In vivo mouse inferior olive neurons exhibit heterogeneous subthreshold oscillations and spiking patterns

136

145

The output of the cerebellar cortex is controlled by two main inputs, (i.e., the climbing fiber and mossy fiber-parallel fiber pathway) and activations of these inputs elicit characteristic effects in its Purkinje cells: that is, the so-called complex spikes and simple spikes. Target neurons of the Purkinje cells in the cerebellar nuclei show rebound firing, which has been implicated in the processing and storage of motor coordination signals. Yet, it is not known to what extent these rebound phenomena depend on different modes of Purkinje cell activation. Using extracellular as well as patch-clamp recordings, we show here in both anesthetized and awake rodents that simple and complex spike-like train stimuli to the cerebellar cortex, as well as direct activation of the inferior olive, all result in rebound increases of the firing frequencies of cerebellar nuclei neurons for up to 250 ms, whereas single-pulse stimuli to the cerebellar cortex predominantly elicit well-timed spiking activity without changing the firing frequency of cerebellar nuclei neurons. We conclude that the rebound phenomenon offers a rich and powerful mechanism for cerebellar nuclei neurons, which should allow them to differentially process the climbing fiber and mossy fiber inputs in a physiologically operating cerebellum.olivo-cerebellar loop | rebound firing | Purkinje cell | complex spikes | simple spikes N eurons in the cerebellar nuclei (CN) form the main output of the cerebellum (1). They include GABAergic neurons that provide an inhibitory feedback to the inferior olive (IO) and excitatory neurons that project to various other brainstem nuclei exerting motor control (2-4). In turn, each CN neuron receives a prominent inhibitory GABAergic input from tens of Purkinje cells, a substantial excitatory input from climbing fiber and mossy fiber collaterals, and a modest input from the local interneurons (4-7). Apart from the impact of these inputs, the firing pattern of CN neurons is largely determined by their intrinsic activities (4,(8)(9)(10)(11)(12)(13)(14). Interestingly, following inhibitory current injections or activation of their Purkinje cell input, CN neurons can show a "rebound" depolarization of the membrane potential, accompanied by action-potential firing (8, 11). Even though little is known about the prominence of rebound firing in the awake state, various models on cerebellar function consider this rebound phenomenon in the nuclei as an essential mechanism to process and store relevant information on motor coordination (15-18). The conductances that allow the rebound firing to emerge involve various types of Ca 2+ -channels, the distribution of which probably varies among the different types of neurons in the CN (8,11,14,(19)(20)(21)(22)(23). Regardless of the type of CN neuron, it is tempting to hypothesize that the climbing fibers and parallel fibers, which evoke complex spikes and simple spikes (24-27), respectively, have a differential impact on the generation of rebound activities in the CN neurons.To test this hypothe...

Section: Resultsmentioning

confidence: 99%

Differential olivo-cerebellar cortical control of rebound activity in the cerebellar nuclei

Hoebeek

Witter

Ruigrok

et al. 2010

136

145

“…The present experiments support the former hypothesis by providing direct evidence that primate IO neurons contain the same pacemaking currents as rodent IO neurons and that primate IO neurons can generate STOs in membrane potential. Primate STOs often were episodic, as measured in rodents in vivo (51,52), and their frequency (5.1 Hz) was within the frequency range seen in rodents and deduced on the basis of multielectrode recording in vivo during movement (53). The conservation of those properties through phylogeny suggests a vital role for IO oscillation in sensory-motor integration.…”

Section: Discussionmentioning

confidence: 99%

Bidirectional plasticity in the primate inferior olive induced by chronic ethanol intoxication and sustained abstinence

Welsh¹,

Han

Rossi

et al. 2011

The brain adapts to chronic ethanol intoxication by altering synaptic and ion-channel function to increase excitability, a homeostatic counterbalance to inhibition by alcohol. Delirium tremens occurs when those adaptations are unmasked during withdrawal, but little is known about whether the primate brain returns to normal with repeated bouts of ethanol abuse and abstinence. Here, we show a form of bidirectional plasticity of pacemaking currents induced by chronic heavy drinking within the inferior olive of cynomolgus monkeys. Intracellular recordings of inferior olive neurons demonstrated that ethanol inhibited the tail current triggered by release from hyperpolarization (I tail ). Both the slow deactivation of hyperpolarization-activated cyclic nucleotide-gated channels conducting the hyperpolarization-activated inward current and the activation of Ca v 3.1 channels conducting the T-type calcium current (I T ) contributed to I tail , but ethanol inhibited only the I T component of I tail . Recordings of inferior olive neurons obtained from chronically intoxicated monkeys revealed a significant up-regulation in I tail that was induced by 1 y of daily ethanol self-administration. The up-regulation was caused by a specific increase in I T which (i) greatly increased neurons' susceptibility for rebound excitation following hyperpolarization and (ii) may have accounted for intention tremors observed during ethanol withdrawal. In another set of monkeys, sustained abstinence produced the opposite effects: (i) a reduction in rebound excitability and (ii) a down-regulation of I tail caused by the down-regulation of both the hyperpolarizationactivated inward current and I T . Bidirectional plasticity of two hyperpolarization-sensitive currents following chronic ethanol abuse and abstinence may underlie persistent brain dysfunction in primates and be a target for therapy.A cute ethanol withdrawal affects millions of people and can require management of a syndrome that consists of dysautonomia, seizures, cognitive disturbance, and tremor (1, 2). It generally is agreed that the washout of ethanol from the brain during acute withdrawal unmasks the physiological adaptations of neurons that allow them to function while they are bathed in ethanol (3, 4). It sometimes is assumed that once the symptoms of acute withdrawal are managed, long-term abstinence from ethanol gradually restores the brain to a preethanol state. Nevertheless, an alcoholic's drive to ingest ethanol can persist even after months or years of abstinence, and alcoholics can undergo multiple abstinences from alcohol in their lifetime.We tested the hypothesis that adaptations in the intrinsic electrical properties of inferior olive (IO) neurons are changed by chronic ethanol intake and by subsequent abstinence. We used patch-clamp recordings of IO neurons in acutely prepared brainstem slices from chronically intoxicated cynomolgus monkeys (5-7) to examine changes in intrinsic electrical properties with ethanol intake and repeated abstinences. We addressed two qu...

“…Without harmaline, IO oscillations are nonstationary and intermittent (31), with only a minority of subthreshold oscillation cycles producing output spikes (18). Recordings in the cerebellar cortex therefore pose severe limitations on the detection of nonzero-phase differences.…”

Section: Discussionmentioning

confidence: 99%

“…First, parallel fibers have been suggested to activate Purkinje cells (PCs) with accurate delays (12)(13)(14) subserving timing. Second, oscillations in the inferior olive (IO) (15)(16)(17)(18) have been proposed to act as a clock signal for timing. Both these mechanisms fail to cover the required range of 10-500 ms, the former because the length of a parallel fiber is exhausted within Ϸ10 ms and therefore can only support shorter time scales, and the latter because an olivary clock signal can only support temporal coordination at multiples of the clock cycle (Ϸ100-200 ms) (19).…”

mentioning

confidence: 99%

Invariant phase structure of olivo-cerebellar oscillations and its putative role in temporal pattern generation

Jacobson

Lev

Yarom

et al. 2009

Complex movements require accurate temporal coordination between their components. The temporal acuity of such coordination has been attributed to an internal clock signal provided by inferior olivary oscillations. However, a clock signal can produce only time intervals that are multiples of the cycle duration. Because olivary oscillations are in the range of 5-10 Hz, they can support intervals of Ϸ100 -200 ms, significantly longer than intervals suggested by behavioral studies. Here, we provide evidence that by generating nonzero-phase differences, olivary oscillations can support intervals shorter than the cycle period. Chronically implanted multielectrode arrays were used to monitor the activity of the cerebellar cortex in freely moving rats. Harmaline was administered to accentuate the oscillatory properties of the inferior olive. Olivaryinduced oscillations were observed on most electrodes with a similar frequency. Most importantly, oscillations in different recording sites retained a constant phase difference that assumed a variety of values in the range of 0 -180°, and were maintained across large global changes in the oscillation frequency. The inferior olive may thus underlie not only rhythmic activity and synchronization, but also temporal patterns that require intervals shorter than the cycle duration. The maintenance of phase differences across frequency changes enables the olivo-cerebellar system to replay temporal patterns at different rates without distortion, allowing the execution of tasks at different speeds. cerebellar cortex ͉ harmaline ͉ inferior olive ͉ multielectrode arrays C erebellar involvement in timing is well-established, with evidence encompassing both normal and pathological conditions. Motor coordination in the 7-9 Hz range has been shown to involve the cerebellum (1), and pathologies associated with the cerebellum can either disrupt motor timing (2-4) or exaggerate tremor in this frequency range (5). The cerebellum also plays a pivotal role in timing of sensory and cognitive functions (6-11). The olivocerebellar system thus seems to be crucial for accurate timing in the range of tens to hundreds milliseconds. Two mechanisms have been proposed for cerebellar timing. First, parallel fibers have been suggested to activate Purkinje cells (PCs) with accurate delays (12-14) subserving timing. Second, oscillations in the inferior olive (IO) (15-18) have been proposed to act as a clock signal for timing. Both these mechanisms fail to cover the required range of 10-500 ms, the former because the length of a parallel fiber is exhausted within Ϸ10 ms and therefore can only support shorter time scales, and the latter because an olivary clock signal can only support temporal coordination at multiples of the clock cycle (Ϸ100-200 ms) (19). Time intervals shorter than the cycle duration could be generated by creating phase differences between different subgroups of IO neurons. Although in vitro studies demonstrate that IO oscillations can exhibit rich spatiotemporal dynamics (20, 21), the possi...