Pathophysiology of cerebellar-induced motor disorders
Başlık çevirisi mevcut değil.
- Tez No: 401307
- Danışmanlar: DR. KAMRAN KHODAKHAH
- Tez Türü: Doktora
- Konular: Nöroloji, Nöroşirürji, Neurology, Neurosurgery
- Anahtar Kelimeler: Belirtilmemiş.
- Yıl: 2012
- Dil: İngilizce
- Üniversite: Yeshıva Unıversıty
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Nörobilim Ana Bilim Dalı
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: Belirtilmemiş.
Özet
Özet yok.
Özet (Çeviri)
The cerebellum is the brain region that ensures the proper timing and coordination of movements. Not surprisingly, the best appreciated symptom of cerebellar dysfunction is ataxia, a loss of motor coordination. Mounting evidence however, implicates the cerebellum in a host of motor disorders characterized by involuntary muscle contractions such as dyskinesia and dystonia. Given the commonly ascribed function of the cerebellum, that it coordinates movements but does not initiate them, the fact that it not only plays a role in but often is the source of dysfunction in many such disorders is counterintuitive. Episodic ataxia type-2 (EA2) is one such condition that results from mutations in the gene encoding P/Q-type voltage-gated calcium channel. In humans, the phenotype is characterized by a moderate basal ataxia as well as paroxysmal attacks of severe ataxia and dyskinesia triggered by caffeine, ethanol and psychological stress. The tottering mouse is a faithful model of EA2 and mimics the human EA2 condition both genetically and phenotypically. In the first study, we used the spectrum of motor dysfunction displayed by the tottering to delineate the cerebellar output patterns associated with the disorder's episodic phenotype. Extracellular recordings from single Purkinje cells in the awake tottering in the presence and absence of dyskinesia episodes revealed that during attacks, their simple spike activity is significantly altered and characterized by erratic firing and bursts of high frequency. This activity pattern was necessary and sufficient for the expression of attacks, and resulted in an aberrant cerebellar output. Moreover, we found the severity of the tottering's motor symptoms to be correlated with the extent of Purkinje cell burst firing and the noise in the consequent cerebellar output. Episodic channelopathies such as EA2 are characterized by a normal or mildly symptomatic baseline phenotype, interrupted by attacks of severe symptoms. A common feature of these disorders is that in all of them, attacks are induced by a same set of triggers, caffeine, alcohol, and stress. This suggests the existence of a shared mechanism for attack initiation. In the next study, we used the tottering as a model for episodic neurological disorders and combined electrophysiological techniques with a pharmacological approach to examine the pathway by which stress triggers attacks of dyskinesia. We found blocking cerebellar noradrenergic receptors to prevent stress from triggering an attack and the release of norepinephrine from the locus ceruleus to be necessary and sufficient to induce the transient motor symptoms. Further examination revealed the norepinephrine-induced inhibition of small-conductance calcium-activated potassium channels as a potential mechanism underlying the dysfunctional firing patterns observed in vivo. To further examine the cerebellar output patterns associated with dysfunctional motor phenotypes, we examined them in a mouse model of spinocerebellar ataxia as well as the car8 mutant mouse, whose phenotype is characterized by a severe form of ataxia and appendicular dystonia. In both mice, we found the extent of aberrant output from the cerebellum to predict the severity of the motor dysfunction, which could be alleviated by forcing Purkinje cells to fire more regularly. We then recorded the activity of DCN neurons in wild type mice while they performed a variety of cerebellar-dependent motor tasks. The erratic firing pattern observed in mutants never occurred in wild types during any of the physiologically relevant conditions, further substantiating a causal relationship between aberrant cerebellar output and motor dysfunction. Taken together, the results from this thesis support the conclusion that cerebellar ataxia is caused by diminished information content of the cerebellar output signals, whereas dystonia and dyskinesia result from bursting activity in the output nuclei acting as erroneous command signals to cause aberrant muscle contractions. In EA2, stress transiently triggers such a change in cerebellar output via norepinephrine-induced burst firing at the level of Purkinje cells.
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