Dataset Information

Functional Alteration of Cerebello-Cerebral Coupling in an Experimental Mouse Model of Parkinson's Disease.

ABSTRACT: In Parkinson's disease, the degeneration of the midbrain dopaminergic neurons is consistently associated with modified metabolic activity in the cerebellum. Here we examined the functional reorganization taking place in the cerebello-cerebral circuit in a murine model of Parkinson's disease with 6-OHDA lesion of midbrain dopaminergic neurons. Cerebellar optogenetic stimulations evoked similar movements in control and lesioned mice, suggesting a normal coupling of cerebellum to the motor effectors after the lesion. In freely moving animals, the firing rate in the primary motor cortex was decreased after the lesion, while cerebellar nuclei neurons showed an increased firing rate. This increase may result from reduced inhibitory Purkinje cells inputs, since a population of slow and irregular Purkinje cells was observed in the cerebellar hemispheres of lesioned animals. Moreover, cerebellar stimulations generated smaller electrocortical responses in the motor cortex of lesioned animals suggesting a weaker cerebello-cerebral coupling. Overall these results indicate the presence of functional changes in the cerebello-cerebral circuit, but their ability to correct cortical dysfunction may be limited due to functional uncoupling between the cerebellum and cerebral cortex.

SUBMITTER: Menardy F

PROVIDER: S-EPMC6418382 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Functional Alteration of Cerebello-Cerebral Coupling in an Experimental Mouse Model of Parkinson's Disease.

Menardy Fabien F Varani Andrés Pablo AP Combes Adèle A Léna Clément C Popa Daniela D

Cerebral cortex (New York, N.Y. : 1991) 20190401 4

In Parkinson's disease, the degeneration of the midbrain dopaminergic neurons is consistently associated with modified metabolic activity in the cerebellum. Here we examined the functional reorganization taking place in the cerebello-cerebral circuit in a murine model of Parkinson's disease with 6-OHDA lesion of midbrain dopaminergic neurons. Cerebellar optogenetic stimulations evoked similar movements in control and lesioned mice, suggesting a normal coupling of cerebellum to the motor effector ...[more]

PMID: 30715237

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Project description:Parkinson's disease (PD) is a chronic, progressive movement disorder of adults and the second most common neurodegenerative disease after Alzheimer's disease. Neuropathologic diagnosis of PD requires moderate-to-marked neuronal loss in the ventrolateral substantia nigra pars compacta and ?-synuclein (?S) Lewy body pathology. Nigrostriatal dopaminergic neurodegeneration correlates with the Parkinsonian motor features, but involvement of other peripheral and central nervous system regions leads to a wide range of non-motor features. Nigrostriatal dopaminergic neurodegeneration is shared with other parkinsonian disorders, including some genetic forms of parkinsonism, but many of these disorders do not have Lewy bodies. An ideal animal model for PD, therefore, should exhibit age-dependent and progressive dopaminergic neurodegeneration, motor dysfunction, and abnormal ?S pathology. Rodent models of PD using genetic or toxin based strategies have been widely used in the past several decades to investigate the pathogenesis and therapeutics of PD, but few recapitulate all the major clinical and pathologic features of PD. It is likely that new strategies or better understanding of fundamental disease processes may facilitate development of better animal models. In this review, we highlight progress in generating rodent models of PD based on impairments of four major cellular functions: mitochondrial oxidative phosphorylation, autophagy-lysosomal metabolism, ubiquitin-proteasome protein degradation, and endoplasmic reticulum stress/unfolded protein response. We attempt to evaluate how impairment of these major cellular systems contribute to PD and how they can be exploited in rodent models. In addition, we review recent cell biological studies suggesting a link between ?S aggregation and impairment of nuclear membrane integrity, as observed during cellular models of apoptosis. We also briefly discuss the role of incompetent phagocytic clearance and how this may be a factor to consider in developing new rodent models of PD.

Project description:Alzheimer's disease (AD), the most common form of dementia, is characterized by neuronal degeneration and cerebrovascular dysfunction. Increasing evidence indicates that cerebrovascular dysfunction may be a key or an aggravating pathogenic factor in AD. This emphasizes the importance to investigate the tight coupling between neuronal activity and cerebral blood flow (CBF) termed neurovascular coupling (NVC). NVC depends on all cell types of the neurovascular unit within which astrocytes are important players in the progression of AD. Hence, the objective of this study was to characterize the hippocampal NVC in a mouse model of AD. Hippocampal NVC was studied in 6-month-old amyloid-beta precursor protein (APP) transgenic mice and their corresponding wild-type littermates using in vivo laser Doppler flowmetry to measure CBF in area CA1 of the hippocampus in response to Schaffer collaterals stimulation. Ex vivo two-photon microscopy experiments were performed to determine astrocytic Ca2+ and vascular responses to electrical field stimulation (EFS) or caged Ca2+ photolysis in hippocampal slices. Neuronal synaptic transmission, astrocytic endfeet Ca2+ in correlation with reactive oxygen species (ROS), and vascular reactivity in the presence or absence of Tempol, a mimetic of superoxide dismutase, were further investigated using electrophysiological, caged Ca2+ photolysis or pharmacological approaches. Whisker stimulation evoked-CBF increases and ex vivo vascular responses to EFS were impaired in APP mice compared with their age-matched controls. APP mice were also characterized by decreased basal synaptic transmission, a shorter astrocytic Ca2+ increase, and altered vascular response to elevated perivascular K+. However, long-term potentiation, astrocytic Ca2+ amplitude in response to EFS, together with vascular responses to nitric oxide remained unchanged. Importantly, we found a significantly increased Ca2+ uncaging-induced ROS production in APP mice. Tempol prevented the vascular response impairment while normalizing astrocytic Ca2+ in APP mice. These findings suggest that NVC is altered at many levels in APP mice, at least in part through oxidative stress. This points out that therapies against AD should include an antioxidative component to protect the neurovascular unit.

Dataset Information

Functional Alteration of Cerebello-Cerebral Coupling in an Experimental Mouse Model of Parkinson's Disease.

Publications

Functional Alteration of Cerebello-Cerebral Coupling in an Experimental Mouse Model of Parkinson's Disease.

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