Non-motor symptoms in Parkinson’s disease : modeling and mechanisms
Author: Masini, Débora
Date: 2018-05-16
Location: Petrénsalen, Nobels väg 12 B, Solna
Time: 9:30
Department: Inst för neurovetenskap / Dept of Neuroscience
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Thesis (1.673Mb)
Abstract
Parkinson’s disease (PD) is a common neurodegenerative disorder, typically characterized by
the progressive death of midbrain dopaminergic neurons projecting from the substantia nigra
to other areas within the basal ganglia. Historically, PD has been diagnosed as a purely motor
disorder dominated by bradykinesia (slowness of movement), rigidity, resting tremor, and
postural instability. While there are no approved disease-modifying therapies, these
symptoms can be counteracted by dopamine replacement therapies based on the use of LDopa
and dopamine receptor agonists.
In the past decades, the classic view of PD as an exclusively motor disease has been challenged by increasing evidence showing that patients display a wide range of non-motor symptoms (NMS), including hyposmia, sleep disturbances, cognitive impairment, depression and anxiety. These ailments often appear in the early, pre-motor stage of the disease and progressively worsen, significantly affecting the patient’s quality of life. The neuropathological mechanisms underlying NMS are still poorly understood, but clinical findings have consistently shown the involvement of both the dopaminergic and nondopaminergic systems. Interestingly, these symptoms only partially respond to dopaminergic treatments used to handle motor deficits, complicating the pharmacological management of patients. The increasing demand for more effective therapies for NMS indicates the importance of developing translational approaches based on the use of appropriate animal models.
In this thesis, we developed and validated a mouse model of PD for the study of NMS. This model is characterized by a bilateral partial degeneration of the dopaminergic system achieved through intra-striatal injection of 6-hydroxydopamine (6-OHDA). We found that this model presents only subtle gait modifications reminiscent of early stage PD. Most importantly, we showed that the 6-OHDA lesion impairs olfactory discrimination, disrupts circadian rhythm, causes long-term memory deficits, as well as depression- and anxiety-like behaviors. Using a combination of anatomical and pharmacological approaches, we validated this model for the study of NMS and described the effects produced on these deficits by administration of dopaminergic and non-dopaminergic drugs.
Altogether, these studies provide a well-characterized tool for the study of NMS in PD, as well as information on molecular and neural targets implicated, thereby opening new vistas for the design of broader therapeutic interventions.
In the past decades, the classic view of PD as an exclusively motor disease has been challenged by increasing evidence showing that patients display a wide range of non-motor symptoms (NMS), including hyposmia, sleep disturbances, cognitive impairment, depression and anxiety. These ailments often appear in the early, pre-motor stage of the disease and progressively worsen, significantly affecting the patient’s quality of life. The neuropathological mechanisms underlying NMS are still poorly understood, but clinical findings have consistently shown the involvement of both the dopaminergic and nondopaminergic systems. Interestingly, these symptoms only partially respond to dopaminergic treatments used to handle motor deficits, complicating the pharmacological management of patients. The increasing demand for more effective therapies for NMS indicates the importance of developing translational approaches based on the use of appropriate animal models.
In this thesis, we developed and validated a mouse model of PD for the study of NMS. This model is characterized by a bilateral partial degeneration of the dopaminergic system achieved through intra-striatal injection of 6-hydroxydopamine (6-OHDA). We found that this model presents only subtle gait modifications reminiscent of early stage PD. Most importantly, we showed that the 6-OHDA lesion impairs olfactory discrimination, disrupts circadian rhythm, causes long-term memory deficits, as well as depression- and anxiety-like behaviors. Using a combination of anatomical and pharmacological approaches, we validated this model for the study of NMS and described the effects produced on these deficits by administration of dopaminergic and non-dopaminergic drugs.
Altogether, these studies provide a well-characterized tool for the study of NMS in PD, as well as information on molecular and neural targets implicated, thereby opening new vistas for the design of broader therapeutic interventions.
List of papers:
I. Bonito-Oliva A, Masini D, Fisone G. (2014) A mouse model of non-motor symptoms in Parkinson’s disease: focus on pharmacological interventions targeting affective dysfunctions. Frontiers in Behavioral Neurosciences 8:290.
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II. Masini D, Lopes-Aguiar C, Bonito-Oliva A, Papadia D, Andersson R, Fisahn A, Fisone G. (2017). The histamine H3 receptor antagonist thioperamide rescues circadian rhythm and memory function in experimental parkinsonism. Translational Psychiatry 7(4):e1088.
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III. Masini D, Bonito-Oliva A, Bertho M, Fisone G. (2018) Inhibition of mTORC1 signaling reverts cognitive and affective deficits in a mouse model of Parkinson’s disease. Frontiers in Neurology 9:208.
Fulltext (DOI)
Pubmed
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I. Bonito-Oliva A, Masini D, Fisone G. (2014) A mouse model of non-motor symptoms in Parkinson’s disease: focus on pharmacological interventions targeting affective dysfunctions. Frontiers in Behavioral Neurosciences 8:290.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Masini D, Lopes-Aguiar C, Bonito-Oliva A, Papadia D, Andersson R, Fisahn A, Fisone G. (2017). The histamine H3 receptor antagonist thioperamide rescues circadian rhythm and memory function in experimental parkinsonism. Translational Psychiatry 7(4):e1088.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Masini D, Bonito-Oliva A, Bertho M, Fisone G. (2018) Inhibition of mTORC1 signaling reverts cognitive and affective deficits in a mouse model of Parkinson’s disease. Frontiers in Neurology 9:208.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Fisone, Gilberto
Co-supervisor: Bonito-Oliva, Alessandra; Petrovic, Predrag; Fisahn, André
Issue date: 2018-04-26
Rights:
Publication year: 2018
ISBN: 978-91-7831-068-5
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