Cerebellar output controls generalized spike-and-wave discharge occurence

© 2015 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (CC BY-NC-ND 4.0) which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Disrupting thalamocortical activity patterns has proven to be a promising approach to stop generalized spike-and-wave discharges (GSWDs) characteristic of absence seizures. Here, we investigated to what extent modulation of neuronal firing in cerebellar nuclei (CN), which are anatomically in an advantageous position to disrupt cortical oscillations through their innervation of a wide variety of thalamic nuclei, is effective in controlling absence seizuresPeer reviewedFinal Published versio

Dynamical principles in neuroscience

Dynamical modeling of neural systems and brain functions has a history of success over the last half century. This includes, for example, the explanation and prediction of some features of neural rhythmic behaviors. Many interesting dynamical models of learning and memory based on physiological experiments have been suggested over the last two decades. Dynamical models even of consciousness now exist. Usually these models and results are based on traditional approaches and paradigms of nonlinear dynamics including dynamical chaos. Neural systems are, however, an unusual subject for nonlinear dynamics for several reasons: (i) Even the simplest neural network, with only a few neurons and synaptic connections, has an enormous number of variables and control parameters. These make neural systems adaptive and flexible, and are critical to their biological function. (ii) In contrast to traditional physical systems described by well-known basic principles, first principles governing the dynamics of neural systems are unknown. (iii) Many different neural systems exhibit similar dynamics despite having different architectures and different levels of complexity. (iv) The network architecture and connection strengths are usually not known in detail and therefore the dynamical analysis must, in some sense, be probabilistic. (v) Since nervous systems are able to organize behavior based on sensory inputs, the dynamical modeling of these systems has to explain the transformation of temporal information into combinatorial or combinatorial-temporal codes, and vice versa, for memory and recognition. In this review these problems are discussed in the context of addressing the stimulating questions: What can neuroscience learn from nonlinear dynamics, and what can nonlinear dynamics learn from neuroscience?This work was supported by NSF Grant No. NSF/EIA-0130708, and Grant No. PHY 0414174; NIH Grant No. 1 R01 NS50945 and Grant No. NS40110; MEC BFI2003-07276, and Fundación BBVA

Cerebellar Codings for Control of Compensatory Eye Movements

This thesis focuses on the control of the cerebellum on motor behaviour, and more specifically on the role of the cerebellar Purkinje cells in exerting this control. As the cerebellum is an online control system, we look at both motor performance and learning, trying to identify components involved at the molecular, cellular and network level. To study the cerebellum we used the vestibulocerebellum, with visual and vestibular stimulation as input and eye movements as recorded output. The advantage of the vestibulocerebellum over other parts is that the input given is highly controllable, while the output can be reliably measured, and performance and learning can be easily studied. In addition, we conducted electrophysiological recordings from the vestibulocerebellum, in particular of Purkinje cells in the flocculus. Combining the spiking behaviour of Purkinje cells with visual input and eye movement output allowed us to study how the cerebellum functions and using genetically modified animals we could determine the role of different elements in this system. To provide some insights in the techniques used and the theory behind them, we will discuss the following topics in this introduction: compensatory eye movements, the anatomy of pathways to, within and out of the flocculus, the cellular physiology of Purkinje cells in relation to performance and the plasticity mechanisms related to motor learning

Kv3 channels in the murine lumbo-sacral spinal cord

Ion channels are important in a range of physiological processes and can be targeted pharmacologically and therapeutically. Kv3 channels are voltage-gated potassium ion channels important in neuronal firing and synaptic transmission and are highly expressed in the brain and spinal cord. The main aim of this thesis was to investigate the role of Kv3 channels in the spinal cord and we did this in three ways. Using fluorescence immunohistochemistry we identified, for the first time, expression of Kv3 subunits in the murine lumbosacral spinal cord, at the level of neuronal circuitry that regulates bladder function. Specifically, some of this expression could be attributed to both excitatory and inhibitory synaptic structures closely apposed to bladder motoneurones, the final output neurones in the control of bladder function. Kv3 expression at these locations was susceptible to ageing and was reduced in aged mice. Kv3 channels were functional in synapses as Kv3 blockade with TEA increased the amplitude of the post-synaptic response. To determine the role of Kv3 channels in a function of the spinal cord, specifically, control over bladder function, we used a modulator AUT1 (Autifony Therapeutics Ltd), which is selective for Kv3 channels, Treatment with AUT1 reduced bladder output in a dose-dependent manner, acutely in young mice and chronically in aged mice suggesting involvement of Kv3 channels in bladder output. The effect of AUT1 on specific Kv3 subunits was determined in HEK expression cell lines where it was found to modulate both a previously unexplored subunit (Kv3.4a) and a physiologically relevant heteromer. In lumbosacral spinal cord slices, AUT1 suppressed the excitability of interneurones, suggesting that the reduction in bladder output could be occurring at the level of interneurones in the lumbosacral spinal cord. Modulating Kv3 channels in this way may be a viable therapeutic strategy for conditions presenting with an overactive bladder