PATHOPHYSIOLOGY OF THE CEREBELLUM Department of Pathophysiology Faculty
![PATHOPHYSIOLOGY OF THE CEREBELLUM Department of Pathophysiology Faculty of Medicine in Pilsen Charles University PATHOPHYSIOLOGY OF THE CEREBELLUM Department of Pathophysiology Faculty of Medicine in Pilsen Charles University](https://slidetodoc.com/presentation_image_h/1341d308db68136a5b716fb058c37269/image-1.jpg)
PATHOPHYSIOLOGY OF THE CEREBELLUM Department of Pathophysiology Faculty of Medicine in Pilsen Charles University 1
![STRUCTURE OF THE CEREBELLUM • Cortex - stratum moleculare (A) - stratum gangliosum (B) STRUCTURE OF THE CEREBELLUM • Cortex - stratum moleculare (A) - stratum gangliosum (B)](http://slidetodoc.com/presentation_image_h/1341d308db68136a5b716fb058c37269/image-2.jpg)
STRUCTURE OF THE CEREBELLUM • Cortex - stratum moleculare (A) - stratum gangliosum (B) - stratum granulosum (C) • White matter B A C • Cerebellar nuclei - nc. dentatus - nc. emboliformis - nc. globosus - nc. fastigii 2
![stellate cell stratum moleculare basket cell Purkinje cell stratum gangliosum granule cells stratum granulosum stellate cell stratum moleculare basket cell Purkinje cell stratum gangliosum granule cells stratum granulosum](http://slidetodoc.com/presentation_image_h/1341d308db68136a5b716fb058c37269/image-3.jpg)
stellate cell stratum moleculare basket cell Purkinje cell stratum gangliosum granule cells stratum granulosum efferent cerebellar pathways white matter mossy fibre cerebellar nuclei climbing fibre excitatory synapse inhibitory synapse 3
![FUNCTION OF THE CEREBELLUM 1. Archicerebelum (vestibulocerebellum): equilibrium maintenance, head and eye movement coordination FUNCTION OF THE CEREBELLUM 1. Archicerebelum (vestibulocerebellum): equilibrium maintenance, head and eye movement coordination](http://slidetodoc.com/presentation_image_h/1341d308db68136a5b716fb058c37269/image-4.jpg)
FUNCTION OF THE CEREBELLUM 1. Archicerebelum (vestibulocerebellum): equilibrium maintenance, head and eye movement coordination 2. Paleocerebelum (spinocerebellum): - muscle tone regulation 3. Neocerebelum (corticocerebellum): - movement coordination 4
![CAUSATIONS OF CEREBELLAR DISORDERS • inborn developmental defects – often accompanied with affections of CAUSATIONS OF CEREBELLAR DISORDERS • inborn developmental defects – often accompanied with affections of](http://slidetodoc.com/presentation_image_h/1341d308db68136a5b716fb058c37269/image-5.jpg)
CAUSATIONS OF CEREBELLAR DISORDERS • inborn developmental defects – often accompanied with affections of the brain-stem • trauma • intoxications - acute or chronic ethanol intoxication • vascular causations – ischemia, hemorrhagia • cerebellar tumours • sclerosis multiplex • inflammations – cerebelitis • hereditary spinocerebelar degenerations A) autosomal recessive: - Friedreich‘s ataxia - ataxia treleangiectatica - abetalopoproteinemia - ataxia with isolated vitamin-E deficiency B) autosomal dominant: - spinocerebelar ataxia SCA 1 – SCA 7 - episodic ataxia type 1 and 2 (EA-1, EA-2) 5
![MANIFESTATIONS OF CEREBELLAR DISORDERS – EXTINCTION SYNDROME Cerebellar ataxia: • posture disorders – titubations, MANIFESTATIONS OF CEREBELLAR DISORDERS – EXTINCTION SYNDROME Cerebellar ataxia: • posture disorders – titubations,](http://slidetodoc.com/presentation_image_h/1341d308db68136a5b716fb058c37269/image-6.jpg)
MANIFESTATIONS OF CEREBELLAR DISORDERS – EXTINCTION SYNDROME Cerebellar ataxia: • posture disorders – titubations, falls (especially rearwards – independent on head position), posture with wide basis • ambulation disorders – wobble, retropulsions and propulsions • hypermetria • movement coordination disorders • adiadochokinesis • speaking disorders – because of adiadochokinesis of orofacial muscles Tremor – intention (during goal-directed movements) Disorders of muscular tone – hypertonia of trunk extensors and hypotonia of limb muscles Defects of cognitive functions 6
![MANIFESTATIONS OF CEREBELLAR DISORDERS – IRRITATION SYNDROME Opposite to the extinction syndrome, similar to MANIFESTATIONS OF CEREBELLAR DISORDERS – IRRITATION SYNDROME Opposite to the extinction syndrome, similar to](http://slidetodoc.com/presentation_image_h/1341d308db68136a5b716fb058c37269/image-7.jpg)
MANIFESTATIONS OF CEREBELLAR DISORDERS – IRRITATION SYNDROME Opposite to the extinction syndrome, similar to parkinsonism • increased plastic tone of flexors • flexion holding of the trunk and limbs • static tremor • hypokinesis or akinesis 7
![Animal model of cerebellar disorder: Lurcher mutant mice - a natural model of olivocerebellar Animal model of cerebellar disorder: Lurcher mutant mice - a natural model of olivocerebellar](http://slidetodoc.com/presentation_image_h/1341d308db68136a5b716fb058c37269/image-8.jpg)
Animal model of cerebellar disorder: Lurcher mutant mice - a natural model of olivocerebellar degeneration, a mutation of the 2 -glutamate receptor gene - used for investigation of consequences of the neurodegeneration and of therapeutic methods Heterozygots (+/Lc) – Lurcher mutants: • complete loss of cerebellar Purkinje cells within 3 months of postnatal life - excitotoxic apoptosis • secondary decrease of number of cerebellar granule cells and inferior olivary neurons • cerebellar ataxia, deterioration of cognitive functions, higher CNS excitability, higher sensitivity to neurotoxic agents Unaffected homozygos (+/+) - wild type: completely healthy Affected homozygots (Lc/Lc): not viable 8
![Cerebellum of Lurcher mutant mice Nissl staining +/+ Nissl staining +/Lc anticalbindin +/+ (P Cerebellum of Lurcher mutant mice Nissl staining +/+ Nissl staining +/Lc anticalbindin +/+ (P](http://slidetodoc.com/presentation_image_h/1341d308db68136a5b716fb058c37269/image-9.jpg)
Cerebellum of Lurcher mutant mice Nissl staining +/+ Nissl staining +/Lc anticalbindin +/+ (P 21) anticalbindin +/Lc (P 21) 9
![Apoptosis of Purkinje cells in Lurcher mutant mice Fluorescent doublestaining: Lucifer Yellow, Di. D Apoptosis of Purkinje cells in Lurcher mutant mice Fluorescent doublestaining: Lucifer Yellow, Di. D](http://slidetodoc.com/presentation_image_h/1341d308db68136a5b716fb058c37269/image-10.jpg)
Apoptosis of Purkinje cells in Lurcher mutant mice Fluorescent doublestaining: Lucifer Yellow, Di. D oil (Kröger a Wagner, 1998) 1 3 2 4 10
![stellate cell stratum moleculare basket cell Purkinje cell stratum gangliosum granule cells stratum granulosum stellate cell stratum moleculare basket cell Purkinje cell stratum gangliosum granule cells stratum granulosum](http://slidetodoc.com/presentation_image_h/1341d308db68136a5b716fb058c37269/image-11.jpg)
stellate cell stratum moleculare basket cell Purkinje cell stratum gangliosum granule cells stratum granulosum efferent cerebellar pathways white matter mossy fibre cerebellar nuclei climbing fibre excitatory synapse inhibitory synapse 11
![stellate cell stratum moleculare basket cell Purkinje cell stratum gangliosum granule cells stratum granulosum stellate cell stratum moleculare basket cell Purkinje cell stratum gangliosum granule cells stratum granulosum](http://slidetodoc.com/presentation_image_h/1341d308db68136a5b716fb058c37269/image-12.jpg)
stellate cell stratum moleculare basket cell Purkinje cell stratum gangliosum granule cells stratum granulosum efferent cerebellar pathways white matter mossy fibre cerebellar nuclei climbing fibre excitatory synapse inhibitory synapse 12
![MOTOR COORDINATION TESTS Fall – ability to land on all four limbs Horizontal bar MOTOR COORDINATION TESTS Fall – ability to land on all four limbs Horizontal bar](http://slidetodoc.com/presentation_image_h/1341d308db68136a5b716fb058c37269/image-13.jpg)
MOTOR COORDINATION TESTS Fall – ability to land on all four limbs Horizontal bar – ability to hold on a horizontal wire Ladder – ability to hold on a slanting ladder Bridge – ability to hold on a narrow horizontal bridge Rotarod – ability to hold on a rotating cylinder 13
![Mouse model of cerebellar ataxia 14 Mouse model of cerebellar ataxia 14](http://slidetodoc.com/presentation_image_h/1341d308db68136a5b716fb058c37269/image-14.jpg)
Mouse model of cerebellar ataxia 14
![HORIZONTAL BAR • The mouse is hang with its frontal limbs on a horizontal HORIZONTAL BAR • The mouse is hang with its frontal limbs on a horizontal](http://slidetodoc.com/presentation_image_h/1341d308db68136a5b716fb058c37269/image-15.jpg)
HORIZONTAL BAR • The mouse is hang with its frontal limbs on a horizontal wire. • Criterion of the success trial: to stay on the bar for 60 s, or to leave the apparatus actively 15
![HORIZONTAL BAR 16 HORIZONTAL BAR 16](http://slidetodoc.com/presentation_image_h/1341d308db68136a5b716fb058c37269/image-16.jpg)
HORIZONTAL BAR 16
![LADDER • The mouse is placed into the middle of a slanting ladder (head LADDER • The mouse is placed into the middle of a slanting ladder (head](http://slidetodoc.com/presentation_image_h/1341d308db68136a5b716fb058c37269/image-17.jpg)
LADDER • The mouse is placed into the middle of a slanting ladder (head up position). • Criterion of the success trial: to stay on the ladder for 60 s, or to leave the apparatus actively 17
![LADDER 18 LADDER 18](http://slidetodoc.com/presentation_image_h/1341d308db68136a5b716fb058c37269/image-18.jpg)
LADDER 18
![BRIDGE • The mouse is placed transversally into the middle of a narrow horizontal BRIDGE • The mouse is placed transversally into the middle of a narrow horizontal](http://slidetodoc.com/presentation_image_h/1341d308db68136a5b716fb058c37269/image-19.jpg)
BRIDGE • The mouse is placed transversally into the middle of a narrow horizontal bridge. • Criterion of the success trial: to stay on the bar for 120 s, or to leave the apparatus actively 19
![BRIDGE 20 BRIDGE 20](http://slidetodoc.com/presentation_image_h/1341d308db68136a5b716fb058c37269/image-20.jpg)
BRIDGE 20
![ROTAROD • The mouse is placed on a rotating cylinder (head in the direction ROTAROD • The mouse is placed on a rotating cylinder (head in the direction](http://slidetodoc.com/presentation_image_h/1341d308db68136a5b716fb058c37269/image-21.jpg)
ROTAROD • The mouse is placed on a rotating cylinder (head in the direction of rotation). • Criterion of the success trial: to stay on the bar for 60 s, or to leave the apparatus actively 21
![ROTAROD 22 ROTAROD 22](http://slidetodoc.com/presentation_image_h/1341d308db68136a5b716fb058c37269/image-22.jpg)
ROTAROD 22
![EVALUATION OF MOTOR COORDINATION TESTS Mean success rate in motor coordination tests in wild EVALUATION OF MOTOR COORDINATION TESTS Mean success rate in motor coordination tests in wild](http://slidetodoc.com/presentation_image_h/1341d308db68136a5b716fb058c37269/image-23.jpg)
EVALUATION OF MOTOR COORDINATION TESTS Mean success rate in motor coordination tests in wild type (WT) and Lurcher mutant mice (Lc) - in % of trials bar ladder rotarod 23
![THE END 24 THE END 24](http://slidetodoc.com/presentation_image_h/1341d308db68136a5b716fb058c37269/image-24.jpg)
THE END 24
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