Central control of dendritic spikes shapes the responses of Purkinje-like cells through spike timing-dependent synaptic plasticity.

Cerebellum-like structures process peripheral sensory information in combination with parallel fiber inputs that convey information about sensory and motor contexts. Activity-dependent changes in the strength of parallel fiber synapses act as an adaptive filter, removing predictable features of the sensory input. In the electrosensory lobe (ELL) of mormyrid fish, a main cellular site for this adaptive processing is the Purkinje-like medium ganglion (MG) cell. MG cells exhibit two types of spikes: narrow axon spikes (N spikes) and broad dendritic spikes (B spikes). N spikes shape ELL output by inhibiting efferent cells, whereas B spikes drive plasticity at parallel fiber synapses. Despite their critical role in plasticity, little is known about the relative importance of various classes of MG cell inputs in driving B spikes or to what extent B spikes can be controlled independently of N spikes. Using in vivo intracellular recordings, measurements of synaptic conductance, and pharmacological blockade of inhibition, we provide evidence for corollary discharge-evoked inhibition that exerts potent control over the timing and probability of B spikes with little apparent effect on N spikes. The timing of this inhibition corresponds to the period during which repeated occurrence of B spikes causes depression of corollary discharge-evoked synaptic responses and a reduction in N spikes. B spikes occurring before or after the period of inhibition lead to increases in corollary discharge-evoked excitation. Thus, by controlling the timing of B spikes, central inhibition shapes the output of MG cells through spike timing-dependent synaptic plasticity. Our findings are consistent with a model of ELL function in which feedback guides adaptive processing by regulating B spikes.

Synaptic plasticity and calcium signaling in Purkinje cells of the central cerebellar lobes of mormyrid fish.

Climbing fiber (CF)-evoked calcium transients play a key role in plasticity at parallel fiber (PF) to Purkinje cell synapses in the mammalian cerebellum. Whereas PF activation alone causes long-term potentiation (LTP), coactivation of the heterosynaptic CF input, which evokes large dendritic calcium transients, induces long-term depression (LTD). This unique type of heterosynaptic interaction is a hallmark feature of synaptic plasticity in mammalian Purkinje cells. Purkinje cells in the cerebellum of mormyrid electric fish are characterized by a different architecture of their dendritic trees and by a more pronounced separation of CF and PF synaptic contact sites. We therefore examined the conditions for bidirectional plasticity at PF synapses onto Purkinje cells in the mormyrid cerebellum in vitro. PF stimulation at elevated frequencies induces LTP, whereas LTD results from PF stimulation at enhanced intensities and depends on dendritic calcium influx and metabotropic glutamate receptor type 1 activation. LTD can also be observed after pairing of low intensity PF stimulation with CF stimulation. Using a combination of whole-cell patch-clamp recordings and fluorometric calcium imaging, we characterized calcium transients in Purkinje cell dendrites. CF activation elicits calcium transients not only within the CF input territory (smooth proximal dendrites) but also within the PF input territory (spiny palisade dendrites). Paired PF and CF activation elicits larger calcium transients than stimulation of either input alone. A major source for dendritic calcium signaling is provided by P/Q-type calcium channels. Our data show that despite the spatial separation between the two inputs CF activity facilitates LTD induction at PF synapses.

Adaptive processing in electrosensory systems: links to cerebellar plasticity and learning.

The first central stage of electrosensory processing in fish takes place in structures with local circuitry that resembles the cerebellum. Cerebellum-like structures and the cerebellum itself share common patterns of gene expression and may also share developmental and evolutionary origins. Given these similarities it is natural to ask whether insights gleaned from the study of cerebellum-like structures might be useful for understanding aspects of cerebellar function and vice versa. Work from electrosensory systems has shown that cerebellum-like circuitry acts to generate learned predictions about the sensory consequences of the animals' own behavior through a process of associative plasticity at parallel fiber synapses. Subtraction of these predictions from the actual sensory input serves to highlight unexpected and hence behaviorally relevant features. Learning and prediction are also central to many current ideas regarding the function of the cerebellum itself. The present review draws comparisons between cerebellum-like structures and the cerebellum focusing on the properties and sites of synaptic plasticity in these structures and on connections between plasticity and learning. Examples are drawn mainly from the electrosensory lobe (ELL) of mormyrid fish and from extensive work characterizing the role of the cerebellum in Pavlovian eyelid conditioning and vestibulo-ocular reflex (VOR) modification. Parallels with other cerebellum-like structures, including the gymnotid ELL, the elasmobranch dorsal octavolateral nucleus (DON), and the mammalian dorsal cochlear nucleus (DCN) are also discussed.

Effects of sensing behavior on a latency code.

Sensory information is often acquired through active exploration, yet relatively little is known about how neurons encode sensory stimuli in the context of natural patterns of sensing behavior. We examined the effects of sensing behavior on a spike latency code in the active electrosensory system of mormyrid fish. These fish actively probe their environment by emitting brief electric organ discharge (EOD) pulses. Nearby objects alter the spatial pattern of current flowing through the skin. These changes are encoded by small shifts in the latency of individual electroreceptor afferent spikes after the EOD. In nature, the temporal pattern of EOD intervals is highly structured and varies depending on the behavioral context. We performed experiments in which we varied both the EOD amplitude and the intervals between EODs to understand how sensing behavior affects afferent latency coding. We use white-noise stimuli and linear filter estimation methods to develop simple models characterizing the dependence of afferent spike latency on the preceding sequence of EOD intervals and amplitudes. Comparing the predictions of these models with actual afferent responses for natural patterns of EOD intervals and amplitudes reveals an unexpectedly rich interplay between sensing behavior and stimulus encoding. Implications of our results for how afferent spike latency is decoded at central stages of electrosensory processing are discussed.

Anatomy of the posterior caudal lobe of the cerebellum and the eminentia granularis posterior in a mormyrid fish.

The cerebellum of mormyrid fish is of interest for its large size and unusual histology. The mormyrid cerebellum, as in all ray-finned fishes, has three subdivisions--valvula, corpus, and caudal lobe. The structures of the mormyrid valvula and corpus have been examined previously, but the structure of the mormyrid caudal lobe has not been studied. The mormyrid caudal lobe includes a posterior caudal lobe associated with the electrosense and an anterior caudal lobe associated with lateral line and eighth nerve senses. In this article we describe cellular elements of the posterior caudal lobe and of the eminentia granularis posterior (EGp) in the mormyrid fish Gnathonemus petersii. The EGp gives rise to the parallel fibers of the posterior caudal lobe. We used intracellular injection of biocytin, extracellular injection of biotinylated dextran amine, and immunohistochemistry with antibodies to gamma-aminobutyric acid, inositol triphosphate receptor I, calretinin, and Zebrin II. The histological structure of the posterior caudal lobe is markedly irregular in comparison to that of the corpus and the valvula, and a tight modular organization of cerebellar elements is less apparent here. Most Purkinje cell bodies are in the middle of the molecular region. Their dendrites are only roughly oriented in the sagittal plane, extend both ventrally and dorsally, and branch irregularly. Climbing fibers terminate only on smooth dendrites near the soma. Most Purkinje cell axons terminate locally on eurydendroid cells that project outside the cortex. The results provide an additional variant to the already large set of different cerebellar and cerebellum-like structures.

From sparks to spikes: information processing in the electrosensory systems of fish.

Recent work on electrosensory systems in fish has combined traditional neuroethological approaches with quantitative methods for characterizing neural coding. These studies have shed light on general issues in sensory processing, including how peripheral sensory receptors encode external stimuli and how these representations are transformed at subsequent stages of processing.

Cell morphology and circuitry in the central lobes of the mormyrid cerebellum.

The cerebellum of mormyrid electric fish is large and unusually regular in its histological structure. We have examined the morphology of cellular elements in the central lobes of the mormyrid cerebellum. We have used intracellular injection of biocytin to determine the morphology of cells with somas in the cortex, and we have used extracellular placement of anterograde tracers in the inferior olive to label climbing fibers. Our results confirm previous Golgi studies and extend them by providing a more complete description of axonal trajectories. Most Purkinje cells in mormyrids and other actinopterygian fishes are interneurons that terminate locally in the cortex on efferent neurons that are equivalent to cerebellar nucleus cells in mammals. We confirm the markedly sagittal distribution of the fan-like dendrites of Purkinje cells, efferent cells, and molecular layer interneurons. We show that Purkinje cell axons extend further than was previously thought in the sagittal plane. We show that climbing fibers are distributed in narrow sagittal strips and that these fibers terminate exclusively in the ganglionic layer below the molecular layer where parallel fibers terminate. Our results together with those of others show that the central lobes of the mormyrid cerebellum, similar to the mammalian cerebellum, are composed of sagittally oriented modules made up of Purkinje cells, climbing fibers, molecular layer interneurons, and cerebellar efferent cells (cerebellar nucleus cells in mammals) that Purkinje cells inhibit. This modular organization is more apparent and more sharply defined in the mormyrid than in the mammal.

Physiology of cells in the central lobes of the mormyrid cerebellum.

The cerebellum of mormyrid electric fish is unusual for its size and for the regularity of its histology. The circuitry of the mormyrid cerebellum is also different from that of the mammalian cerebellum in that mormyrid Purkinje cell axons terminate locally within the cortex on efferent cells, and the cellular regions of termination for climbing fibers and parallel fibers are well separated. These and other features suggest that the mormyrid cerebellum may be a useful site for addressing some functional issues regarding cerebellar circuitry. We have therefore begun to examine the physiology of the mormyrid cerebellum by recording intracellularly from morphologically identified Purkinje cells, efferent cells, Golgi cells, and stellate cells in in vitro slices. Mormyrid Purkinje cells respond to parallel fiber input with an AMPA-mediated EPSP that shows paired pulse facilitation and to climbing fiber input with a large all-or-none AMPA-mediated EPSP that shows paired pulse depression. Recordings from the somas of Purkinje cells show three types of spikes in response to injected current: a small, narrow sodium spike; a large, broad sodium spike; and a large broad calcium spike. Efferent cells, Golgi cells, and stellate cells respond to parallel fiber input with an EPSP or EPSP-IPSP sequence and show only large, narrow spikes in response to intracellular current injection. We conclude that the physiology of the mormyrid cerebellum is similar in many ways to the mammalian cerebellum but is also different in ways that may prove instructive concerning the functional circuitry of the cerebellum.

Immunocytochemical identification of cell types in the mormyrid electrosensory lobe.

The electrosensory lobes (ELLs) of mormyrid and gymnotid fish are useful sites for studying plasticity and descending control of sensory processing. This study used immunocytochemistry to examine the functional circuitry of the mormyrid ELL. We used antibodies against the following proteins and amino acids: the neurotransmitters glutamate and gamma-aminobutyric acid (GABA); the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD); GABA transporter 1; the anchoring protein for GABA and glycine receptors, gephyrin; the calcium binding proteins calbindin and calretinin; the NR1 subunit of the N-methyl-D-aspartate glutamate receptor; the metabotropic glutamate receptors mGluR1alpha, mGluR2/3, and mGluR5; and the intracellular signaling molecules calcineurin, calcium calmodulin kinase IIalpha (CAMKIIalpha) and the receptor for inositol triphosphate (IP3R1alpha). Selective staining allowed for identification of new cell types including a deep granular layer cell that relays sensory information from primary afferent fibers to higher order cells of ELLS. Selective staining also allowed for estimates of relative numbers of different cell types. Dendritic staining of Purkinje-like medium ganglion cells with antibodies against metabotropic glutamate receptors and calcineurin suggests hypotheses concerning mechanisms of the previously demonstrated synaptic plasticity in these cells. Finally, several cell types including the above-mentioned granular cells, thick-smooth dendrite cells, and large multipolar cells of the intermediate layer were present in the two zones of ELL that receive input from mormyromast electroreceptors but were absent in the zone of ELL that receives input from ampullary electroreceptors, indicating markedly different processing for these two types of input. J. Comp. Neurol. 483:124-142, 2005. (c) 2005 Wiley-Liss, Inc.

Active control of spike-timing dependent synaptic plasticity in an electrosensory system.

A spike timing dependent learning rule is present at the synapse between parallel fibers and Purkinje-like medium ganglion cells in the electrosensory lobe of mormyrid electric fish. The synapse is depressed when a postsynaptic dendritic spike occurs within 50 ms of the onset of a parallel fiber excitatory postsynaptic potential, but is enhanced at all other timing relations. Operation of this learning rule results in the cancellation of predictable membrane potential changes, driving the cell towards a constant output frequency. But medium ganglion cells show a strong and predictable response to corollary discharge signals associated with the motor command that initiates the electric organ discharge. The modeling study presented here resolves this conflict by proposing an active control of dendritic spike threshold during the brief period of medium ganglion cell response.

Cerebellum-like structures and their implications for cerebellar function.

The nervous systems of most vertebrates include both the cerebellum and structures that are architecturally similar to the cerebellum. The cerebellum-like structures are sensory structures that receive input from the periphery in their deep layers and parallel fiber input in their molecular layers. This review describes these cerebellum-like structures and compares them with the cerebellum itself. The cerebellum-like structures in three groups of fish act as adaptive sensory processors in which the signals conveyed by parallel fibers in the molecular layer predict the patterns of sensory input to the deep layers through a process of associative synaptic plasticity. Similarities between the cerebellum-like structures and the cerebellum suggest that the cerebellum may also generate predictions about expected sensory inputs or states of the system, as suggested also by clinical, experimental, and theoretical studies of the cerebellum. Understanding the process of predicting sensory patterns in cerebellum-like structures may therefore be a source of insight into cerebellar function.

Morphological analysis of the mormyrid cerebellum using immunohistochemistry, with emphasis on the unusual neuronal organization of the valvula.

This study used immunohistochemistry, Golgi impregnation, and electron microscopy to examine the circuitry of the cerebellum of mormyrid fish. We used antibodies against the following antigens: the neurotransmitters glutamate and gamma-aminobutyric acid (GABA); the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD); GABA transporter 1; the anchoring protein for GABA and glycine receptors, gephyrin; the calcium binding proteins calbindin and calretinin; the NR1 subunit of the N-methyl-D-aspartate glutamate receptor; the metabotropic glutamate receptors mGluR1alpha and mGluR2/3; the intracellular signaling molecules calcineurin and calcium calmodulin kinase IIalpha (CAMKIIalpha); and the receptor for inositol triphosphate (IP3RIalpha). Purkinje cells are immunoreactive to anti-IP3R1alpha, anticalcineurin, and anti-mGluR1alpha. Cerebellar efferent cells (eurydendroid cells) are anticalretinin and anti-NR1 positive in the valvula but not in the corpus and caudal lobe. In contrast, climbing fibers are anticalretinin and anti-NR1 immunopositive in the corpus and caudal lobe but not in the valvula. Purkinje cells, Golgi cells, and stellate cells are GABA positive, whereas efferent cells are glutamate positive. Unipolar brush cells are immunoreactive to anti-mGluR2/3, anticalretinin, and anticalbindin. We describe a "new" cell type in the mormyrid valvula, the deep stellate cell. These cells are GABA, calretinin, and calbindin positive. They are different from superficial stellate cells in having myelinated axons that terminate massively with GAD- and gephyrin-positive terminals on the cell bodies and proximal dendrites of efferent cells. We discuss how the valvula specializations described here may act in concert with the palisade pattern of Purkinje cell dendrites for analyzing spatiotemporal patterns of parallel fiber activity.

Granular cells of the mormyrid electrosensory lobe and postsynaptic control over presynaptic spike occurrence and amplitude through an electrical synapse.

Primary afferent fibers from the electroreceptors of mormyrid electric fish use a latency code to signal the intensity of electrical current evoked by the fish's own electric organ discharge (EOD). The afferent fibers terminate centrally in the deep and superficial granular layers of the electrosensory lobe with morphologically mixed chemical-electrical synapses. The granular cells in these layers seem to decode afferent latency through an interaction between primary afferent input and a corollary discharge input associated with the EOD motor command. We studied the physiology of deep and superficial granular cells in a slice preparation with whole cell patch recording and electrical stimulation of afferent fibers. Afferent stimulation evoked large all-or-none electrical excitatory postsynaptic potentials (EPSPs) and large all or none GABAergic inhibitory postsynaptic potentials (IPSPs) in both superficial and deep granular cells. The amplitudes of the electrical EPSPs depended on postsynaptic membrane potential, with maximum amplitudes at membrane potentials between -65 and -110 mV. Hyperpolarization beyond this level resulted in either the abrupt disappearance of EPSPs, a step-like reduction to a smaller EPSP, or a graded reduction in EPSP amplitude. Depolarization to membrane potentials lower than that yielding a maximum caused a linear decrease in EPSP amplitude, with EPSP amplitude reaching 0 mV at potentials between -55 and -40 mV. We suggest that the dependence of EPSP size on postsynaptic membrane potential is caused by close linkage of pre- and postsynaptic membrane potentials through a high-conductance gap junction. We also suggest that this dependence may result in functionally important nonlinear interactions between synaptic inputs.

Recurrent feedback in the mormyrid electrosensory system: cells of the preeminential and lateral toral nuclei.

Many sensory regions integrate information ascending from peripheral receptors with descending inputs from other central structures. However, the significance of these descending inputs remains poorly understood. Descending inputs are prominent in the electrosensory system of mormyrid fish and include both recurrent connections from higher to lower stages of electrosensory processing and electric organ corollary discharge (EOCD) signals associated with the motor command that drives the electric organ discharge. The preeminential nucleus (PE) occupies a key position in a feedback loop that returns information from higher stages of electrosensory processing to the initial stage of processing in the electrosensory lobe (ELL). This feedback reflects the integration of ascending electrosensory input from ELL, descending input from the lateral toral nucleus (torus), and EOCD inputs to PE. We used intracellular recording and axonal tracing of stained cells to characterize EOCD and electrosensory responses of several cell types in PE and the torus. PE and toral cells exhibit prominent EOCD responses that are not due to EOCD inputs from ELL. PE cells giving rise to a direct feedback projection to ELL respond to electrosensory stimuli with rapid, precisely timed spikes that will affect ELL neurons early during the same EOD cycle. EOCD and electrosensory responses in toral cells are similar to those observed in PE and may be important in shaping feedback to ELL. These results provide an initial description of electrosensory feedback to ELL as well as information about how ascending, descending, and EOCD inputs are combined at higher stages of electrosensory processing.

Evolution of cerebellum-like structures.

All vertebrate brains have a cerebellum, and most of them have one or more additional structures that are histologically similar to the cerebellum. The cerebellum-like structures include the medial octavolateral nucleus in most aquatic vertebrates; the dorsal octavolateral nucleus in many aquatic vertebrates with an electrosensory system; the marginal layer of the optic tectum in ray-finned fishes; electrosensory lobes in the few groups of advanced bony fish with an electrosensory system; the rostrolateral nucleus of the thalamus in a few widely scattered groups of bony fish; and the dorsal cochlear nucleus in all mammals except monotremes. All of these structures receive topographically organized sensory input in their deep layers. Purkinje-like cells receive the sensory input near their cell bodies. These cells extend apical dendrites up into the molecular layer where they receive synaptic input from parallel fibers. The cerebellum itself can be included within this characterization by considering the climbing fiber as at least in part a conveyor of sensory information and by recalling that climbing fibers in more basal vertebrates terminate on smooth dendrites close to the soma. Physiological findings from three different systems suggest the hypothesis that cerebellum-like structures remove predictable features from the sensory inflow. Phylogenetic homology can explain the similarities across different taxa for some types of cerebellum-like structures, but similarities within other types cannot be explained in this way. Moreover, phylogenetic homology cannot explain the similarities among different types of cerebellum-like structures. Evolutionary convergence provides the best explanation for all these similarities that cannot be explained by homology. The convergence is almost surely constrained by the availability of a genetic-developmental program for creating cerebellum-like circuitry and by the need within many different systems for the type of information processing that cerebellum-like circuitry can provide.

Spike timing dependent synaptic plasticity in biological systems.

Association of a presynaptic spike with a postsynaptic spike can lead to changes in synaptic efficacy that are highly dependent on the relative timing of the pre- and postsynaptic spikes. Different synapses show varying forms of such spike-timing dependent learning rules. This review describes these different rules, the cellular mechanisms that may be responsible for them, and the computational consequences of these rules for information processing and storage in the nervous system.

The mormyromast region of the mormyrid electrosensory lobe. I. Responses to corollary discharge and electrosensory stimuli.

This is the first of two papers on the electrosensory lobe (ELL) of mormyrid electric fish. The ELL is the first stage in the central processing of electrosensory information from electroreceptors. Cells of the mormyrid ELL are affected at the time of the electric organ discharge (EOD) by two different inputs, EOD-evoked reafferent input from electroreceptors and corollary discharge input associated with the motor command that elicits the EOD. This first paper examines the intracellular responses of ELL cells to these two different inputs in the region of ELL that receives primary afferent fibers from mormyromast electroreceptors. Mormyromast electroreceptors are responsible for active electrolocation. The paper extends previous studies of the mormyrid ELL by describing the physiological responses of cell types, which had been previously identified only morphologically, including: the two types of Purkinje-like medium ganglionic cells, MG1 and MG2; the thick smooth dendrite cells; and the medium fusiform cells. In addition, two previously unrecognized cell types, the large thick smooth dendrite cell and the interzonal cell, are described both morphologically and physiologically for the first time. Finally, new information is provided on the two types of ELL efferent cells, the large ganglionic and large fusiform cells. All cell types, except for the medium fusiform cell, show nonlinear interactions between electrosensory and corollary discharge inputs. All cell types, except for the medium fusiform cell and the interzonal cell, also show plasticity of the corollary discharge response after pairing with electrosensory stimuli.

The mormyromast region of the mormyrid electrosensory lobe. II. Responses to input from central sources.

This is the second in a series of two papers on the mormyromast regions of the electrosensory lobe (ELL) of mormyrid electric fish. In this study, we examined the effects of artificial stimulation of two of the three major central inputs to ELL on different morphologically identified cell types of ELL. The three major central inputs to ELL are the eminentia granularis posterior, the juxtalobar nucleus, and the preeminential nucleus. We stimulated the juxtalobar and preeminential nuclei. We compared the effects of such stimulation with effects of the electric organ corollary discharge (EOCD) on the same cells to understand the origins of EOCD effects in ELL. Responses to juxtalobar stimulation were different in different cell types and remarkably similar to corollary discharge responses in the same cells. In addition, responses to juxtalobar stimulation were consistently depressed when the stimulus was delivered immediately after the naturally occurring EOCD response. These findings indicate that the juxtalobar nucleus is a major source of the EOCD responses of ELL cells. In contrast, preeminential stimulation evoked similar responses in medium ganglionic cells, and the two types of efferent cells that were quite different from the EOCD responses of these cells, suggesting that the preeminential nucleus is less important than the juxtalobar nucleus in determining the EOCD responses of ELL cells. Preeminential responses of medium ganglionic and efferent cells consisted of a short-latency excitatory postsynaptic potential (EPSP) followed by a long-lasting inhibitory postsynaptic potential (IPSP). Both the EPSPs and IPSPs were facilitated when brief bursts of closely spaced stimuli were delivered.