The importance of complex spikes in cerebellar contributions to behaviour.

Lead Research Organisation: University of Bristol
Department Name: Physiology and Pharmacology

Abstract

The cerebellum is a major region of the brain vital for the coordination of movements. When in mammals (including humans) it is damaged ? e.g. due to stroke, genetic disorders, or tumours ? voluntary movements such as reaching to grasp an object become inaccurate and poorly timed; balance is severely disrupted; and our ability to learn new motor skills is impaired. How the internal circuitry of the cerebellum ensures that movements are performed smoothly and accurately remains unknown. Neurones called Purkinje cells are central to this function because they form the only output of the cerebellar cortex. They influence activity in the cerebellar nuclei, which, in turn, provide the output of the cerebellum, so the way in which cerebellar nuclear activity is modified by Purkinje cells is central to understanding how the cerebellum exerts its control over movement. Purkinje cells are exceptional in the mammalian brain in that they discharge two very different types of electrical impulse - simple spikes and complex spikes. The latter are thought to hold the key to cerebellar operation but their role in movement control remains a hotly debated issue. In pilot experiments we have found that complex spikes can be further categorized into two different types: spiking and non-spiking; and that the type of complex spike generated at any given time by a Purkinje cell has an effect on the on-going simple spike activity of the same cell. This has important implications for cerebellar information processing because the two types of complex spike are likely to produce distinct patterns of activity in the cerebellar nuclei, providing powerful timing signals that could underlie cerebellar contributions to coordinating movement. Using neuronal recording techniques we will determine how the two different types of complex spike: i) modify simple spike activity, and ii) influence cerebellar nuclear activity. One of the unique features of our experiments is that the neural recordings will include the natural activity patterns of complex spikes in action in animals performing a skilled reach-to-grasp movement under carefully controlled conditions. The results from this project will therefore shed light on fundamental brain processes underlying our ability to perform coordinated movements.

Technical Summary

The cerebellum is the largest sensorimotor structure in the brain and is crucial for the regulation of movements. It is a key target of damage in many diseases, including chronic alcoholism, fetal alcohol syndrome, a range of genetic disorders, tumours and stroke. Cerebellar damage causes impairment in motor function characterized by ataxia, dysmetria of voluntary movements and an impaired ability to learn new motor skills. How the cerebellum exerts its influence to control movements remains an issue of considerable uncertainty and debate. Because Purkinje cells are the only output of the cerebellar cortex, and their main target is the cerebellar nuclei, the behavioural consequences of cerebellar cortical damage ultimately must result from the abnormal synaptic control of the cerebellar nuclei by altered Purkinje cell activity. Purkinje cells discharge two types of impulse: simple spikes and complex spikes. In pilot experiments we have found that complex spikes can be further subdivided into two distinct waveforms (?spiking? and ?non-spiking?), and the type of complex spike a Purkinje cell discharges at any given time can influence simple spike firing rate of the cell under study. A fundamental gap in our knowledge of cerebellar information processing is the effect of Purkinje cell activity on nuclear output. Using a range of systems level approaches in anaesthetized, decerebrate and awake behaving animals (rats and cats), our overarching aim is therefore to determine how ?spiking? and ?non-spiking? complex spike activity modifies activity in the cerebellar nuclei. Specifically, we will test the hypothesis that ?spiking? and ?non-spiking? complex spikes exert a distinct inhibitory impact on cerebellar output: (i) indirectly, by differentially altering levels of Purkinje cell simple spike activity; and (ii) directly, by transmitting different amounts of information themselves to shape cerebellar nuclear activity. Acute experiments will study mechanisms in detail while chronic recording experiments will study Purkinje cell-cerebellar nuclear interactions during performance of a reach-retrieval task, including motor adaptation. Overall, the results from this project will significantly advance our understanding of how complex spike activity is translated into activity in the cerebellar nuclei and the behavioural significance of this transform. This should lead to an improved understanding of how movement disorders resulting from cerebellar damage occur.

Publications

10 25 50
 
Description PhD studentship
Amount £140,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2013 
End 09/2016
 
Description Strategic Skills Award
Amount £34,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2013 
End 09/2016
 
Description Eric Lang 
Organisation NYU Langone Medical Center
Department Neuroscience and Physiology Department
Country United States 
Sector Academic/University 
PI Contribution Dr Nadia Cerminara visited Dr Lang's lab to conduct pilot acute electrophysiological experiments. Dr Cerminara has been carrying out electrophysiological experiments in relation to this collaboration. Both Professor Richard Apps and Dr Nadia Cerminara met with Dr Eric Lang whilst attending the Society for Neuroscience meeting to discuss the outline/draft of a paper from this collaboration. The first paper from this collaboration has now been published and a further two papers are currently being drafted.
Collaborator Contribution Dr Eric Lang undertook a visit to Bristol to discuss experimental design and data analysis in relation to the collaboration. Dr Lang's lab has been conducting electrophysiological experiments in relation to this collaboration.
Impact Xiao et al (2014) Distinct patterns of Purkinje cell spontaneous activity in positive and negative zebrin bands. Abstracts - Society for Neuroscience. Society for Neuroscience 341.02 Xiao et al (2014) Systematic regional variations in purkinje cell spiking patterns. PLoS One. ;9(8):e105633 Cerminara et al (2012) Simple spike activity of cerebellar Purkinje cells associated with complex spike waveform variations. Abstracts - Society for Neuroscience. Society for Neuroscience 580.04 Xiao et al (2012) Investigation of potential determinants of the complex spike waveform: Zebrin reactivity and simple spike activity. Abstracts - Society for Neuroscience. Society for Neuroscience 580.05
Start Year 2010
 
Description Takeda 
Organisation Takeda Cambridge Ltd
Country United Kingdom 
Sector Private 
PI Contribution Pilot experiments to test effects of new compound on cerebellar activity in awake rats.
Collaborator Contribution Supply of test compound
Impact Too soon to report any results.
Start Year 2014
 
Description ' Research Without Borders' - Bristol Public engagement event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Industry/Business
Results and Impact An engagement event hosted by the Bristol Doctoral College to enable cross department discussions and networking.

Posters of own research presented ( at the level of the lay person) during the evening. Interactive display allowed attendees to experience behavioural concepts of the research (prism adaptation), as well as examples of neural probes used for data recording. Discussion of implications of (potential) research outcomes in context of the wider community ( understanding brain functions, brain-machine-interfaces, robotics and prostheses, etc)
Year(s) Of Engagement Activity 2016
 
Description Action Medicval Research charity event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact approx 50 fund raisers attended a meeting where my presentation was followed by a Q and A session about the work they had helped fund.

Inspired fund raisers to continue their efforts
Year(s) Of Engagement Activity 2012
 
Description Bristol Neuroscience festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact As Director of Bristol Neuroscience in 2013 I organised a major 2 day public event celebrating our 10th anniversary. Over 3000 members of the public attended.

In 2016, Dr Nadia Cerminara gave a public lecture and many other members of the group participated on interactive stands.

Pupils from over 15 local schools attended and provided enthusiastic feedback on how the event had educated them in neuroscience.
Year(s) Of Engagement Activity 2013,2016
 
Description Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Bennett, Apps, Cerminara, Whone, Goodfellow. (2018). Examining cerebellar-thalamo-cortical network dynamics in the harmaline rodent model of Essential Tremor. 1st International Tremor Congress.
Year(s) Of Engagement Activity 2018
 
Description Meet & greet Poster session with BBSRC management 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact As a part of a campus visit by BBSRC management persons, a small number of current SWBio DTP students presented posters of current works. Various aspects of the project were discussed.
Year(s) Of Engagement Activity 2008,2018
 
Description Royal Society MP/Scientist Pairing Scheme 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Thirty scientists spent the week at Westminster to learn how we can engage with government in terms of science policy through the various government departments and Parliament.

As a result from my participation in the scheme, the Centre for Public Engagement at the University of Bristol will be writing a story to highlight the ways in which researchers from the University can work with policy makers.
Year(s) Of Engagement Activity 2012