Clusters of cerebellar Purkinje cells control their afferent climbing fiber discharge

Abstract

Climbing fibers, the projections from the inferior olive to the cerebellar cortex, carry sensorimotor error and clock signals that trigger motor learning by controlling cerebellar Purkinje cell synaptic plasticity and discharge. Purkinje cells target the deep cerebellar nuclei, which are the output of the cerebellum and include an inhibitory GABAergic projection to the inferior olive. This pathway identifies a potential closed loop in the olivo-cortico-nuclear network. Therefore, sets of Purkinje cells may phasically control their own climbing fiber afferents. Here, using in vitro and in vivo recordings, we describe a genetically modified mouse model that allows the specific optogenetic control of Purkinje cell discharge. Tetrode recordings in the cerebellar nuclei demonstrate that focal stimulations of Purkinje cells strongly inhibit spatially restricted sets of cerebellar nuclear neurons. Strikingly, such stimulations trigger delayed climbing-fiber input signals in the stimulated Purkinje cells. Therefore, our results demonstrate that Purkinje cells phasically control the discharge of their own olivary afferents and thus might participate in the regulation of cerebellar motor learning.motor control | olivo-cerebellar loop | complex spikes T he cerebellar cortex is involved in a wealth of functions, from the control of posture to higher cognitive processes (1-3). Purkinje cells (PCs) are key processing units of the cerebellar cortex (4): each PC receives more than 175,000 parallel fiber synaptic inputs carrying information about the ongoing sensorymotor context. It also receives a single inferior olive afferent, the climbing fiber, which triggers a complex spike (CS), modulates PC firing (5), controls synaptic input plasticity, and has been proposed to carry error and clock signals to the cerebellum (2, 4-8). PCs are grouped in multiple parasagittal microzones, each receiving projections from separate areas of the inferior olive and projecting to subregions of the cerebellar nuclei (CN) (9-12). In the CN, PCs make inhibitory contacts on excitatory neurons that project to various premotor areas and propagate cerebellar computations to the motor system. Anatomical evidence indicates that PC terminals also contact CN inhibitory neurons that target inferior olive cells (13,14). This nucleoolivary pathway is topographically organized in multiple parallel projections to the inferior olive subnuclei (15), suggesting the existence of closed olivary-cortico-nuclear loops. Therefore, the discharge of a population of PCs in a microzone might not only shape the output of the cerebellum but also control its afferent climbing-fiber signal. Previous studies have shown that stimulation of the nucleo-olivary pathway significantly reduces olivary cell firing (16-18) and that pharmacological and genetic manipulations of PCs or olivary cell activity induce reciprocal modulations of the firing rate of PCs and climbing fibers (19, 20).These results indicate that PCs may tonically modulate the nucleo-olivary pathway. However, whether...

Purkinje cell activity during classical conditioning with different conditional stimuli explains central tenet of Rescorla–Wagner model

“…This is in perfect agreement with the observation that Purkinje cells control cells in the inferior olive from which they receive their climbing-fiber afferents (29,46).…”

In vivo analysis of Purkinje cell firing properties during postnatal mouse development

“…Unfortunately, we have a limited understanding of how motor behavior arises during development (Jacquelin et al 2012). In the future, it would be interesting to test whether the changes in firing during development indeed influence the relationship between spike types and if an increased interdependence of simple spikes and complex spikes correlates with improved motor control (Cerminara and Rawson 2004;Chaumont et al 2013;White et al 2014).…”

“…Even though the basal properties of simple spikes are determined intrinsically, sensory-induced afferent activity can influence their ultimate firing characteristics (Armstrong and Rawson 1979;Thach 1967;Wise et al 2010). They are characterized by a relatively regular pattern and high frequency of firing (ϳ40 -50 Hz) (Ruigrok 2011;Shin et al 2007), although they can fire over a wide range of frequencies in both anesthetized (Bosman et al 2010;de Solages et al 2008;White et al 2014) and awake preparations (Chaumont et al 2013;Cheron et al 2009;Goossens et al 2004;Shin et al 2007;Witter et al 2013;Zhou et al 2014). The second type of spike is called the "complex" spike.…”

“…This is important for motor behavior because Purkinje cell firing influences cerebellar nuclear output (Person and Raman 2012). Thus Purkinje cell activity is central to cerebellar function and the control of movement (Badura et al 2013;Chaumont et al 2013;Medina and Lisberger 2008;Popa et al 2013;Witter et al 2013). However, a poorly understood aspect of this activity is how it arises during development.…”

Behavioral Correlates of Complex Spike Synchrony in Cerebellar Microzones

“…Its two main input channels, the mossy fiber and climbing fiber (CF) pathways, converge in the Purkinje cell (PC) layer, where mossy fibers modulate PC intrinsic simple spike firing indirectly and CFs directly elicit complex spikes (CSs) in PCs (Eccles et al, 1964). PCs receive input from a single CF and synapse onto cerebellar nuclei (CN) neurons that project back to the source of that CF (Andersson and Hesslow, 1987;De Zeeuw et al, 1997). Consequently, the cerebellum is said to consist of microcomplexes or microzones (Ito, 1997;Bengtsson and Hesslow, 2006): functional ensembles spanning mediolateral distances of several tens to a few hundred micrometers (Oscarsson, 1979;Ozden et al, 2009), falling well within the bounds of cerebellar zones of ϳ1 mm (Oscarsson, 1979;Apps and Garwicz, 2005).…”