Journal of Neural Transmission-supplement最新文献

Parkinson's disease (PD) is a neurodegenerative disorder caused by a progressive degeneration of the midbrain dopamine (DA) neurons in the substantia nigra pars compacta (SNc) that predominantly affects the ventral population projecting to the dorsal striatum and leads to a gradual dysfunction of the motor system. There is currently no cure for PD. Pharmacological and surgical (e.g. deep brain stimulation) interventions can alleviate some of the symptoms, but lose their efficacy over time. The distinct loss of DA neurons in the SN offers the opportunity to assay neuronal cell replacement, and the clinical transplantation of fetal midbrain neuroblasts in PD patients has shown that this approach is feasible. However, there are multiple problems associated with the use of fetus-derived material, including limited availability. DA neurons derived from stem cells (SC) represent an alternative and unlimited cell source for cell replacement therapies. Currently, human pluripotent SC, such as embryonic (ES), and most recently, induced pluripotent stem cells (iPS), and multipotent (tissue-specific) adult SC are available, although the methodology for a reliable and efficient production of DA neurons necessary for biomedical applications is still underdeveloped. Here, we discuss some essentials for SC and SC-derived DA neurons to become therapeutic agents.

Nigral dopaminergic areas from Parkinsonian patients show an increase of reactive astrocytes and active microglia. The reaction of these two cell types is a clear evidence of inflammatory response associated with dopaminergic cell loss. However, the function of this glial reaction remains unclear. This histological hallmark is also reproduced in induced Parkinsonian animals such as MPTP-treated monkeys. In this work, we analyze with confocal microscopy the number of processes of microglial cells and astrocytes in the SNpc of MPTP-treated monkeys and compare with control animals. We observe that secondary branches from microglia and astrocytes increase in MPTP-treated animals, while the scaffold of primary branches does not change. These results demonstrate that glial reaction in MPTP-treated monkeys is characterized by the emission of new filaments after the dopaminergic degeneration, suggesting that glial cells may increase their scanning progress and modify their microanatomy after dopaminergic injury.

The firing pattern of midbrain dopamine neurons is thought to have important behavioral consequences. Although these neurons fire regularly in vitro when deprived of their afferent inputs, they usually fire irregularly in vivo. It is not known whether the irregularity is functionally important and whether it derives from the intrinsic properties of dopamine neurons or network interactions. It is also not known whether the irregular firing pattern is fundamentally stochastic or deterministic in nature. Distinguishing between the deterministic nonlinear structure associated with chaos and other sources of structure including correlated noise is an inherently nontrivial problem. Here we explain the geometric tools provided by the field of nonlinear dynamics and their application to the analysis of interspike interval (ISI) data from midbrain dopamine neurons. One study failed to find strong evidence of nonlinear determinism, but others have identified such a structure and correlated it with network interactions.

The degeneration of nigral dopaminergic (DA-) neurons is the histopathologic hallmark of Parkinson's disease (PD), but not all nigral DA-cells show the same susceptibility to degeneration. This starts in DA-cells in the ventrolateral and caudal regions of the susbtantia nigra (SN) and progresses to DA-cells in the dorsomedial and rostral regions of the SN and the ventral tegmental area, where many neurons remain intact until the final stages of the disease. This fact indicates a relationship between the topographic distribution of midbrain DA-cells and their differential vulnerability, and the possibility that this differential vulnerability is associated with phenotypic differences between different subpopulations of nigral DA-cells. Studies carried out during the last two decades have contributed to establishing the existence of different compartments of nigral DA-cells according to their neurochemical profile, and a possible relationship between the expression of some factors and the relative vulnerability or resistance of DA-cell subpopulations to degeneration. These aspects are reviewed and discussed here.

During aging, decline in memory and cognitive abilities as well as motor weakening is of great concern. The dopaminergic system mediates some aspects of manual dexterity, in addition to cognition and emotion, and may be especially vulnerable to aging. A common neurodegenerative disorder of this system, Parkinson's disease, is characterized by a selective, progressive loss of dopaminergic neurons in the substantia nigra pars compacta. This review includes studies quantifying age and Parkinson's-related changes of the substantia nigra, with emphasis on stereological studies performed in the substantia nigra pars compacta.

The potential neuroprotective or neurotoxic effects of 3,4-dihydroxyphenylalanine (L-DOPA) are yet to be understood. We examined the behavioral, immunohistochemical, tyrosine hydroxylase (TH) expression and neurochemical parameters after an intranigral administration of L-DOPA (10 microM) in rats. L-DOPA elicited a 30.5% reduction in dopaminergic neurons, while 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (100 microg microL(-1)) produced a 53.6% reduction. A combined infusion of MPTP and L-DOPA generated a 42% reduction of nigral neurons. Motor parameters revealed that both the MPTP and L-DOPA groups presented impairments; however, the concomitant administration evoked a partial restorative effect. In addition, MPTP and L-DOPA separately induced reductions of TH protein expression within the substantia nigra. In contrast, the coadministration of MPTP and L-DOPA did not demonstrate such difference. The striatal levels of dopamine were reduced after MPTP or L-DOPA, with an increased turnover only for the MPTP group. In view of such results, it seems reasonable to suggest that L-DOPA could potentially produce dopaminergic neurotoxicity.

Although substantia nigra dopaminergic neurons are spontaneously active both in vivo and in vitro, this activity does not depend on afferent input as these neurons express an endogenous calcium-dependent oscillatory mechanism sufficient to drive action potential generation. However, afferents to these neurons, a large proportion of them GABAergic and arising from other nuclei in the basal ganglia, play a crucial role in modulating the activity of dopaminergic neurons. In the absence of afferent activity or when in brain slices, dopaminergic neurons fire in a very regular, pacemaker-like mode. Phasic activity in GABAergic, glutamatergic, and cholinergic inputs modulates the pacemaker activity into two other modes. The most common is a random firing pattern in which interspike intervals assume a Poisson-like distribution, and a less common pattern, often in response to a conditioned stimulus or a reward in which the neurons fire bursts of 2-8 spikes time-locked to the stimulus. Typically in vivo, all three firing patterns are observed, intermixed, in single nigrostriatal neurons varying over time. Although the precise mechanism(s) underlying the burst are currently the focus of intensive study, it is obvious that bursting must be triggered by afferent inputs. Most of the afferents to substantia nigra pars compacta dopaminergic neurons comprise monosynaptic inputs from GABAergic projection neurons in the ipsilateral neostriatum, the globus pallidus, and the substantia nigra pars reticulata. A smaller fraction of the basal ganglia inputs, something less than 30%, are glutamatergic and arise principally from the ipsilateral subthalamic nucleus and pedunculopontine nucleus. The pedunculopontine nucleus also sends a cholinergic input to nigral dopaminergic neurons. The GABAergic pars reticulata projection neurons also receive inputs from all of these sources, in some cases relaying them disynaptically to the dopaminergic neurons, thereby playing a particularly significant role in setting and/or modulating the firing pattern of the nigrostriatal neurons.

Parkinson's disease and other neurodegenerative disorders share a common pathologic pathway with aggregation and deposition of misfolded proteins causing a disruption of particular neuronal networks. Several mechanisms have been implicated in the downstream events following deposition of misfolded proteins including free radical formation and failure of cellular defences such as autophagy or protein-degradation by the ubiquitin-proteasome pathway among many others. Treatments, however, capable of arresting or at least effectively modifying the course of disease do not yet exist. Recently, immunization approaches including passive and active immunization have been tested in animal models of various neurodegenerative disorders and have already entered into clinical trials for the treatment of Alzheimer's disease. In this review, we specifically focus on the current status of immune-based approaches that are presently developed as a potential therapy of Parkinson's disease.

Clinical characteristics of Parkinson's disease (PD) are the result of the degeneration of the neurons of the substantia nigra pars compacta (SNpc). Several mechanisms are implicated in the degeneration of nigrostriatal neurons such as oxidative stress, mitochondrial dysfunction, protein misfolding, disturbances of dopamine (DA) metabolism and transport, neuroinflammation, and necrosis/apoptosis. The literature widely explores the neurotoxic models elicited by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA). Because of the models, it is known that basal ganglia, particularly substantia nigra, have been related to a diversity of functions, from motor to sleep regulation. Nevertheless, a current debate concerning the role of DA on the sleep-wake cycle is in progress. In summary, it is suggested that the dopaminergic system is implicated in the physiology of sleep, with particular regard to the influence of the SNpc neurons. The understanding of the functioning and connectivity of the SNpc neurons has become fundamental to discovering the neurobiology of these neurons.

The roles of the nigrostriatal pathway are far beyond the simple control of motor functions. The tonic release of dopamine in the dorsal and ventral striatum controls the choice of proper actions toward a given environmental situation. In the striatum, a specific action is triggered by a specific stimulus associated with it. When the subject faces a novel and salient stimulus, the phasic release of dopamine allows synaptic plasticity in the cortico-striatal synapses. Neurons of different regions of cortical areas make synapses that converge to the same medium spine neurons of the striatum. The convergent associations form functional units encoding body parts, objects, locations, and symbolic representations of the subject's world. Such units emerge in the striatum in a repetitive manner, like a mosaic of broken mirrors. The phasic release of dopamine allows the association of units to encode an action of the subject directed to an object or location with the outcome of this action. Reinforced stimulus-action-outcome associations will affect future decision making when the same stimulus (object, location, idea) is presented to the subject in the future. In the absence of a minimal amount of striatal dopamine, no action is initiated as seen in Parkinson's disease subjects. The abnormal and improper association of these units leads to the initiation of unpurposeful and sometimes repetitive actions, as those observed in dyskinetic patients. The association of an excessive reinforcement of some actions, like drug consumption, leads to drug addiction. Improper associations of ideas and unpleasant outcomes may be related to traumatic and depressive symptoms common in many diseases, including Parkinson's disease. The same can be said about the learning and memory impairments observed in demented and nondemented Parkinson's disease patients.