SSA:Cholinergic modulation of cerebellar dependent motor learning
Lead Research Organisation:
University of Bristol
Department Name: Physiology and Pharmacology
Abstract
The improvement of motor skills with practice occurs through motor learning in the cerebellum and
is required for everyday life. Acetylcholine (ACh) is required for learning and memory and regulation
of sleep/wake cycles. An extensive network of cholinergic fibres courses throughout the cerebellum
but little is known about the significance of ACh projections to the cerebellum. This project will test
the hypothesis that cholinergic projections from the pedunculopontine nucleus (PPN) to the
cerebellum regulate synaptic and neuronal function to bring about encoding, consolidation and
maintenance of motor learning during different phases of sleep and wake. The student will join an
interdisciplinary team of 7 postdocs and 8 PhD students supervised by Profs Bashir and Apps.
The hypothesis will be tested directly using in vitro and in vivo electrophysiological methods,
optogenetic manipulation of cholinergic inputs to cerebellum, behavioural investigation of motor
learning and computational modelling. The in vitro methods allow the study of cellular mechanisms in
ways not possible in behaving animals, whereas the awake in vivo animal experiments allow study of
neural circuits and their functional and behavioural significance. The brain slice and whole animal work
will be mutually reinforcing. In vivo work: forelimb motor learning paradigms will be used in freely
moving animals.
Rats will be chronically implanted with tetrodes in the PPN, cerebellar cortex and/or cerebellar nuclei
to monitor single unit and LFP activity during motor learning. Pharmacological antagonists and/or
optogenetic manipulation of cholinergic inputs will determine the role of different ACh receptor
subtypes and the timing of ACh inputs during learning.
In vitro Work: whole cell patch clamp recordings from cerebellar slices combined with optogenetic
stimulation of ACh inputs will investigate how ACh controls: i) intrinsic properties; ii) synaptic inputs;
and iii) the plasticity of these synaptic inputs in Purkinje cells and CN output neurons to provide an
essential foundation for understanding molecular, cellular and synaptic mechanisms by which ACh
controls cerebellar function. The in vitro and in vivo data will be implemented within a biophysical
model to test hypotheses of ACh modulation of cerebellar neuronal networks.
Together results from this project will forge new understanding of how ACh controls cerebellar
function to bring about motor skills that are essential for everyday life.
is required for everyday life. Acetylcholine (ACh) is required for learning and memory and regulation
of sleep/wake cycles. An extensive network of cholinergic fibres courses throughout the cerebellum
but little is known about the significance of ACh projections to the cerebellum. This project will test
the hypothesis that cholinergic projections from the pedunculopontine nucleus (PPN) to the
cerebellum regulate synaptic and neuronal function to bring about encoding, consolidation and
maintenance of motor learning during different phases of sleep and wake. The student will join an
interdisciplinary team of 7 postdocs and 8 PhD students supervised by Profs Bashir and Apps.
The hypothesis will be tested directly using in vitro and in vivo electrophysiological methods,
optogenetic manipulation of cholinergic inputs to cerebellum, behavioural investigation of motor
learning and computational modelling. The in vitro methods allow the study of cellular mechanisms in
ways not possible in behaving animals, whereas the awake in vivo animal experiments allow study of
neural circuits and their functional and behavioural significance. The brain slice and whole animal work
will be mutually reinforcing. In vivo work: forelimb motor learning paradigms will be used in freely
moving animals.
Rats will be chronically implanted with tetrodes in the PPN, cerebellar cortex and/or cerebellar nuclei
to monitor single unit and LFP activity during motor learning. Pharmacological antagonists and/or
optogenetic manipulation of cholinergic inputs will determine the role of different ACh receptor
subtypes and the timing of ACh inputs during learning.
In vitro Work: whole cell patch clamp recordings from cerebellar slices combined with optogenetic
stimulation of ACh inputs will investigate how ACh controls: i) intrinsic properties; ii) synaptic inputs;
and iii) the plasticity of these synaptic inputs in Purkinje cells and CN output neurons to provide an
essential foundation for understanding molecular, cellular and synaptic mechanisms by which ACh
controls cerebellar function. The in vitro and in vivo data will be implemented within a biophysical
model to test hypotheses of ACh modulation of cerebellar neuronal networks.
Together results from this project will forge new understanding of how ACh controls cerebellar
function to bring about motor skills that are essential for everyday life.
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/M009122/1 | 01/10/2015 | 31/03/2024 | |||
| 2279396 | Studentship | BB/M009122/1 | 01/10/2019 | 30/09/2023 | Cristiana Iosif |
| Description | This work studied the role of acetylcholine, a projection described anatomically, in modulating cerebellar behaviours. The cholinergic inputs to the cerebellum mainly arise from the pedunculopontine tegmental nucleus in the brainstem. This work has found that selective blockage of nicotinic and muscarinic receptors in the cerebellar nuclei has opposing effects on motor performance. In this work, inhibiting transmission via nicotinic receptors in the cerebellar nuclei in the behaving animal using pharmacological agents significantly improved motor performance. Similarly, inhibiting the projection from the pedunculopontine tegmental nucleus to the cerebellar nuclei also improved motor performance. This would potentially suggest the existence of a new therapeutic avenue for motor disorders. On the other hand, using pharmacological agents to inhibit transmission via muscarinic receptors has led to a significant worsening in motor performance, suggesting that signalling via muscarinic receptors may impact healthy motor performance. |
| Exploitation Route | The importance of the projection from the pedunculopontine nucleus to the cerebellar nuclei for motor performance is a novel finding and could contribute, down the line, to studies and therapies for motor degenerative diseases. |
| Sectors | Pharmaceuticals and Medical Biotechnology |