Fundamental role of inferior olive connexin 36 in muscle coherence during tremor

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...

Section: Discussionsupporting

confidence: 76%

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

Jacobson

Lev

Yarom

et al. 2009

“…In rodents, I T was inhibited acutely by ethanol and long-chain aliphatic alcohols (19,20), whereas I h was augmented by ethanol (21). Recent studies demonstrated that the tremor mediated by the IO requires Ca V 3.1 T-type calcium channels (22,23) and is synchronized by gap junctions (24).Here, we demonstrate that primate IO neurons are oscillatory pacemakers and that chronic intoxication for over 1 y in monkeys is associated with potentiated Ca V 3.1 channel function within the IO and acute withdrawal tremor. Our experiments indicate that sustained (30-d) abstinence following chronic intoxication does not return the brain to the preethanol state but rather is associated with a below-normal decrease in rebound excitability in IO neurons and therefore reveals a form of bidirectional plasticity of pacemaking excitability.…”

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confidence: 69%

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confidence: 99%

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

Welsh¹,

Han

Rossi

et al. 2011

Self Cite

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...

“…As such, then, the main coherence control parameter is the mutual temporal shifts among sequences of action potentials innervating different muscles. Recent experimental work indicates that such a temporal signal mechanism is provided by the sequence of oscillatory events in the olivo-cerebellar system (7). The possibility that a ''universal control system,'' based on olivo-cerebellar physiology, may be implemented in analog hardware electronic chips has been proposed (8).…”

mentioning

confidence: 99%

“…Electrophysiological studies have indicated that such motor intention patterns require proper olivocerebellar system function (1)(2)(3)(4). And, in particular, sets of time-coherent inferior olive (IO) action potentials reach given motor neuron pools by means of the cerebellar nuclei (1,(5)(6)(7). To provide the required synchrony of muscle activation, the IO signals must be temporally coherent at the final motor path regardless of the distance between the activated muscle groups.…”

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confidence: 99%

Self-referential phase reset based on inferior olive oscillator dynamics

Kazantsev

Nekorkin

Makarenko

et al. 2004

The olivo-cerebellar network is a key neuronal circuit that provides high-level motor control in the vertebrate CNS. Functionally, its network dynamics is organized around the oscillatory membrane potential properties of inferior olive (IO) neurons and their electrotonic connectivity. Because IO action potentials are generated at the peaks of the quasisinusoidal membrane potential oscillations, their temporal firing properties are defined by the IO rhythmicity. Excitatory inputs to these neurons can produce oscillatory phase shifts without modifying the amplitude or frequency of the oscillations, allowing well defined time-shift modulation of action potential generation. Moreover, the resulting phase is defined only by the amplitude and duration of the reset stimulus and is independent of the original oscillatory phase when the stimulus was delivered. This reset property, henceforth referred to as selfreferential phase reset, results in the generation of organized clusters of electrically coupled cells that oscillate in phase and are controlled by inhibitory feedback loops through the cerebellar nuclei and the cerebellar cortex. These clusters provide a dynamical representation of arbitrary motor intention patterns that are further mapped to the motor execution system. Being supplied with sensory inputs, the olivo-cerebellar network is capable of rearranging the clusters during the process of movement execution. Accordingly, the phase of the IO oscillators can be rapidly reset to a desired phase independently of the history of phase evolution. The goal of this article is to show how this selfreferential phase reset may be implemented into a motor control system by using a biologically based mathematical model. neuron ͉ nonlinear ͉ oscillation ͉ Andronov-Hopf bifurcation C oordinated motor control signals addressing large numbers of muscles at a given time must implement strict temporal coherence, also known as ''temporal motor binding,'' to generate appropriate motricity (1). Electrophysiological studies have indicated that such motor intention patterns require proper olivocerebellar system function (1-4). And, in particular, sets of time-coherent inferior olive (IO) action potentials reach given motor neuron pools by means of the cerebellar nuclei (1, 5-7). To provide the required synchrony of muscle activation, the IO signals must be temporally coherent at the final motor path regardless of the distance between the activated muscle groups. As such, then, the main coherence control parameter is the mutual temporal shifts among sequences of action potentials innervating different muscles. Recent experimental work indicates that such a temporal signal mechanism is provided by the sequence of oscillatory events in the olivo-cerebellar system (7). The possibility that a ''universal control system,'' based on olivo-cerebellar physiology, may be implemented in analog hardware electronic chips has been proposed (8).Indeed, temporal motor intention patterns may be formed as oscillatory phase clusters in the IO (9-12). ...