Acetylcholine Modulates Cerebellar Granule Cell Spiking by Regulating the Balance of Synaptic Excitation and Inhibition.
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Sensorimotor integration in the cerebellum is essential for refining motor output, and the first stage of this processing occurs in the granule cell layer. Recent evidence suggests that granule cell layer synaptic integration can be contextually modified, although the circuit mechanisms that could mediate such modulation remain largely unknown. Here we investigate the role of ACh in regulating granule cell layer synaptic integration in male rats and mice of both sexes. We find that Golgi cells, interneurons that provide the sole source of inhibition to the granule cell layer, express both nicotinic and muscarinic cholinergic receptors. While acute ACh application can modestly depolarize some Golgi cells, the net effect of longer, optogenetically induced ACh release is to strongly hyperpolarize Golgi cells. Golgi cell hyperpolarization by ACh leads to a significant reduction in both tonic and evoked granule cell synaptic inhibition. ACh also reduces glutamate release from mossy fibers by acting on presynaptic muscarinic receptors. Surprisingly, despite these consistent effects on Golgi cells and mossy fibers, ACh can either increase or decrease the spike probability of granule cells as measured by noninvasive cell-attached recordings. By constructing an integrate-and-fire model of granule cell layer population activity, we find that the direction of spike rate modulation can be accounted for predominately by the initial balance of excitation and inhibition onto individual granule cells. Together, these experiments demonstrate that ACh can modulate population-level granule cell responses by altering the ratios of excitation and inhibition at the first stage of cerebellar processing.SIGNIFICANCE STATEMENT The cerebellum plays a key role in motor control and motor learning. While it is known that behavioral context can modify motor learning, the circuit basis of such modulation has remained unclear. Here we find that a key neuromodulator, ACh, can alter the balance of excitation and inhibition at the first stage of cerebellar processing. These results suggest that ACh could play a key role in altering cerebellar learning by modifying how sensorimotor input is represented at the input layer of the cerebellum.
Published Version (Please cite this version)
Fore, Taylor R, Benjamin N Taylor, Nicolas Brunel and Court Hull (2020). Acetylcholine Modulates Cerebellar Granule Cell Spiking by Regulating the Balance of Synaptic Excitation and Inhibition. The Journal of neuroscience : the official journal of the Society for Neuroscience, 40(14). pp. 2882–2894. 10.1523/jneurosci.2148-19.2020 Retrieved from https://hdl.handle.net/10161/23345.
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We use theoretical models of brain systems to investigate how they process and learn information from their inputs. Our current work focuses on the mechanisms of learning and memory, from the synapse to the network level, in collaboration with various experimental groups. Using methods from
statistical physics, we have shown recently that the synaptic
connectivity of a network that maximizes storage capacity reproduces
two key experimentally observed features: low connection probability
and strong overrepresentation of bidirectionnally connected pairs of
neurons. We have also inferred `synaptic plasticity rules' (a
mathematical description of how synaptic strength depends on the
activity of pre and post-synaptic neurons) from data, and shown that
networks endowed with a plasticity rule inferred from data have a
storage capacity that is close to the optimal bound.
We study neural circuits in the rodent cerebellum involved with motor timing, coordination, and learning. Our approaches include high-speed multiphoton imaging from cerebellar neurons in vivo during behavior, extracellular and intracellular electrophysiology in vivo as well as in acute brain slices, and anatomical techniques such as cell type-specific viral labeling to identify functional circuit pathways that connect the cerebellum with other brain regions.
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