Examining the computational circuitry of the cerebellar cortex
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The main function of the cerebellum is to integrate information from the body and other brain regions to direct the smooth coordination of muscles. Most of the processing of this information occurs in the cerebellar cortex, where it is distributed to billions of excitatory granule cells in the input layer, is modulated by inhibitory interneurons, and converges in the output layer for processing by a much smaller number of Purkinje cells. In this thesis we set out to explore specific factors contributing to shaping the output of Purkinje cells, at both intrinsic and network levels. In a first study, we probed Purkinje cell excitability (Chapter II). Our lab recently showed that reduced activity of the sodium pump in cerebellar neurons causes dystonia. Our experiments using whole-cell current clamp in rat cerebellar slices show that blocking pump activity increases the gain of the Purkinje cell input-output function, revealing a surprising mechanism by which Purkinje cell output can be dynamically regulated. In the second study, we probed the circuitry surrounding Purkinje cells, and characterized the functional organization of granule cell inputs to Purkinje cells and their modulation by inhibition. These studies applying extracellular and whole-cell voltage clamp recording and flash photolysis of caged glutamate in rat cerebellar slices revealed that 1) the bidirectional activation of Purkinje cells exhibits a center-surround organization, with responses exhibiting a systematic progression from pure excitation to pure inhibition moving laterally from a given Purkinje cell (Chapter III); and 2) the strengths of the two types of granule cell input to Purkinje cells are functionally comparable (Appendix). Finally, in Chapter IV, we took advantage of a mouse model of ataxia to probe dysfunction of Purkinje cells. Using a combination of in vitro and in vivo electrophysiology, we found that Purkinje cells in the ataxic mice are more excitable, and likely through network compensation, that inhibition is potentiated. This increased inhibition on Purkinje cells decreases their firing rate as well as makes it more erratic. Our findings thus highlight how a combination of altered excitability and disruption in synaptic inhibition can transform the output of Purkinje cells and cause ataxia.
Source: Dissertation Abstracts International, Volume: 73-05, Section: B, page: 2702.;Advisors: Kamran Khodakhah.