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Table of contents
Abstract
Résumé
List of figures an tables
Abbreviations
Chapter I – Introduction
I) Magnetic stimulation: a non-invasive approach to enhance neuroplasticity?
I.1) What is neuroplasticity?
I.2) Neuroplasticity over the lifespan
I.3) What is rTMS?
I.4) Basic principle of rTMS
I.5) TMS and rTMS applications
I.6) rTMS parameters
I.6.1) Pulse shapes and coil types
I.6.2) Stimulation intensity
I.6.3) rTMS frequency
II) Potential mechanisms underlying high-intensity rTMS
II.1) Synaptic plasticity: evidence from human studies
II.2) Direct evidence for synaptic plasticity induced by rTMS in animal models
II.2.1) rMS induced synaptic plasticity at excitatory synapses
II.2.2) rTMS modulation of inhibitory networks
II.2.3) Neurobiological effects of rTMS underlying induced plasticity
III) Low intensity magnetic stimulation
III.1) A need for a defined terminology and reproducible parameters
III.2) ELF-MF effects on the human brain
III.2.1) Effects on cortical excitability and brain oscillations
III.2.2) Effects on human brain functions and potential therapeutic applications
III.3) ELF-MF effects on animal models and underlying mechanisms
III.3.1) Magnetoreception: the cryptochrome radical-pair mechanism hypothesis
III.3.2) Biological events induced by ELF-MF
III.4) LI-rTMS effects on the rodent brain
III.5) Conclusion
IV) The cerebellum as a model to study LI-rTMS induced plasticity
IV.1) Cerebellum
IV.1.1) Cerebellar circuitry
IV.1.2) Cerebellar afferents
IV.2) The olivocerebellar pathway (OCP)
IV.2.1) The inferior olivary nucleus
IV.2.2) Climbing fibers and the OCP
IV.3) Development of the OCP
IV.3.1) Morphological PC differentiation
IV.3.2) Synaptogenesis of the olivocerebellar pathway and refinement of CF Projections
IV.4) Plasticity of the OCP following lesion
IV.4.1) Developmental plasticity of the OCP
IV.4.2) Plasticity in the mature OCP
IV.5) Ageing of the cerebellum
V) Summary and aims
Chapter II – Article1
Abstract
Introduction
Materials and Methods
Animals
Administration of Magnetic Stimulation
Behavioural analysis
Electrophysiological recording and biocytine filling
Morphological Analysis
Spine density
Sholl analysis
Statistical analysis
Results
Early postnatal PC dendritic development and synaptic maturation are not altered by LIrTMS
Mature Purkinje cell dendrites change little with age
Short-term treatment with LI-rTMS increases PC spine density and alters spine
morphology
Long-term treatment with LI-rTMS alters PC dendritic morphology
Handling and behavioural testing alone did not change dendritic morphology but
did alter spine density
Chronic LI-rTMS treatment does not alter motor function, but improves spatial
memory
Discussion
References
Figures and Legends
Chapter III – Article 2
Abstract
Introduction
Methods
Animals
In vivo olivocerebellar axonal transection (pedunculotomy)
Organotypic Cultures and cerebellar denervation
Magnetic stimulation
Immunohistochemistry
Histological analysis
qRT-PCR and gene analysis
Statistical analysis
Results
LI-rTMS induces CF reinnervation in vivo
LI-rMS induces PC reinnervation in vitro in a frequency dependent manner
LI-rMS induced reinnervation requires simultaneous stimulation of both pre-and postsynaptic
structures of the OCP
LI-rMS activates Purkinje cells and interneurons
LI-rMS modulates gene expression appropriately for PC reinnervation
Cryptochrome is required for LI-rMS-induced post-lesion repair
Discussion
Post-lesion repair depends on stimulation pattern, not numbers of pulses ………..
LI-rMS modifies gene expression in a frequency-dependent manner
LI-rMS potentially activates c-fos in PC and interneurons
Cryptochromes magnetoreceptors are key elements for the transduction of the
magnetic field into biological effect
Conclusions
References
Figures and Legends
Chapter IV– Article 3
Abstract
Introduction
Materials and Methods
Animals
Organotypic Cultures and cerebellar denervation
Genotyping
Administration of LI-rTMS
Behavioural analysis
Electrophysiological recording and biocytin filling
Immunohistochemistry and Histological analysis
qRT-PCR
Statistical analysis
Results
Post-lesion repair by LI-rMS is impaired in RORα haplodeficient hindbrain explants
Four weeks LI-rTMS and psychomotor activity moderately alters PC dendritic
morphology
Chronic LI-rTMS treatment does not alter motor or spatial behaviour of RORα+/
animals
RORα
PC responses to acute LI-rTMS treatment are small and differ with age
Discussion
References
Figures and Legends
Chapter V – General Discussion
V) Discussion
V.1) Mechanisms underlying the effectsof LI-rTMS
V.1.1) LI-rTMS pattern of frequency are crucial for the induction of biological effects
V.1.2) LI-rTMS requires cryptochromes to interact with biological tissue and potentially activate the transcription of signalling pathways
V.1.3) Intracellular calcium may be a second messenger mediating the biological effects of cryptoctochrome activation by LI-rMS
V.1.3.1) Intracellular levels and downstream signalling cascades
V.1.3.2) ROS production
V.1.4) RORα seems necessary to observe neural circuit plasticity and behavioural improvements induced by LI-rTMS
V.2) Biological effects of LI-rTMS
V.2.1) LI-rTMS targeting the cerebellum induces neuronal structural plasticity
and improvements in cerebellar related behaviour in adult mice
V.2.2) Reduced neural plasticity in aged mice may explain reduced LI-rTMS effects on cerebellar structural plasticity and behaviour
V.2.3) Further investigation into the effects of magnetic stimulation are required prior to eventual clinical use in young patients
VI Conclusions
