Decreases in CaMKII activity trigger persistent potentiation of intrinsic excitability in spontaneously firing vestibular nucleus neurons

Calcium/calmodulin-dependent protein kinase II (CaMKII) has been described as a biochemical switch that is turned on by increases in intracellular calcium to mediate synaptic plasticity. Here, we show that reductions in CaMKII activity trigger persistent increases in intrinsic excitability. In spontaneously firing vestibular nucleus neurons, CaMKII activity is near maximal, and blockade of CaMKII activity increases excitability by reducing BK-type calcium-activated potassium currents. Firing rate potentiation, a form of plasticity in which synaptic inhibition induces long-lasting increases in excitability, is occluded by prior blockade of CaMKII and blocked by addition of constitutively active CaMKII. Reductions in CaMKII activity are necessary and sufficient to induce firing rate potentiation and may contribute to motor learning in the vestibulo-ocular reflex.     

Long-lasting increases in intrinsic excitability triggered by inhibition

Although experience-dependent changes in neural circuits are commonly assumed to be mediated by synaptic plasticity, modifications of intrinsic excitability may serve as a complementary mechanism. In whole-cell recordings from spontaneously firing vestibular nucleus neurons, brief periods of inhibitory synaptic stimulation or direct membrane hyperpolarization triggered long-lasting increases in spontaneous firing rates and firing responses to intracellular depolarization. These increases in excitability, termed firing rate potentiation, were induced by decreases in intracellular calcium and expressed as reductions in the sensitivity to the BK-type calcium-activated potassium channel blocker iberiotoxin. Firing rate potentiation is a novel form of cellular plasticity that could contribute to motor learning in the vestibulo-ocular reflex.     

Synaptic Plasticity in Medial Vestibular Nucleus Neurons: Comparison with Computational Requirements of VOR Adaptation

Background

Vestibulo-ocular reflex (VOR) gain adaptation, a longstanding experimental model of cerebellar learning, utilizes sites of plasticity in both cerebellar cortex and brainstem. However, the mechanisms by which the activity of cortical Purkinje cells may guide synaptic plasticity in brainstem vestibular neurons are unclear. Theoretical analyses indicate that vestibular plasticity should depend upon the correlation between Purkinje cell and vestibular afferent inputs, so that, in gain-down learning for example, increased cortical activity should induce long-term depression (LTD) at vestibular synapses.

Methodology/Principal Findings

Here we expressed this correlational learning rule in its simplest form, as an anti-Hebbian, heterosynaptic spike-timing dependent plasticity interaction between excitatory (vestibular) and inhibitory (floccular) inputs converging on medial vestibular nucleus (MVN) neurons (input-spike-timing dependent plasticity, iSTDP). To test this rule, we stimulated vestibular afferents to evoke EPSCs in rat MVN neurons in vitro. Control EPSC recordings were followed by an induction protocol where membrane hyperpolarizing pulses, mimicking IPSPs evoked by flocculus inputs, were paired with single vestibular nerve stimuli. A robust LTD developed at vestibular synapses when the afferent EPSPs coincided with membrane hyperpolarisation, while EPSPs occurring before or after the simulated IPSPs induced no lasting change. Furthermore, the iSTDP rule also successfully predicted the effects of a complex protocol using EPSP trains designed to mimic classical conditioning.

Conclusions

These results, in strong support of theoretical predictions, suggest that the cerebellum alters the strength of vestibular synapses on MVN neurons through hetero-synaptic, anti-Hebbian iSTDP. Since the iSTDP rule does not depend on post-synaptic firing, it suggests a possible mechanism for VOR adaptation without compromising gaze-holding and VOR performance in vivo.     

Bidirectional plasticity gated by hyperpolarization controls the gain of postsynaptic firing responses at central vestibular nerve synapses

Linking synaptic plasticity with behavioral learning requires understanding how synaptic efficacy influences postsynaptic firing in neurons whose role in behavior is understood. Here, we examine plasticity at a candidate site of motor learning: vestibular nerve synapses onto neurons that mediate reflexive movements. Pairing nerve activity with changes in postsynaptic voltage induced bidirectional synaptic plasticity in vestibular nucleus projection neurons: long-term potentiation relied on calcium-permeable AMPA receptors and postsynaptic hyperpolarization, whereas long-term depression relied on NMDA receptors and postsynaptic depolarization. Remarkably, both forms of plasticity uniformly scaled synaptic currents evoked by pulse trains, and these changes in synaptic efficacy were translated into linear increases or decreases in postsynaptic firing responses. Synapses onto local inhibitory neurons were also plastic but expressed only long-term depression. Bidirectional, linear gain control of vestibular nerve synapses onto projection neurons provides a plausible mechanism for motor learning underlying adaptation of vestibular reflexes.     

Eye movements and brainstem neuronal responses evoked by cerebellar and vestibular stimulation in chicks

Summary The vestibulo-ocular reflex undergoes adaptive changes that require inputs from the cerebellar flocculus onto brainstem vestibular neurons. As a step toward developing an in vitro preparation in chicks for studying the synaptic basis of those changes, we have elucidated the organization of the pathways through which the flocculus influences vestibulo-ocular movements. Electrical stimulation of the vestibular ampulla evoked brief, contralaterally directed movements in both eyes. Although single current pulses to the flocculus elicited no response, conjunctive stimulation of the flocculus and the vestibular apparatus significantly reduced the vestibularly-evoked movement. Trains of current pulses applied to the flocculus and ampulla evoked eye movements directed toward and away from the side of stimulation, respectively. Recordings from the brainstem revealed neurons that were activated by ipsilateral vestibular stimulation and inhibited by ipsilateral floccular stimulation. Our sample included neurons in the lateral vestibular nucleus, the ventrolateral portion of the medial vestibular nucleus, and the superior vestibular nucleus. Similarities between these findings and those of similar studies in mammals indicate that the chick will provide a good model system for cellular studies of adaptive changes in the vestibulo-ocular reflex.Abbreviations FTN flocculus target neuron - VOR vestibuloocular reflex     

Analysis and Neural Network Modeling of the Nonlinear Correlates of Habituation in the Vestibulo-ocular Reflex

Through the process of habituation, continued exposure to low-frequency (0.01 Hz) rotation in the dark produced suppression of the low-frequency response of the vestibulo-ocular reflex (VOR) in goldfish. The response did not decay gradually, as might be expected from an error-driven learning process, but displayed several nonlinear and nonstationary features. They included asymmetrical response suppression, magnitude-dependent suppression for lower- but not higher-magnitude head rotations, and abrupt-onset suppressions suggestive of a switching mechanism. Microinjection of lidocaine into the vestibulocerebellum of habituated goldfish resulted in a temporary dishabituation. This suggests that the vestibulocerebellum mediates habituation, presumably through Purkinje cell inhibition of vestibular nuclei neurons. The habituated VOR data were simulated with a feed-forward, nonlinear neural network model of the VOR in which only Purkinje cell inhibition of vestibular nuclei neurons was varied. The model suggests that Purkinje cell inhibition may switch in to introduce nonstationarities, and cause asymmetry and magnitude-dependency in the VOR to emerge from the essential nonlinearity of vestibular nuclei neurons.     

Cerebellar supervised learning revisited: biophysical modeling and degrees-of-freedom control

The biophysical models of spike-timing-dependent plasticity have explored dynamics with molecular basis for such computational concepts as coincidence detection, synaptic eligibility trace, and Hebbian learning. They overall support different learning algorithms in different brain areas, especially supervised learning in the cerebellum. Because a single spine is physically very small, chemical reactions at it are essentially stochastic, and thus sensitivity-longevity dilemma exists in the synaptic memory. Here, the cascade of excitable and bistable dynamics is proposed to overcome this difficulty. All kinds of learning algorithms in different brain regions confront with difficult generalization problems. For resolution of this issue, the control of the degrees-of-freedom can be realized by changing synchronicity of neural firing. Especially, for cerebellar supervised learning, the triangle closed-loop circuit consisting of Purkinje cells, the inferior olive nucleus, and the cerebellar nucleus is proposed as a circuit to optimally control synchronous firing and degrees-of-freedom in learning.     

Impairment of LTD and cerebellar learning by Purkinje cell-specific ablation of cGMP-dependent protein kinase I

The molecular basis for cerebellar plasticity and motor learning remains controversial. Cerebellar Purkinje cells (PCs) contain a high concentration of cGMP-dependent protein kinase type I (cGKI). To investigate the function of cGKI in long-term depression (LTD) and cerebellar learning, we have generated conditional knockout mice lacking cGKI selectively in PCs. These cGKI mutants had a normal cerebellar morphology and intact synaptic calcium signaling, but strongly reduced LTD. Interestingly, no defects in general behavior and motor performance could be detected in the LTD-deficient mice, but the mutants exhibited an impaired adaptation of the vestibulo-ocular reflex (VOR). These results indicate that cGKI in PCs is dispensable for general motor coordination, but that it is required for cerebellar LTD and specific forms of motor learning, namely the adaptation of the VOR.     

Membrane and firing properties of avian medial vestibular nucleus neuronsin vitro

The intrinsic membrane and firing properties of medial vestibular nucleus (MVN) neurons were investigated in slices of the chick brainstem using intracellular recording and current injection. Avian MVN neurons fired spontaneous action potentials with very regular interspike intervals. The rapid repolarization of all action potentials was followed by an after-hyperpolarization. Intracellular injection of steps of hyperpolarizing current revealed both an inward rectification of the membrane potential during the step and a rebound depolarization following the offset of the step. In some neurons, the rebound depolarization resulted in bursts of action potentials. Steps of depolarizing current applied to spontaneously active neurons evoked increases in firing rate that were higher at the onset of the step than during the steady-state response. The relationship between current and firing rate was linear. The membrane and firing properties of avian MVN neurons were distributed continuously across the population of recorded neurons. These properties appear identical to those of rodent MVN neurons, suggesting that the composition and distribution of ion channels in the MVN neuronal membrane has been highly conserved across vertebrate species.Abbreviations MVN medial vestibular nucleus - VOR vestibulo-ocular reflex - AHP after-hyperpolarization     

The development of vestibulo-ocular circuitry in the chicken embryo.

This article reviews studies of the organization and development of the vestibulo-ocular reflex arc in the chicken embryo. It summarizes some of the principal features that characterize the development of this circuit, including the gradual clustering of motoneurons in the oculomotor nucleus into functionally identifiable motoneuron pools, the patterning of vestibular projection neurons into coherent clusters with specific axonal trajectories and terminations onto the oculomotor motoneuron pools, the reverse order of synapse formation during development (motoneuron to muscle, then vestibular projection neuron to motoneuron), and the selectivity of initial synaptic termination at both the ultimate and penultimate relays within the reflex arc. Reference to studies in other vertebrate species is made to provide a comparative context, and potential mechanisms are discussed that may contribute to the underlying synaptic specificity in this circuit.     

A recipe for bidirectional motor learning: using inhibition to cook plasticity in the vestibular nuclei

In this issue of Neuron, McElvain et?al. demonstrate for the first time plasticity at the synapse between vestibular nerve afferents and their postsynaptic targets in the medial vestibular nuclei. This new type of plasticity, which is gated by inhibition, is well suited to drive motor learning during adaptation of the vestibulo-ocular reflex.     

Distributed parallel processing in the vertical vestibulo-ocular reflex: Learning networks compared to tensor theory

The vestibulo-ocular reflex (VOR) is capable of producing compensatory eye movements in three dimensions. It utilizes the head rotational velocity signals from the semicircular canals to control the contractions of the extraocular muscles. Since canal and muscle coordinate frames are not orthogonal and differ from one another, a sensorimotor transformation must be produced by the VOR neural network. Tensor theory has been used to construct a linear transformation that can model the three-dimensional behavior of the VOR. But tensor theory does not take the distributed, redundant nature of the VOR neural network into account. It suggests that the neurons subserving the VOR, such as vestibular nucleus neurons, should have specific sensitivity-vectors. Actual data, however, are not in accord. Data from the cat show that the sensitivity-vectors of vestibular nucleus neurons, rather than aligning with any specific vectors, are dispersed widely. As an alternative to tensor theory, we modeled the vertical VOR as a three-layered neural network programmed using the back-propagation learning algorithm. Units in mature networks had divergent sensitivity-vectors which resembled those of actual vestibular nucleus neurons in the cat. This similarity suggests that the VOR sensorimotor transformation may be represented redundantly rather than uniquely. The results demonstrate how vestibular nucleus neurons can encode the VOR sensorimotor transformation in a distributed manner.     

Inhibition by enkephalin of medial vestibular nucleus neurons responding to horizontal pendular rotation

Electrophysiological studies were performed to determine whether or not enkephalin modulates the activities of medial vestibular nucleus (MVN) neurons responding to horizontal pendular rotation using alpha-chloralose anesthetized cats. The effects of microiontophoretically applied drugs were examined in type I and type II neurons identified according to responses to horizontal, sinusoidal rotation; type I and type II neurons showed an increase and decrease in firing with rotation ipsilateral to the recording site and vice versa with contralateral rotation, respectively. Iontophoretic application of enkephalin suppressed spike firing induced by rotation of the animals in type I neuron, but not in type II neuron. The spike firing induced by iontophoretically applied glutamate was also inhibited during the application of enkephalin. The inhibition by enkephalin of both rotation- and glutamate-induced firing was antagonized by naloxone which was given simultaneously. These results suggest that enkephalin acts on MVN type I neuron to inhibit transmission from the vestibule, thereby controlling vestibulo-ocular reflex.     

Adaptive feedback control models of the vestibulocerebellum and spinocerebellum

We extend the cerebellar learning model proposed by Kawato and Gomi (1992) to the case where a specific region of the cerebellum executes adaptive feed-back control as well as feedforward control. The model is still based on the feedback-error-learning scheme. The proposed adaptive feedback control model is developed in detail as a specific neural circuit model for three different regions of the cerebellum and the learning of the corresponding representative movements: (i) the flocculus and adaptive modification of the vestibulo-ocular reflex and optokinetic eye-movement responses, (ii) the vermis and adaptive posture control, and (iii) the intermediate zones of the hemisphere and adaptive control of locomotion. As a representative example, simultaneous adaptation of the vestibulo-ocular reflex and the optokinetic eye-movement response was successfully simulated while the Purkinje cells receive copies of motor commands through recurrent neural connections as well as vestibular and retinal-slip parallel-fiber inputs.     

Stability of complex spike timing-dependent plasticity in cerebellar learning

Dynamics of spike-timing dependent synaptic plasticity are analyzed for excitatory and inhibitory synapses onto cerebellar Purkinje cells. The purpose of this study is to place theoretical constraints on candidate synaptic learning rules that determine the changes in synaptic efficacy due to pairing complex spikes with presynaptic spikes in parallel fibers and inhibitory interneurons. Constraints are derived for the timing between complex spikes and presynaptic spikes, constraints that result from the stability of the learning dynamics of the learning rule. Potential instabilities in the parallel fiber synaptic learning rule are found to be stabilized by synaptic plasticity at inhibitory synapses if the inhibitory learning rules are stable, and conditions for stability of inhibitory plasticity are given. Combining excitatory with inhibitory plasticity provides a mechanism for minimizing the overall synaptic input. Stable learning rules are shown to be able to sculpt simple-spike patterns by regulating the excitability of neurons in the inferior olive that give rise to climbing fibers.     

A Calcium-Dependent Plasticity Rule for HCN Channels Maintains Activity Homeostasis and Stable Synaptic Learning

Theoretical and computational frameworks for synaptic plasticity and learning have a long and cherished history, with few parallels within the well-established literature for plasticity of voltage-gated ion channels. In this study, we derive rules for plasticity in the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, and assess the synergy between synaptic and HCN channel plasticity in establishing stability during synaptic learning. To do this, we employ a conductance-based model for the hippocampal pyramidal neuron, and incorporate synaptic plasticity through the well-established Bienenstock-Cooper-Munro (BCM)-like rule for synaptic plasticity, wherein the direction and strength of the plasticity is dependent on the concentration of calcium influx. Under this framework, we derive a rule for HCN channel plasticity to establish homeostasis in synaptically-driven firing rate, and incorporate such plasticity into our model. In demonstrating that this rule for HCN channel plasticity helps maintain firing rate homeostasis after bidirectional synaptic plasticity, we observe a linear relationship between synaptic plasticity and HCN channel plasticity for maintaining firing rate homeostasis. Motivated by this linear relationship, we derive a calcium-dependent rule for HCN-channel plasticity, and demonstrate that firing rate homeostasis is maintained in the face of synaptic plasticity when moderate and high levels of cytosolic calcium influx induced depression and potentiation of the HCN-channel conductance, respectively. Additionally, we show that such synergy between synaptic and HCN-channel plasticity enhances the stability of synaptic learning through metaplasticity in the BCM-like synaptic plasticity profile. Finally, we demonstrate that the synergistic interaction between synaptic and HCN-channel plasticity preserves robustness of information transfer across the neuron under a rate-coding schema. Our results establish specific physiological roles for experimentally observed plasticity in HCN channels accompanying synaptic plasticity in hippocampal neurons, and uncover potential links between HCN-channel plasticity and calcium influx, dynamic gain control and stable synaptic learning.     

Neural mechanisms of reward-related motor learning

The analysis of the neural mechanisms responsible for reward-related learning has benefited from recent studies of the effects of dopamine on synaptic plasticity. Dopamine-dependent synaptic plasticity may lead to strengthening of selected inputs on the basis of an activity-dependent conjunction of sensory afferent activity, motor output activity, and temporally related firing of dopamine cells. Such plasticity may provide a link between the reward-related firing of dopamine cells and the acquisition of changes in striatal cell activity during learning. This learning mechanism may play a special role in the translation of reward signals into context-dependent response probability or directional bias in movement responses.     

Frequency-independent synaptic transmission supports a linear vestibular behavior

The vestibular system is responsible for transforming head motion into precise eye, head, and body movements that rapidly stabilize gaze and posture. How do central excitatory synapses mediate behavioral outputs accurately matched to sensory inputs over a wide dynamic range? Here we demonstrate that vestibular afferent synapses in vitro express frequency-independent transmission that spans their in vivo dynamic range (5-150 spikes/s). As a result, the synaptic charge transfer per unit time is linearly related to vestibular afferent activity in both projection and intrinsic neurons of the vestibular nuclei. Neither postsynaptic glutamate receptor desensitization nor saturation affect the relative amplitude or frequency-independence of steady-state transmission. Finally, we show that vestibular nucleus neurons can transduce synaptic inputs into linear changes in firing rate output without relying on one-to-one calyceal transmission. These data provide a physiological basis for the remarkable linearity of vestibular reflexes.     

Time and tide in cerebellar memory formation

The notion that the olivocerebellar system is crucial for motor learning is well established. In recent years, it has become evident that there can be many forms of both synaptic and non-synaptic plasticity within this system and that each might have a different role in developing and maintaining motor learning across a wide range of tasks. There are several possible molecular and cellular mechanisms that could underlie adaptation of the vestibulo-ocular reflex and eyeblink conditioning. Although causal relationships between particular cellular processes and individual components of a learned behaviour have not been demonstrated unequivocally, an overall picture is emerging that the different types and sites of cellular plasticity relate importantly to the stage of learning and/or its temporal specifics.