Robust transmission of rate coding in the inhibitory Purkinje cell to cerebellar nuclei pathway in awake mice.

Neural coding through inhibitory projection pathways remains poorly understood. We analyze the transmission properties of the Purkinje cell (PC) to cerebellar nucleus (CN) pathway in a modeling study using a data set recorded in awake mice containing respiratory rate modulation. We find that inhibitory transmission from tonically active PCs can transmit a behavioral rate code with high fidelity. We parameterized the required population code in PC activity and determined that 20% of PC inputs to a full compartmental CN neuron model need to be rate-comodulated for transmission of a rate code. Rate covariance in PC inputs also accounts for the high coefficient of variation in CN spike trains, while the balance between excitation and inhibition determines spike rate and local spike train variability. Overall, our modeling study can fully account for observed spike train properties of cerebellar output in awake mice, and strongly supports rate coding in the cerebellum

Acetylcholine in the Interpositus Cerebellar Nuclei

The interpositus cerebellar nuclei are important for motor control and coordinate movementsacross multiple muscle groups, including limbs, face, and neck. The interpositus nuclei receivedense cholinergic inputs from the pedunculopontine tegmental nucleus (PPN), one of themain sources of cerebellar acetylcholine, but the role of this cholinergic neuromodulatoryinput is not completely understood.The work presented in this thesis found that activating cholinergic receptors in vitro had mixedeffects on the electrophysiological properties of cells in the interpositus cerebellar nuclei. Theintrinsic membrane, action potential and firing properties of cells were recorded at baseline,and after application of cholinergic agonist carbachol. Post-hoc, principal component analysisand k-means cluster analysis were employed to group the cells into two putative groups basedon their different baseline electrophysiological features. These were likely to be two types ofprojection neurons from the interpositus nuclei.The aim of the other work presented in this thesis was to study the role of cholinergicsignalling in motor control. These experiments found that pharmacologically inhibitingmuscarinic receptor signalling in vivo using antagonists impaired performance on the beamwalking task: animals were fully trained on the task that required skilled paw placement tocross a narrow beam. Conversely, blocking signalling via nicotinic receptors improved beamwalking performance.Similarly, chemogenetic inhibition of the PPN projection to the interpositus cerebellar nucleialso improved motor performance on the beam. Finally, a pilot study using transgenic rats(ChAT-Cre to selectively target cholinergic projections), found that chemogenetic inhibition ofthe cholinergic projection from the PPN to the cerebellar nuclei improved motor performance.However, chemogenetic cholinergic inhibition at the start of beam walking training impairedmotor learning.In conclusion, this thesis has presented evidence supporting the role of cholinergic signallingin the cerebellar nuclei in modulating motor performance, motor learning and consummatorybehaviours