the caudate nucleus and putamen; this was associated with a loss of D(1) receptors in the caudate nucleus and putamen and a loss of both CB(1) and D(1) receptors in the substantia nigra. Finally, advanced grades of Huntington's disease showed an almost total loss of CB(1) receptors and the further depletion of D(1) receptors in the caudate nucleus, putamen and globus pallidus internus, and an increase in GABA(A) receptor binding in the globus pallidus internus.These findings suggest that there is a sequential but overlapping pattern of neurodegeneration of GABAergic striatal efferent projection neurons in increasing neuropathological grades of Huntington's disease. First, GABA/enkephalin striatopallidal neurons projecting to the globus pallidus externus are affected in the very early grades of the disease. Second, GABA/substance P striatonigral neurons projecting to the substantia nigra are involved at intermediate neuropathological grades. Finally, GABA/substance P striatopallidal neurons projecting to the globus pallidus internus are affected in the late grades of the disease. In addition, the finding that cannabinoid receptors are dramatically reduced in all regions of the basal ganglia in advance of other receptor changes in Huntington's disease suggests a possible role for cannabinoids in the progression of neurodegeneration in Huntington's disease.     

Anticataleptic effects of 5-HT1B receptors in the globus pallidus

The globus pallidus occupies an important position in the indirect pathway of the basal ganglia. Being a monoamine neurotransmitter, 5-HT is involved in mediating many physiological functions and pathophysiological processes in several movement disorders. Morphological studies have revealed that the globus pallidus receives serotonergic innervation arising from the raphe nuclei, mainly the dorsal raphe nucleus. A high level of 5-HT and 5-HT_1B receptors were detected in the globus pallidus. In the present study, bilateral microinjection of 5-HT or 5-HT_1B receptor agonist, CP-93129, into the globus pallidus significantly alleviated the symptoms of rigidity caused by haloperidol. To further elucidate 5-HT_1B receptor-induced anticatalepsy, in vivo extracellular recordings were performed to examine the effects of 5-HT_1B receptor activation on the firing activity of the globus pallidus neurons under the presence of haloperidol. Micro-pressure ejection of 5-HT or CP-93129 increased the spontaneous firing rate of the pallidal neurons. Furthermore, by using immunohistochemistry, positive staining of 5-HT_1B receptor was observed in the globus pallidus neurons. Taken together, the present findings provide evidence that activation of 5-HT_1B receptor may exert anticataleptic effects by increasing the activity of pallidal neurons.     

Zinc modulates GABAergic neurotransmission in rat globus pallidus

The globus pallidus plays a critical role in the regulation of movement, and abnormal activity of its neurons is associated with some basal ganglia motor diseases. A relatively high level of zinc has been reported in the globus pallidus, which is increased significantly after 6-OHDA treatments. To elucidate the action of zinc on GABAergic neurotransmission in the globus pallidus, whole-cell patch-clamp recordings were made from rat globus pallidus neurons. Superfusion of zinc significantly reduced both spontaneous and miniature inhibitory postsynaptic currents. The inhibition was selective to the amplitude with no change in the frequency, decay time and rise time. Furthermore, the reduction of spontaneous inhibitory postsynaptic currents (34.1 ± 4.0%) was stronger than that of miniature inhibitory postsynaptic currents (19.7 ± 3.2%). These results suggest that spontaneous inhibitory postsynaptic currents generated mainly by axonal collaterals and miniature inhibitory postsynaptic currents generated mainly by striatopallidal inputs may be mediated by different GABA_A receptor combinations.     

Basal ganglia circuits changes in Parkinson's disease patients

Functional changes in basal ganglia circuitry are responsible for the major clinical features of Parkinson's disease (PD). Current models of basal ganglia circuitry can only partially explain the cardinal symptoms in PD. We used functional MRI to investigate the causal connectivity of basal ganglia networks from the substantia nigra pars compacta (SNc) in PD in the movement and resting state. In controls, SNc activity predicted increased activity in the supplementary motor area, the default mode network, and dorsolateral prefrontal cortex, but, in patients, activity predicted decreases in the same structures. The SNc had decreased connectivity with the striatum, globus pallidus, subthalamic nucleus, thalamus, supplementary motor area, dorsolateral prefrontal cortex, insula, default mode network, temporal lobe, cerebellum, and pons in patients compared to controls. Levodopa administration partially normalized the pattern of connectivity. Our findings show how the dopaminergic system exerts influences on widespread brain networks, including motor and cognitive networks. The pattern of basal ganglia network connectivity is abnormal in PD secondary to dopamine depletion, and is more deviant in more severe disease. Use of functional MRI with network analysis appears to be a useful method to demonstrate basal ganglia pathways in vivo in human subjects.