Nathaniel B. Sawtell

A temporal basis for predicting the sensory consequences of motor commands in an electric fish

Mormyrid electric fish are a model system for understanding how neural circuits predict the sensory consequences of motor acts. Medium ganglion cells in the electrosensory lobe create negative images that predict sensory input resulting from the fishs electric organ discharge (EOD). Previous studies have shown that negative images can be created through plasticity at granule cell–medium ganglion cell synapses, provided that granule cell responses to the brief EOD command are sufficiently varied and prolonged. Here we show that granule cells indeed provide such a temporal basis and that it is well-matched to the temporal structure of self-generated sensory inputs, allowing rapid and accurate sensory cancellation and explaining paradoxical features of negative images. We also demonstrate an unexpected and critical role of unipolar brush cells (UBCs) in generating the required delayed responses. These results provide a mechanistic account of how copies of motor commands are transformed into sensory predictions.

Neural mechanisms for filtering self-generated sensory signals in cerebellum-like circuits

This review focuses on recent progress in understanding mechanisms for filtering self-generated sensory signals in cerebellum-like circuits in fish and mammals. Recent in vitro studies in weakly electric gymnotid fish have explored the interplay among anti-Hebbian plasticity, synaptic dynamics, and feedforward inhibition in canceling self-generated electrosensory inputs. Studies of the mammalian dorsal cochlear nucleus have revealed multimodal integration and anti-Hebbian plasticity, suggesting that this circuit may adaptively filter incoming auditory information. In vivo studies in weakly electric mormryid fish suggest a key role for granule cell coding in sensory filtering. The clear links between synaptic plasticity and systems level sensory filtering in cerebellum-like circuits may provide insights into hypothesized adaptive filtering functions of the cerebellum itself.

Transformations of Electrosensory Encoding Associated with an Adaptive Filter

Sensory information is often acquired through active exploration. However, an animals own movements may result in changes in patterns of sensory input that could interfere with the detection and processing of behaviorally relevant sensory signals. Neural mechanisms for predicting the sensory consequences of movements are thus likely to be of general importance for sensory systems. Such mechanisms have been identified in cerebellum-like structures associated with electrosensory processing in fish. These structures are hypothesized to act as adaptive filters, removing correlations between incoming sensory input and central predictive signals through associative plasticity at parallel fiber synapses. The present study tests the adaptive filter hypothesis in the electrosensory lobe (ELL) of weakly electric mormyrid fish. We compared the ability of electroreceptors and ELL efferent neurons to encode the position of moving objects in the presence and absence of self-generated electrosensory signals caused by tail movements. Tail movements had strong effects on the responses of electroreceptors, substantially reducing the amount of information they conveyed about object position. In contrast, responses of efferent neurons were relatively unaffected by tail movements, and the information they conveyed about object position was preserved. We provide evidence that the electrosensory consequences of tail bending are opposed by proprioceptive inputs conveyed by parallel fibers and that the effects of proprioceptive inputs to efferent cells are plastic. These results support the idea that cerebellum-like structures learn and remove the predictable sensory consequences of behavior and link mechanisms of adaptive filtering to selective encoding of behaviorally relevant sensory information.

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.

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.

Plastic corollary discharge predicts sensory consequences of movements in a cerebellum-like circuit.

The capacity to predict the sensory consequences of movements is critical for sensory, motor, and cognitive function. Though it is hypothesized that internal signals related to motor commands, known as corollary discharge, serve to generate such predictions, this process remains poorly understood at the neural circuit level. Here we demonstrate that neurons in the electrosensory lobe (ELL) of weakly electric mormyrid fish generate negative images of the sensory consequences of the fishs own movements based on ascending spinal corollary discharge signals. These results generalize previous findings describing mechanisms for generating negative images of the effects of the fishs specialized electric organ discharge (EOD) and suggest that a cerebellum-like circuit endowed with associative synaptic plasticity acting on corollary discharge can solve the complex and ubiquitous problem of predicting sensory consequences of movements.

A cerebellum-like circuit in the auditory system cancels responses to self-generated sounds

The dorsal cochlear nucleus (DCN) integrates auditory nerve input with a diverse array of sensory and motor signals processed in circuitry similar to that of the cerebellum. Yet how the DCN contributes to early auditory processing has been a longstanding puzzle. Using electrophysiological recordings in mice during licking behavior, we show that DCN neurons are largely unaffected by self-generated sounds while remaining sensitive to external acoustic stimuli. Recordings in deafened mice, together with neural activity manipulations, indicate that self-generated sounds are cancelled by non-auditory signals conveyed by mossy fibers. In addition, DCN neurons exhibit gradual reductions in their responses to acoustic stimuli that are temporally correlated with licking. Together, these findings suggest that DCN may act as an adaptive filter for cancelling self-generated sounds. Adaptive filtering has been established previously for cerebellum-like sensory structures in fish, suggesting a conserved function for such structures across vertebrates.

A Role for Mixed Corollary Discharge and Proprioceptive Signals in Predicting the Sensory Consequences of Movements

Animals must distinguish behaviorally relevant patterns of sensory stimulation from those that are attributable to their own movements. In principle, this distinction could be made based on internal signals related to motor commands, known as corollary discharge (CD), sensory feedback, or some combination of both. Here we use an advantageous model system—the electrosensory lobe (ELL) of weakly electric mormyrid fish—to directly examine how CD and proprioceptive feedback signals are transformed into negative images of the predictable electrosensory consequences of the fishs motor commands and/or movements. In vivo recordings from ELL neurons and theoretical modeling suggest that negative images are formed via anti-Hebbian plasticity acting on random, nonlinear mixtures of CD and proprioception. In support of this, we find that CD and proprioception are randomly mixed in spinal mossy fibers and that properties of granule cells are consistent with a nonlinear recoding of these signals. The mechanistic account provided here may be relevant to understanding how internal models of movement consequences are implemented in other systems in which similar components (e.g., mixed sensory and motor signals and synaptic plasticity) are found.

Responses of cerebellar Purkinje cells during fictive optomotor behavior in larval zebrafish

Although most studies of the cerebellum have been conducted in mammals, cerebellar circuitry is highly conserved across vertebrates, suggesting that studies of simpler systems may be useful for understanding cerebellar function. The larval zebrafish is particularly promising in this regard because of its accessibility to optical monitoring and manipulations of neural activity. Although several studies suggest that the cerebellum plays a role in behavior at larval stages, little is known about the signals conveyed by particular classes of cerebellar neurons. Here we use electrophysiological recordings to characterize subthreshold, simple spike, and climbing fiber responses in larval zebrafish Purkinje cells in the context of the fictive optomotor response (OMR)-a paradigm in which fish adjust motor output to stabilize their virtual position relative to a visual stimulus. Although visual responses were prominent in Purkinje cells, they lacked the direction or velocity sensitivity that would be expected for controlling the OMR. On the other hand, Purkinje cells exhibited strong responses during fictive swim bouts. Temporal characteristics of these responses are suggestive of a general role for the larval zebrafish cerebellum in controlling swimming. Climbing fibers encoded both visual and motor signals but did not appear to encode signals that could be used to adjust OMR gain, such as retinal slip. Finally, the observation of diverse relationships between simple spikes and climbing fiber responses in individual Purkinje cells highlights the importance of distinguishing between these two types of activity in calcium imaging experiments.

Neural Mechanisms for Predicting the Sensory Consequences of Behavior: Insights from Electrosensory Systems

Perception of the environment requires differentiating between external sensory inputs and those that are self-generated. Some of the clearest insights into the neural mechanisms underlying this process have come from studies of the electrosensory systems of fish. Neurons at the first stage of electrosensory processing generate negative images of the electrosensory consequences of the animals own behavior. By canceling out the effects of predictable, self-generated inputs, negative images allow for the selective encoding of unpredictable, externally generated stimuli. Combined experimental and theoretical studies of electrosensory systems have led to detailed accounts of how negative images are formed at the level of synaptic plasticity rules, cells, and circuits. Here, I review these accounts and discuss their implications for understanding how predictions of the sensory consequences of behavior may be generated in other sensory structures and the cerebellum.