The Development and Function of Cerebellar Nucleo-Olivary Neurons

Student thesis: Doctoral ThesisDoctor of Philosophy


The neuronal circuitry between the cerebellum and inferior olive is of crucial importance in motor function. While the climbing fibres that send olivary signals to the cerebellum have been shown to play a significant role in modulating cerebellar output, little is known of the origins or function of the nucleo-olivary neurons of the cerebellar nuclei that send reciprocal feedback to the inferior olive.
In this thesis, the Sox14 gene is identified as a novel genetic developmental marker for nucleo-olivary neurons of the lateral and interposed, but not medial, cerebellar nuclei. Using Sox14-GFP and Sox14-Cre knock-in and Sox14 knock-out mouse lines, in combination with birth dating, marker analysis and tract tracing techniques, I characterised the projections and development of nucleo-olivary neurons. These experiments established that Sox14 is expressed in early born GABAergic nuclear projection neurons that exclusively target the inferior olive. A separate population of Sox14+ cells in Nucleus Y target the oculomotor nucleus. Sox14 expression is observed from E12.5 directly ventral to the nuclear transitory zone, where glutamatergic nuclear cells are known to reside during development.
Injection of Cre-dependent AAV-mCherry-flex-dtA was used to drive expression of diphtheria toxin A subunit in Sox14 expressing cells. Ablation of Sox14+ nucleo-olivary neurons leads to some deficits in motor performance and motor learning. However, no deficits in associative motor learning were observed, suggesting that models of associative learning that invoke a key role for the nucleo-olivary feedback may be incorrect or incomplete.
This work establishes that nucleo-olivary neurons of the lateral and interposed cerebellar nuclei comprise a homogeneous and genetically distinct population and sheds light on the function of this projection in cerebellar function. Furthermore, this thesis establishes Sox14 transgenic mice as a unique tool in cerebellar research that will provide an important window on the function of the cerebellum in future studies.
Date of Award2018
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorRichard Wingate (Supervisor), Malcolm Logan (Supervisor) & Alessio Delogu (Supervisor)

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