Mossy Fiber Inputs Research Articles

Modeling sharp wave - ripple complexes and their interactions with cortical slow oscillations through a cortico-CA3-CA1 model

The hippocampus, and particularly the CA3 and CA1 areas, exhibit a variety of oscillatory rhythms that span frequencies from the slow theta range (4-10 Hz) up to fast ripples (~200 Hz). Various computational models of different complexities have been developed in an effort to simulate such population oscillations. Nevertheless the mechanism that underlies the so called sharp wave-ripple complex, observed in extracellular recordings in CA1, still remains elusive. We present a combination of two computational models of the rat CA3 and CA1 hippocampal areas respectively. Both models are simple one-dimensional arrays of pyramidal and interneuronal populations, interacting only via fast AMPA and GABAA synapses. Connectivity schemes and postsynaptic potentials are based on biological data, rendering the network topology as realistic as possible. Both models are first validated individually by showing that they reproduce a number of established anatomical and/or functional characteristic properties of the corresponding areas, including population bursts in CA3 and gamma oscillations in CA1. The two networks are coupled in a full CA3-CA1 model through a feedforward scheme mimicking Schaffer collaterals. Quasi-synchronous population bursts in CA3 result in transient responses in CA1, consisting of deep depolarizations in the dendritic layer accompanied by transient ~150-200 Hz field oscillations in the somatic layer. These responses are shown to accurately reproduce a number of basic characteristic features of sharp wave-ripple complexes, reported previously in a variety of neurophysiological studies. By examining these features through our model, we are led to the formulation of a novel mechanism for the generation of ripples, based purely on chemical interactions and avoiding any use of gap junctions. The depolarizing input from CA3, produces intense interneuronal firing in CA1 which is regulated and synchronized by strong, fast-decaying, recurrent inhibition, resulting in a field oscillation within the ripple frequency range. Pyramidal cells, trapped within this inhibitory barrage, have a more passive role, with a small subset of them producing most of the excitatory spikes in a ripple. Through our proposed mechanism, we are able to interpret neurophysiological observations, such as the ripple disruption by halothane and the selective firing of pyramidal cells during ripples, which has various implications on memory consolidation. Finally, the CA3-CA1 model is coupled with a cortical network exhibiting slow oscillations, in a feedback loop involving the mossy fiber and temporoammonic pathway inputs to the hippocampus and monosynaptic projections from CA1 to prefrontal cortex. We study the resulting correlations between hippocampal and cortical activity in an effort to uncover important parameters and mechanisms on which they depend. We show how the spiking activities of CA3 and CA1 depend on the inhibition-excitation ratio, induced by the two hippocampal inputs, and how this ratio can affect established correlations between cortical UP states and ripples. Such correlations have been suggested to be important for the transferring of memories to the cortex for long-term storage.

Excitation-inhibition balance in the CA3 network - neuronal specificity and activity-dependent plasticity

Activation of the axons of the granule cells, the mossy fibers, excites pyramidal cells and interneurons in the CA3 area, which, in turn, inhibit pyramidal cells. The integration of the various inputs that converge onto CA3 cells has been studied by pharmacological dissection of either the excitatory or inhibitory components. This strategy has the disadvantage of partially isolating the recorded cell from the network, ignoring the sources and the impact of concurrent inputs. To overcome this limitation, we dissociated excitatory and inhibitory synaptic conductances by mathematical extraction techniques, and analysed the dynamics of the integration of excitatory and inhibitory inputs in pyramidal cells and stratum lucidum interneurons (Sl-Ints) of CA3. We have uncovered a shunting mechanism that decreases the responsiveness of CA3 output cells to mossy fiber input after a period of enhanced excitability. The activation of the dentate gyrus (DG) after applying a kindling-like protocol in vitro, or after producing one or several seizures in vivo, results in a graded and reversible increase of inhibitory conductances in pyramidal cells, while in Sl-Ints, an increase of excitatory conductances occurs. Thus, interneurons reach more depolarized membrane potentials on DG activation yielding a high excitatory postsynaptic potential-spike coupling, while the contrary occurs in pyramidal cells. This effective activation of feedforward inhibition is synergized by the emergence of direct DG-mediated inhibition on pyramidal cells. These factors force the synaptic conductance to peak at a potential value close to resting membrane potential, thus producing shunt inhibition and decreasing the responsiveness of CA3 output cells to mossy fiber input.

Robustness effect of gap junctions between Golgi cells on cerebellar cortex oscillations

BackgroundPrevious one-dimensional network modeling of the cerebellar granular layer has been successfully linked with a range of cerebellar cortex oscillations observed in vivo. However, the recent discovery of gap junctions between Golgi cells (GoCs), which may cause oscillations by themselves, has raised the question of how gap-junction coupling affects GoC and granular-layer oscillations. To investigate this question, we developed a novel two-dimensional computational model of the GoC-granule cell (GC) circuit with and without gap junctions between GoCs.ResultsIsolated GoCs coupled by gap junctions had a strong tendency to generate spontaneous oscillations without affecting their mean firing frequencies in response to distributed mossy fiber input. Conversely, when GoCs were synaptically connected in the granular layer, gap junctions increased the power of the oscillations, but the oscillations were primarily driven by the synaptic feedback loop between GoCs and GCs, and the gap junctions did not change oscillation frequency or the mean firing rate of either GoCs or GCs.ConclusionOur modeling results suggest that gap junctions between GoCs increase the robustness of cerebellar cortex oscillations that are primarily driven by the feedback loop between GoCs and GCs. The robustness effect of gap junctions on synaptically driven oscillations observed in our model may be a general mechanism, also present in other regions of the brain.

A Subtraction Mechanism of Temporal Coding in Cerebellar Cortex

The temporally specific learning displayed by the cerebellum facilitates mechanistic analysis of neural timing and temporal coding. We report evidence for a subtraction-like mechanism of temporal coding in cerebellar cortex in which activity in a subset of granule cells specifically codes the interval between the offset of two mossy fiber inputs. In a large-scale cerebellar simulation, cessation of one of two ongoing mossy fiber inputs produces a robust temporal code in the population of granule cells. This activity supports simulation learning in response to temporal patterns of stimuli, even when those same stimuli do not support learning when presented individually. Using stimulation of mossy fiber inputs to the cerebellum as training stimuli in rabbits, we confirmed these unusual predictions in a cerebellum-dependent form of learning. Analysis of the simulations reveals a specific working hypothesis for this temporal subtraction process that involves interactions between granule cells and the inhibitory Golgi cells. The results suggest how feedforward inhibition, such as that present in the cerebellar cortex, can contribute to temporal coding.

Heterogeneous integration of adult-generated granule cells into the epileptic brain.

The functional impact of adult-generated granule cells in the epileptic brain is unclear, with data supporting both protective and maladaptive roles. These conflicting findings could be explained if new granule cells integrate heterogeneously, with some cells taking neutral or adaptive roles and others contributing to recurrent circuitry supporting seizures. Here, we tested this hypothesis by completing detailed morphological characterizations of age- and experience-defined cohorts of adult-generated granule cells from transgenic mice. The majority of newborn cells exposed to an epileptogenic insult exhibited reductions in dendritic spine number, suggesting reduced excitatory input to these cells. A significant subset, however, exhibited higher spine numbers. These latter cells tended to have enlarged cell bodies, long basal dendrites, or both. Moreover, cells with basal dendrites received significantly more recurrent mossy fiber input through their apical dendrites, indicating that these cells are robustly integrated into the pathological circuitry of the epileptic brain. These data imply that newborn cells play complex--and potentially conflicting--roles in epilepsy.

A modeling based study on the origin and nature of evoked post-synaptic local field potentials in granular layer

Understanding population activities of underlying neurons reveal emergent behavior as patterns of information flow in neural circuits. Evoked local field potentials (LFPs) arise from complex interactions of spatial distribution of current sources, time dynamics, and spatial distribution of dipoles apart underlying conductive properties of the extracellular medium. We reconstructed LFP to test and parameterize the molecular mechanisms of cellular function with network properties. The sensitivity of LFP to local excitatory and inhibitory connections was tested using two novel techniques. In the first, we used a single granule neuron as a model kernel for reconstructing population activity. The second technique consisted using a detailed network model. LTP and LTD regulating the spatiotemporal pattern of granular layer responses to mossy fiber inputs was studied. The effect of changes in synaptic release probability and modulation in intrinsic excitability of granule cell on LFP was studied. The study revealed cellular function and plasticity were represented in LFP wave revealing the activity of underlying neurons. Changes to single cell properties during LTP and LTD were reflected in the LFP wave suggesting the sparse recoding function of granule neurons as spatial pattern generators. Both modeling approaches generated LFP in vitro ( Mapelli and D’Angelo, 2007) and in vivo ( Roggeri et al., 2008) waveforms as reported in experiments and predict that the expression mechanisms revealed in vitro can explain the LFP changes associated with LTP and LTD in vivo.

Golgi Cells Operate as State-Specific Temporal Filters at the Input Stage of the Cerebellar Cortex

Cerebellar processing of incoming information begins at the synapse between mossy fibers and granule cells, a synapse that is strongly controlled through Golgi cell inhibition. Thus, Golgi cells are uniquely positioned to control the flow of information into the cerebellar cortex and understanding their responses during behavior is essential to understanding cerebellar function. Here we show, for the first time, that Golgi cells express a unique oculomotor-related signal that can be used to provide state- and time-specific filtering of granule cell activity. We used newly established criteria to identify the unique electrophysiological signature of Golgi cells and recorded these neurons in the squirrel monkey ventral paraflocculus during oculomotor behaviors. We found that they carry eye movement, but not vestibular or visual, information and that this eye movement information is only expressed within a specific range of eye positions for each neuron. In addition, simultaneous recordings of Golgi cells and nearby mossy fibers revealed that Golgi cells have the opposite directional tuning of the mossy fiber(s) that likely drive their responses, and that these responses are more sluggish than their mossy fiber counterparts. Because the mossy fiber inputs appear to convey the activity of burst-tonic neurons in the brainstem, Golgi cell responses reflect a time-filtered negative image of the motor command sent to the extraocular muscles. We suggest a role for Golgi cells in the construction of forward models of movement, commonly hypothesized as a major function of the cerebellar cortex in motor control.

Spike‐timing‐dependent plasticity in hippocampal CA3 neurons

Synaptic plasticity of different inputs converging onto CA3 pyramidal neurons is central to theories of hippocampal function. The mossy fibre (MF) input to these neurons is thought to exhibit plasticity that is in nearly all aspects fundamentally different from plasticity in other brain regions: in particular, when induced by high frequency presynaptic stimulation, plasticity at these synapses is independent of NMDA receptor (NMDAR) activation and presynaptically expressed. Here, we show that different stimulation protocols that depend on the close timing of MF activity and postsynaptic spikes induce bidirectional plasticity in CA3 neurons in 3-week-old rats. Long-term potentiation (LTP) is observed when an excitatory postsynaptic potential (EPSP), evoked by MF stimulation, precedes a single postsynaptic action potential (AP) or a brief AP burst by 10 ms. Instead, timing-dependent long-term depression (LTD) requires the pairing of a single AP to an EPSP with a delay of 30 ms. The pairing of APs to synaptic activity is required for plasticity induction, since the application of unpaired APs or EPSPs did not alter synaptic strength. Furthermore, our results demonstrate that both timing-dependent LTP and LTD critically depend on the activation of NMDARs. Specifically blocking postsynaptic NMDARs prevents plasticity, demonstrating that NMDARs important to spike-timing-dependent plasticity in CA3 neurons are required at postsynaptic sites. In summary, this study shows that the close timing of APs to MF excitatory synaptic input can alter synaptic efficacy in CA3 neurons in a bidirectional manner.

GluK1 inhibits calcium dependent and independent transmitter release at associational/commissural synapses in area CA3 of the hippocampus

CA3 pyramidal cells receive three main excitatory inputs: the first one is the mossy fiber input, synapsing mainly on the proximal apical dendrites. Second, entorhinal cortex cells form excitatory connections with CA3 pyramidal cells via the perforant path in the stratum lacunosum moleculare. The third input involves the ipsi-and contralateral connections, termed the associational/commissural (A/C) pathway terminating in the stratum radiatum of CA3, thus forming a feedback loop within this region. Since this excitatory recurrent synapse makes the CA3 region extremely prone to seizure development, understanding the regulation of synaptic strength of this connection is of crucial interest. Several studies suggest that kainate receptors (KAR) play a role in the regulation of synaptic strength. Our aim was to characterize the influence of KAR on A/C synaptic transmission: application of ATPA, a selective agonist of the GluK1 KAR, depressed the amplitude fEPSP without affecting the size of the fiber volley. Blockade of GABA receptors had no influence on this effect, arguing against the influence of interneuronal KARs. Pharmacological and genetic deletion studies could show that this effect was selectively due to GluK1 receptor activation. Several lines of evidence, such as PPF changes, coefficient of variance-analysis and glutamate uncaging experiments strongly argue for a presynaptic locus of suppression. This is accompanied by an ATPA-mediated reduction in Ca(2+) influx at excitatory synaptic terminals, which is most likely mediated by a G-Protein dependent mechanism, as suggested by application of pertussis toxin. Finally, analysis of miniature EPSCs in the presence and absence of extracellular Ca(2+) suggest that presynaptic KAR can also reduce transmitter release downstream and therefore independent of Ca(2+) influx.

Visuomotor cerebellum in human and nonhuman primates.

In this paper, we will review the anatomical components of the visuomotor cerebellum in human and, where possible, in non-human primates and discuss their function in relation to those of extracerebellar visuomotor regions with which they are connected. The floccular lobe, the dorsal paraflocculus, the oculomotor vermis, the uvula–nodulus, and the ansiform lobule are more or less independent components of the visuomotor cerebellum that are involved in different corticocerebellar and/or brain stem olivocerebellar loops. The floccular lobe and the oculomotor vermis share different mossy fiber inputs from the brain stem; the dorsal paraflocculus and the ansiform lobule receive corticopontine mossy fibers from postrolandic visual areas and the frontal eye fields, respectively. Of the visuomotor functions of the cerebellum, the vestibulo-ocular reflex is controlled by the floccular lobe; saccadic eye movements are controlled by the oculomotor vermis and ansiform lobule, while control of smooth pursuit involves all these cerebellar visuomotor regions. Functional imaging studies in humans further emphasize cerebellar involvement in visual reflexive eye movements and are discussed.

Area CA3 interneurons receive two spatially segregated mossy fiber inputs

Area CA3 receives two extrinsic excitatory inputs, the mossy fibers (MF), and the perforant path (PP). Interneurons with somata in str. lacunosum moleculare (L-M) of CA3 modulate the influence of the MF and PP on pyramidal cell activity by providing strong feed-forward inhibitory influence to pyramidal cells. Here we report that L-M interneurons receive two separate MF inputs, one to the dorsal dendrites from the suprapyramidal blade of the dentate gyrus (MF(SDG)), and a second to ventral dendrites from the str. lucidum (MF(SL)). Responses elicited from MF(SDG) and MF(SL) stimulation sites have strong paired-pulse facilitation, similar DCG-IV sensitivity, amplitude, and decay kinetics but target spatially segregated domains on the interneuron dendrites. These data demonstrate that certain interneuron subtypes are entrained by two convergent MF inputs to spatially separated regions of the dendritic tree. This anatomical arrangement could make these interneurons considerably more responsive to the excitatory drive from dentate granule cells. Furthermore, temporal summation is linear or slightly sublinear between PP and MF(SL) but supralinear between PP and MF(SDG). This specific boosting of the excitatory drive to interneurons from the SDG location may indicate that L-M interneurons could be specifically involved in the processing of the associational component of the recognition memory.

Repeated administration of methamphetamine blocked cholecystokinin-octapeptide injection-induced c-fos mRNA expression without change in capsaicin-induced junD mRNA expression in rat cerebellum

In the cerebellum, there are numerous cholecystokinin (CCK-8)-containing fibers. Since systemic CCK-8 injection-induced anxiety (psychological stress) activates the locus coeruleus cells that send mossy fiber inputs to the cerebellum, we examined whether systemic CCK-8 injections activate the rat and mouse cerebellum. First, injections of CCK-8 were found to induce c-fos mRNA expression in a vague patchy pattern that is different from single methamphetamine-induced Zebrin band-like c-fos mRNA expression, suggesting that the CCK-8 activating mossy fibers induce gene expression differently from the dopamine-containing mossy fibers in the ventral tegmental area. Second, since CCK-8 facilitates neural activity of dopamine in the midbrain, we examined whether repeated methamphetamine administration that induced behavioral sensitization had similar effects on the cerebellar CCK system. Repeated administration of methamphetamine suppressed the CCK-8-induced c-fos mRNA expression in the rat cerebellum. Third, capsaicin injections (physical stress) into a hind limb of the rat increased junD mRNA expression with no effect on c-fos mRNA expression, and repeated methamphetamine injections had no effect on the capsaicin-induced expression of junD mRNA. Fourth, either single injection of methamphetamine or CCK-8 to mice increased c-fos mRNA expression in the locus coeruleus, and so noradrenalin, but not dopamine, might interact with CCK-8-activating system. However, we considered the possibility unlikely. Thus, we conclude that repeated methamphetamine administration though dopamine selectively inhibits the c-fos mRNA expression after CCK-8 injection in the cerebellum.

Enhanced Functions of Electrical Junctions

Electrical synapses and synchrony are nearly synonymous. In this issue of Neuron, Vervaeke et al. broaden this longstanding association. They found that in the Golgi cell network of the cerebellum, electrical synapses synchronize resting activity, and cause surround inhibition and desynchronization in response to excitatory input.

Rapid Desynchronization of an Electrically Coupled Interneuron Network with Sparse Excitatory Synaptic Input

SummaryElectrical synapses between interneurons contribute to synchronized firing and network oscillations in the brain. However, little is known about how such networks respond to excitatory synaptic input. To investigate this, we studied electrically coupled Golgi cells (GoC) in the cerebellar input layer. We show with immunohistochemistry, electron microscopy, and electrophysiology that Connexin-36 is necessary for functional gap junctions (GJs) between GoC dendrites. In the absence of coincident synaptic input, GoCs synchronize their firing. In contrast, sparse, coincident mossy fiber input triggered a mixture of excitation and inhibition of GoC firing and spike desynchronization. Inhibition is caused by propagation of the spike afterhyperpolarization through GJs. This triggers network desynchronization because heterogeneous coupling to surrounding cells causes spike-phase dispersion. Detailed network models predict that desynchronization is robust, local, and dependent on synaptic input properties. Our results show that GJ coupling can be inhibitory and either promote network synchronization or trigger rapid network desynchronization depending on the synaptic input.

Can cerebellar input calibrate collicular topographic maps?

There is substantial evidence that repeating cerebellar microcircuit implements an adaptive filter algorithm suitable for fine tuning a wide range of sensorimotor skills [1]. Although it is known that multimodal map layer of superior colliculus receives a massive cerebellar input which directly influences collicular output cells [2], there has been little speculation as to function of this influence. We suggest here that these cerebellar inputs play a role in calibrating accuracy of collicular topographic maps. The cerebellum is a plausible candidate for this role for a number of reasons. It is known to be crucial for accuracy of saccades generated by colliculus. It is also known that cerebellar lesions impair prism adaptation of eye movements. A recent imaging study [3] found direct evidence of cerebellar activation during prism adaptation and suggests that the cerebellum is particularly involved in [establishing] a correct spatial mapping among visuomotor and sensorimotor coordinates systems. A modeling study [3] of collicular visuomotor mapping concludes that transformation occurs in brainstem with cerebellum adjusting it for accuracy, stating that ... importance of cerebellum has been neglected in previous modeling studies. Here we investigate whether adaptive filter model of cerebellar microcircuit which has been so successful in conventional sensorimotor contexts can be applied without change to very different computational problem of calibrating a topographic map driving an orienting response. We propose a model in which (i) unimodal sensory topographic maps constitute a probabilistic representation of target position and that these maps are optimally combined to produce a multimodal map [4] whose peak activity drives orienting response, (ii) cerebellar input can bias position of peak map activity (e.g. by a process such as attentional gain modulation [5]), (iii) cerebellum receives sensory information that generates topographic maps on its mossy fibre inputs, and (iv) information about orienting errors caused by miscalibration is made available to cerebellum on its climbing fibre inputs and drives cerebellar learning. We demonstrate in simulation that this mechanism can successfully calibrate topographic maps and go on to investigate its computational properties. For example we investigate a fundamental calibration ambiguity in which sensory maps can be miscalibrated in such a way that their effects on combined estimate cancel. We show that this ambiguity is resolved in a plausible way if error signals are gated whenever a sensor fails to observe target; a similar gating process has been observed in some motor behaviors [6].We also demonstrate that optimality of cerebellar learning rule [7] ensures that Purkinje cell synapses carrying cross-talk between sensors are driven to silence, greatly reducing need to hard-wire connectivity of parallel fiber inputs to cerebellar microzones.

What was the Purkinje doing while the monkey slept?

Statements about the intrinsic firing modes available to the Purkinje neuron have recently found themselves amidst controversy [1,2]. While extracellular recordings from anesthetized animals and slices have shown a Purkinje neuron transitioning from up to down states -- respectively characterized by high frequency firing and longer quiescent periods -- these observations have not been convincingly reproduced in awake and behaving animals. The fulcrum of the controversy is whether the Purkinje neuron possesses intrinsic bistability, and in that case, (1) what triggers the bistability and (2) whether functional consequences can be derived from this fact. The debate has thus far focused on the putative differences between different model organisms (mice, rats, cats, primates) and experimental settings (slices, anesthetics), with observations varying according to the individual combinations. Stepping towards a resolution of this issue we have collected recordings from Monkey's (Macacca Mulata) cerebellar flocculus, both with an awake and behaving monkey, and during sleep. We encounter a range of differences between the activities of the cerebellum in these two states. Specifically, we find that during sleep the Purkinje activity tends to resemble that of anesthetized animals or slices, with longer pauses (up to 500 ms) related to complex spikes, and conversely, the absence of long pauses (<< 100 ms) in the awake and behaving monkey, finding instead a conspicuous rhythmicity in the low gamma frequency (40-80Hz). (Figure ​(Figure11.) Figure 1 Autocorrelation of LFP channels. On the left, a sleeping monkey’s LFP, on the right the LFP of the awake state. It stands to reason that these two modes are related to the mossy fiber input, presumably much more coherent when the input volley relates to sensory and motor afferences (and cortical rhythms), and thereby suppressing the more intrinsic dynamics, which likely relate more closely to cerebellar cytoarchitectonics. By providing context to the seemingly discrepant observations, our conclusions appear both to justify, and thereby to approximate the opposing views, indicating moreover that to know how one type of activity becomes the other one must regard the afferent activity of the waking state as responsible for the transition.

How Synaptic Release Probability Shapes Neuronal Transmission: Information-Theoretic Analysis in a Cerebellar Granule Cell

A nerve cell receives multiple inputs from upstream neurons by way of its synapses. Neuron processing functions are thus influenced by changes in the biophysical properties of the synapse, such as long-term potentiation (LTP) or depression (LTD). This observation has opened new perspectives on the biophysical basis of learning and memory, but its quantitative impact on the information transmission of a neuron remains partially elucidated. One major obstacle is the high dimensionality of the neuronal input-output space, which makes it unfeasible to perform a thorough computational analysis of a neuron with multiple synaptic inputs. In this work, information theory was employed to characterize the information transmission of a cerebellar granule cell over a region of its excitatory input space following synaptic changes. Granule cells have a small dendritic tree (on average, they receive only four mossy fiber afferents), which greatly bounds the input combinatorial space, reducing the complexity of information-theoretic calculations. Numerical simulations and LTP experiments quantified how changes in neurotransmitter release probability (p) modulated information transmission of a cerebellar granule cell. Numerical simulations showed that p shaped the neurotransmission landscape in unexpected ways. As p increased, the optimality of the information transmission of most stimuli did not increase strictly monotonically; instead it reached a plateau at intermediate p levels. Furthermore, our results showed that the spatiotemporal characteristics of the inputs determine the effect of p on neurotransmission, thus permitting the selection of distinctive preferred stimuli for different p values. These selective mechanisms may have important consequences on the encoding of cerebellar mossy fiber inputs and the plasticity and computation at the next circuit stage, including the parallel fiber-Purkinje cell synapses.

Temporal patterns of inputs to cerebellum necessary and sufficient for trace eyelid conditioning.

Trace eyelid conditioning is a form of associative learning that requires several forebrain structures and cerebellum. Previous work suggests that at least two conditioned stimulus (CS)-driven signals are available to the cerebellum via mossy fiber inputs during trace conditioning: one driven by and terminating with the tone and a second driven by medial prefrontal cortex (mPFC) that persists through the stimulus-free trace interval to overlap in time with the unconditioned stimulus (US). We used electric stimulation of mossy fibers to determine whether this pattern of dual inputs is necessary and sufficient for cerebellar learning to express normal trace eyelid responses. We find that presenting the cerebellum with one input that mimics persistent activity observed in mPFC and the lateral pontine nuclei during trace eyelid conditioning and another that mimics tone-elicited mossy fiber activity is sufficient to produce responses whose properties quantitatively match trace eyelid responses using a tone. Probe trials with each input delivered separately provide evidence that the cerebellum learns to respond to the mPFC-like input (that overlaps with the US) and learns to suppress responding to the tone-like input (that does not). This contributes to precisely timed responses and the well-documented influence of tone offset on the timing of trace responses. Computer simulations suggest that the underlying cerebellar mechanisms involve activation of different subsets of granule cells during the tone and during the stimulus-free trace interval. These results indicate that tone-driven and mPFC-like inputs are necessary and sufficient for the cerebellum to learn well-timed trace conditioned responses.

Simulating the shaping of the fastigial deep nuclear saccade command by cerebellar Purkinje cells

Early lesion and physiological studies established the key contributions of the cerebellar cortex and fastigial deep nuclei in maintaining the accuracy of saccades. Recent evidence has demonstrated that fastigial oculomotor region cells (FORCs) provide commands that are critical both for driving and braking saccades. Modeling studies have largely ignored the mechanisms by which the FORC activity patterns, and those of the Purkinje cells (PCs) that inhibit them, are produced by the mossy fiber (MF) inputs common to both. We have created a hybrid network of integrate-and-fire and summation units to model the circuitry between PCs, FORCs, and MFs that can account for all observed PC and FORC activity patterns. The model demonstrates that a crucial component of FORC activity may be due to the rebound depolarization intrinsic to FORC neurons that, like the MF-driven activity of FORCs, is also shaped by PC inhibition and disinhibition. The model further demonstrates that the shaping of the FORC saccade command by PCs can be adaptively modified through plausible learning rules based on cerebellar long-term depression (LTD) and long-term potentiation (LTP), which are guided by climbing fiber (CF) input to PCs that realistically indicates only the direction (but not the magnitude) of saccade error. These modeling results provide new insights into the adaptive control by the cerebellum of the deep nuclear saccade command.

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

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.