Synchrony and neural coding in cerebellar circuits

Abstract

The cerebellum regulates complex movements and is also implicated in cognitive tasks, and cerebellar dysfunction is consequently associated not only with movement disorders, but also with conditions like autism and dyslexia. How information is encoded by specific cerebellar firing patterns remains debated, however. A central question is how the cerebellar cortex transmits its integrated output to the cerebellar nuclei via GABAergic synapses from Purkinje neurons. Possible answers come from accumulating evidence that subsets of Purkinje cells synchronize their firing during behaviors that require the cerebellum. Consistent with models predicting that coherent activity of inhibitory networks has the capacity to dictate firing patterns of target neurons, recent experimental work supports the idea that inhibitory synchrony may regulate the response of cerebellar nuclear cells to Purkinje inputs, owing to the interplay between unusually fast inhibitory synaptic responses and high rates of intrinsic activity. Data from multiple laboratories lead to a working hypothesis that synchronous inhibitory input from Purkinje cells can set the timing and rate of action potentials produced by cerebellar nuclear cells, thereby relaying information out of the cerebellum. If so, then changing spatiotemporal patterns of Purkinje activity would allow different subsets of inhibitory neurons to control cerebellar output at different times. Here we explore the evidence for and against the idea that a synchrony code defines, at least in part, the input-output function between the cerebellar cortex and nuclei. We consider the literature on the existence of simple spike synchrony, convergence of Purkinje neurons onto nuclear neurons, and intrinsic properties of nuclear neurons that contribute to responses to inhibition. Finally, we discuss factors that may disrupt or modulate a synchrony code and describe the potential contributions of inhibitory synchrony to other motor circuits.

Keywords: IPSC; Purkinje; action potential; cerebellar nuclei; corticonuclear; inhibition; interpositus; spatiotemporal.

Figure 1

Diagram of the corticonuclear circuit and mechanisms of corticonuclear signaling. (A) Cerebellar Purkinje cells (PKJ) receive glutamatergic inputs from the granule cell layer (GCL) whose axons form ascending inputs onto Purkinje cells and also ramify to form the parallel fibers, as well as from the inferior olive (IO), whose axons form the climbing fibers. Molecular layer inhibitory neurons are not shown. Purkinje cells form GABAergic synapses onto neurons of the cerebellar nuclei (CBN). (B) Schematized spike rasters showing the key features of three non-mutually-exclusive models of Purkinje cell regulation of nuclear cell firing. Nuclear cell spikes reflect responses to three afferent Purkinje cells. Inverter, nuclear cell firing rate varies inversely with Purkinje cell firing rate. T-type Rebound, nuclear cells are largely silenced by Purkinje cell activity, but fire bursts of action potentials driven by low-voltage-activated Ca currents when Purkinje cells stop firing. Synchrony code, nuclear cells are silenced by asynchronous inhibition but produce short-latency spikes after IPSPs from synchronous inputs.

Figure 2

Comparison of the timing of the activity in the population of 34 Purkinje cells in the cat identified as belonging to cl zone, with the timing of the activity in a population of forelimb-related neurons of nucleus interpositus. (A) Plots showing the proportion of neurons in each population “active” during each tenth of the step cycle. Open circles, cl Purkinje cell population; filled circles, the population of interpositus neurons. (B) The fluctuation in discharge rate amongst the two populations during the course of the step cycle. Open circles represent the Purkinje cells of the cl zone; and filled circles the interpositus neurons. (C and D) Histograms showing the number of neurons attaining their peak discharge rate during each tenth of the step cycle, for the interpositus neurons and the Purkinje cells of the cl zone respectively. Reprinted from Armstrong and Edgley (1984b), with permission.

Figure 3

Simple spike synchrony in Purkinje cells. On-beam Purkinje cells (Pcs) in the paramedian lobe fired precisely synchronized simple spikes (SSs) time-locked to behavior. Each plot represents the time-resolved cross-correlogram of Pc SS activity recorded at two different electrodes during reaching–grasping movements by awake rats. Average cross-correlations were calculated for epochs of 100-ms duration with a temporal resolution of spike delays of 40 μs. In each plot, the abscissa indicates time during the movement. At time 0, the rat has completed paw extension and touches the food pellet. The ordinate indicates the cross-spike train interval. All plots use the same color map (from red = 0.01 through white = 0 to blue = −0.01). Plots to the right side of the time-resolved cross-correlation matrix show the average excess correlation, i.e., the integral along the abscissa. The time-resolved cross-correlations shown here were generated from the data shown in Figure 1 of Heck et al. (2007). Data were analyzed by subdividing the experimental time into 100-ms bins and calculating the average excess correlation within each bin at 40-μ s resolution. The resulting color-coded matrix was smoothed across delays by convolving with a 120-μs Gaussian. (A) Correlation analysis of spike activity recorded with the electrode array in on-beam orientation in the paramedian lobe. (Top to Bottom) Plotted cross-correlations of spike activity recorded on electrode 1 vs. 2, 2 vs. 3, and 1 vs. 3. Behavior-related occurrence of on-beam synchronous activity is visualized by the red lines at zero lag in the on-beam matrix. The occurrence of synchronous activity was not directly correlated with spike rate or change of rate. (B) (Top to Bottom) Arrangement of cross-correlation plots as in (A). Here, the electrode array was in off-beam orientation. No synchronous activity was seen in paired off-beam recordings. (C) Correlation analysis of SS activity recorded during behavior in crus II, an area outside the arm representation, with the electrode array in on-beam orientation. No behavior-modulated SS activity or synchronous firing was observed. Reprinted from Heck et al. (2007), with permission.

Figure 4

Evidence for related functional roles of neighboring Purkinje cells. (A) Schematic illustrating a surface view of the cerebellar cortex with red indicating possible patterns of convergent Purkinje cells. Converging Purkinje cells can be (top to bottom) widespread, clustered, on-beam, or ordered parasagittally. (B) Projections of two rat Purkinje cells that were separated transversely but located in the same aldolase C compartment. Two small injections were made in medial and lateral 5- in the apex of crus IIa. Purkinje cell axons that originated from each of the injections were reconstructed. Blue axons indicate those that were partially reconstructed, except for the fine branches in the terminal arbor. The medial Purkinje cells projected to the lateral anterior interpositus nucleus (AIN) while the lateral Purkinje cells projected to the junction between the dorsolateral hump (DLH) of the anterior interpositus and lateral anterior interpositus nucleus. Scale bar = 500 μm. Panel (B) reprinted from Sugihara et al. (2009), with permission. (C) Labeling of Purkinje after injection of rabies virus into various limb muscles of the rat. Microphotographs showing labeling of a cluster of Purkinje cells in the lateral vermis. Purkinje cells within such a cluster display a uniform level of infection. Scale bar: 100 μm. Panel (C) reprinted from Ruigrok et al. (2008), with permission.

Figure 5

Synchronous Purkinje inputs set spike timing of nuclear neurons, in vitro and in vivo. (A) Responses of a whole-cell current-clamped cerebellar nuclear neuron in a mouse cerebellar slice to dynamically clamped (dyn) IPSPs mimicking 40 asynchronous (top) or 20 asynchronous and 20 synchronous Purkinje inputs (bottom). (B) Normalized interspike interval distributions during partially synchronized (50%, i.e., 20 out of 40) dynIPSPs, where the rates of the synchronous input ranged from 50 to 100 Hz. Abscissa tick marks indicate multiples of the interstimulus intervals of the synchronous subpopulation. Bin width, 2 ms. Black: no current injection. Blue: with 200 pA steady current (DC) applied to increase spike probability during inhibition. (C) Responses of an extracellularly recorded cerebellar nuclear neuron in a ketamine-xylazine anesthetized mouse. Upper trace, response of a nuclear neuron to 40-Hz molecular layer stimulation (bar). Inset, recording site in the cerebellar nuclei recovered after focal Alexa 568 injection. Dashed lines demarcate cerebellar folia. Scale bar, 200 μm. (D) Mean normalized interspike interval distributions during molecular layer stimulation from 20 to 100 Hz. Abscissa tick marks indicate multiples of the interstimulus intervals. Red baseline histogram includes intervals before and after stimulation. Bin width, 2 ms. (E) Black: polar histograms of interspike intervals during stimulation across rates (left) or during baseline periods. Red: net vectors of polar histograms. Reprinted from Person and Raman (2012), with permission.