The prevailing model of cerebellar learning states that climbing fibers (CFs) are both driven by, and serve to correct, erroneous motor output. However, this model is grounded largely in studies of behaviors that utilize hardwired neural pathways to link sensory input to motor output. To test whether this model applies to more flexible learning regimes that require arbitrary sensorimotor associations, we developed a cerebellar-dependent motor learning task that is compatible with both mesoscale and single-dendrite-resolution calcium imaging in mice. We found that CFs were preferentially driven by and more time-locked to correctly executed movements and other task parameters that predict reward outcome, exhibiting widespread correlated activity in parasagittal processing zones that was governed by these predictions. Together, our data suggest that such CF activity patterns are well-suited to drive learning by providing predictive instructional input that is consistent with an unsigned reinforcement learning signal but does not rely exclusively on motor errors.
peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/281055 doi: bioRxiv preprint first posted online Mar. 13, 2018; 52A key role of the cerebellum is to form predictive associations between sensory inputs and 53 motor outputs. These sensorimotor predictions are critical for generating well-timed and accurate 54 movements, and in the absence of cerebellar function, the lack of such predictive motor output 55 severely impairs our ability to generate coordinated responses to stimuli in the external world. 56Classic models posit that the cerebellum generates sensorimotor predictions according to 57 a supervised learning rule [1][2][3] . According to such models, projections from the inferior olive called 58 climbing fibers are thought to signal motor errors, thus providing information to Purkinje cells 59 about discrepancies between the expected consequences of a motor command and subsequent 60 sensory feedback. To correct erroneous motor output, the climbing fibers instruct heterosynaptic 61 long-term depression 4-6 by producing powerful regenerative calcium transients [7][8][9] in Purkinje cell 62 dendrites called complex spikes 10, 11 . In so doing, climbing fibers are thought to appropriately 63 update the cerebellar forward internal model with revised sensorimotor predictions. 64This error-signaling framework provides a compelling explanation for climbing fiber activity 65 in a variety of simple behaviors, such as classical conditioning (e.g. eyeblink conditioning) or 66 adaptation (e.g. vestibulo-ocular reflex gain changes) 12-14 paradigms. These behaviors typically 67 make use of an unconditioned stimulus that drives both climbing fibers and the motor response 68 that requires modification. Hence, there is a yoked relationship between sensory input and motor 69 output that allows the climbing fibers to respond with high fidelity to movement error according to 70 the causal association between stimulus and movement. 71peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/281055 doi: bioRxiv preprint first posted online Mar. 13, 2018; 3 However, many forms of motor learning do not involve modifications to motor programs 72 driven by an unconditioned stimulus. Instead, the correct association between sensory input and 73 motor output must be learned through experience. Behavioral regimes with such requirements 74 are typically classified under the domain of voluntary motor learning, and cerebellar dysfunction 75 is also known to impair this type of learning 15 . However, it is unclear whether the current model of 76 supervised error signaling can account for either climbing fiber activity or the cerebellar 77 contribution to learning in these more flexible regimes. 78To test how the climbing fiber system is engaged under conditions where the sensory and 79 mot...
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.
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, though the circuit mechanisms that could mediate such modulation remain largely unknown. Here we investigate the role of Acetylcholine (ACh) in regulating granule cell layer synaptic integration. 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 non-invasive 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 StatementThe 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, Acetylcholine (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.
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