Erik Harvey-Girard

SK Channels Provide a Novel Mechanism for the Control of Frequency Tuning in Electrosensory Neurons

One important characteristic of sensory input is frequency, with sensory neurons often tuned to narrow stimulus frequency ranges. Although vital for many neural computations, the cellular basis of such frequency tuning remains mostly unknown. In the electrosensory system of Apteronotus leptorhynchus, the primary processing of important environmental and communication signals occurs in pyramidal neurons of the electrosensory lateral line lobe. Spike trains transmitted by these cells can encode low-frequency prey stimuli with bursts of spikes and high-frequency communication signals with single spikes. Here, we demonstrate that the selective expression of SK2 channels in a subset of pyramidal neurons reduces their response to low-frequency stimuli by opposing their burst responses. Apamin block of the SK2 current in this subset of cells induced bursting and increased their response to low-frequency inputs. SK channel expression thus provides an intrinsic mechanism that predisposes a neuron to respond to higher frequencies and thus specific, behaviorally relevant stimuli.

Burst-Induced Anti-Hebbian Depression Acts through Short-Term Synaptic Dynamics to Cancel Redundant Sensory Signals

Weakly electric fish can enhance the detection and localization of important signals such as those of prey in part by cancellation of redundant spatially diffuse electric signals due to, e.g., their tail bending. The cancellation mechanism is based on descending input, conveyed by parallel fibers emanating from cerebellar granule cells, that produces a negative image of the global low-frequency signals in pyramidal cells within the first-order electrosensory region, the electrosensory lateral line lobe (ELL). Here we demonstrate that the parallel fiber synaptic input to ELL pyramidal cell undergoes long-term depression (LTD) whenever both parallel fiber afferents and their target cells are stimulated to produce paired burst discharges. Paired large bursts (4-4) induce robust LTD over pre–post delays of up to ±50 ms, whereas smaller bursts (2-2) induce weaker LTD. Single spikes (either presynaptic or postsynaptic) paired with bursts did not induce LTD. Tetanic presynaptic stimulation was also ineffective in inducing LTD. Thus, we have demonstrated a form of anti-Hebbian LTD that depends on the temporal correlation of burst discharge. We then demonstrated that the burst-induced LTD is postsynaptic and requires the NR2B subunit of the NMDA receptor, elevation of postsynaptic Ca2+, and activation of CaMKIIβ. A model incorporating local inhibitory circuitry and previously identified short-term presynaptic potentiation of the parallel fiber synapses further suggests that the combination of burst-induced LTD, presynaptic potentiation, and local inhibition may be sufficient to explain the generation of the negative image and cancellation of redundant sensory input by ELL pyramidal cells.

Long-term recognition memory of individual conspecifics is associated with telencephalic expression of Egr-1 in the electric fish Apteronotus leptorhynchus.

Primates and songbirds can learn to recognize individual conspecifics based on complex sensory cues; this requires a large, highly differentiated dorsal telencephalon. Here we show that the electric fish Apteronotus leptorhynchus can learn to recognize individual conspecifics based on a simple cue, the beat frequency of their summed sinusoidal electric organ discharges (EOD). Male fish produce transient communication signals (chirps) in response to mimic EODs. The chirp response habituates over repeated stimulus presentations within one experimental session, continues to habituate over successive daily sessions and is nearly extinguished after 5–7 days. Habituation of the chirp response was specific to the presented beat frequency. The conversion of short‐ to long‐term habituation could be disrupted by cooling the head 30 minutes after the daily habituation trials. Consolidation of long‐term memory in mammals is thought to involve induced expression of an immediate early gene, Egr‐1. We cloned the Apteronotid homolog of the Egr‐1 gene and found that chirp‐evoking stimuli induced strong expression of its mRNA within the dorsal (Dd), central (DC), and lateral (DL) subdivisions of the dorsal telencephalon. Interestingly, the dorsolateral region is hypothesized to be homologous to the amniote hippocampal formation. We conclude that A. leptorhynchus can learn to identify individual conspecifics based on their EOD frequency and can remember these frequencies for several days. We hypothesize that this form of learning, as in primates and songbirds, requires a subset of dorsal telencephalic areas and involves a consolidation‐like process that includes the expression of the transcription factor AptEgr‐1. J. Comp. Neurol. 518:2666–2692, 2010.

Frequency-Tuned Cerebellar Channels and Burst-Induced LTD Lead to the Cancellation of Redundant Sensory Inputs

For optimal sensory processing, neural circuits must extract novel, unpredictable signals from the redundant sensory input in which they are embedded, but the detailed cellular and network mechanisms that implement such selective cancellation are presently unknown. Using a combination of modeling and experiment, we characterize in detail a cerebellar circuit in weakly electric fish, showing how it can carry out this computation. We use a model incorporating the wide range of experimentally estimated parallel fiber feedback delays and a burst-induced LTD rule derived from in vitro experiments to explain the precise cancellation of redundant signals observed in vivo. Our model demonstrates how the backpropagation-dependent burst dynamics adjusts the temporal pairing width of the plasticity mechanism to precisely match the frequency of the redundant signal. The model also makes the prediction that this cerebellar feedback pathway must be composed of frequency-tuned channels; this prediction is subsequently verified in vivo, highlighting a novel and general capability of cerebellar circuitry.

Regulated expression of N‐methyl‐D‐aspartate receptors and associated proteins in teleost electrosensory system and telencephalon

Several types of N‐methyl‐D‐aspartate (NMDA) receptor‐dependent synaptic plasticity are characterized by differences in polarity, induction parameters, and duration, which depend on the interactions of NMDARs with intracellular synaptic and signaling proteins. Here, we examine the NMDAR signaling components in the brain of the weakly electric fish Apteronotus leptorhynchus. Compared with mammalian orthologs, high levels of sequence conservation for known functional sites in both NMDAR subunits (NR1, NR2A–C) and signaling proteins (fyn tyrosine kinase, RasGRF‐1 and ‐2) were found. In situ hybridization analysis demonstrated that, similar to the case in the adult mammal brain, NR2A and NR2B are expressed at moderate levels in most brain regions and at very high levels in the dorsal telencephalon. RasGRF‐1 and fyn have a similar distribution and appear to be coexpressed with NR2B in telencephalic regions known to support learning and long‐term memory. Both NR2A and NR2B are highly expressed in pyramidal cells of the electrosensory lateral line lobe (ELL) known to exhibit the short‐term synaptic plasticity that underlies adaptive feedback cancellation of redundant sensory input. In contrast, nonplastic pyramidal cells expressed only the NR2A subunit. Furthermore, field recordings show that ifenprodil‐sensitive NR2B‐containing NMDARs predominate for the plastic feedback input to ELL pyramidal cells. However, RasGRF‐1 and fyn are expressed only at low levels in a subset of these pyramidal cells. Our data suggest that NMDAR functions are highly conserved between fish and mammals and that synaptic plasticity dynamics in different brain regions are related to the expression patterns of the synaptic signaling proteins interacting with NMDARs. J. Comp. Neurol. 505:644–668, 2007.

Organization of the gymnotiform fish pallium in relation to learning and memory: IV. Expression of conserved transcription factors and implications for the evolution of dorsal telencephalon

We have cloned the apteronotid homologs of FoxP2, Otx1, and FoxO3. There was, in the case of all three genes, good similarity between the apteronotid and human amino acid sequences: FoxP2, 78%; Otx1, 54%; FoxO3, 71%. The functional domains of these genes were conserved to a far greater extent, on average: FoxP2, 89%; Otx1, 76%; FoxO3, 82%. This led us to hypothesize that the cellular functions of these genes might also be conserved. We used in situ hybridization to examine the distribution of the mRNA transcripts of these genes in the apteronotid telencephalon. We confined our analysis to the pallial regions previously associated with learning about social signals, whose circuitry has been closely examined in the other articles of this series. We found that AptFoxP2 and AptOtx1 transcripts were expressed predominantly in the dorsocentral division of the pallium (DC); the dorsolateral division of the pallium (DL) contained only weakly labeled neurons. In both cases, the distribution of labeled neurons was very heterogeneous, and unlabeled neurons could be found adjacent to strongly labeled ones. In contrast, we found that most neurons in DL strongly expressed AptFoxO3 mRNA, although there was only weak expression in a small number of cells within DC. We briefly discuss the relevance of our results regarding the functional roles of AptFoxP2/AptOtx1‐expressing neurons in DC for communication vs. foraging behavior. We extensively discuss the implications of our results for possible homologies between DL and DC and medial and dorsal pallium of tetrapods, respectively. J. Comp. Neurol. 520:3395–3413, 2012.

Expression of the cannabinoid CB1 receptor in the gymnotiform fish brain and its implications for the organization of the teleost pallium

Cannabinoid CB1 receptors (CB1R) are widely distributed in the brains of many vertebrates, but whether their functions are conserved is unknown. The weakly electric fish, Apteronotus leptorhynchus (Apt), has been well studied for its brain structure, behavior, sensory processing, and learning and memory. It therefore offers an attractive model for comparative studies of CB1R functions. We sequenced partial AptCB1R mRNAs and performed in situ hybridization to localize its expression. Partial AptCB1R protein sequence was highly conserved to zebrafish (90.7%) and mouse (81.9%) orthologs. AptCB1R mRNA was highly expressed in the telencephalon. Subpallial neurons (dorsal, central, intermediate regions and part of the ventral region, Vd/Vc/Vi, and Vv) expressed high levels of AptCB1R transcript. The central region of dorsocentral telencephalon (DCcore) strongly expressed CB1R mRNA; cells in DCcore project to midbrain regions involved in electrosensory/visual function. The lateral and rostral regions of DC surrounding DCcore (DCshell) lack AptCB1R mRNA. The rostral division of the dorsomedial telencephalon (DM1) highly expresses AptCB1R mRNA. In dorsolateral division (DL) AptCB1R mRNA was expressed in a gradient that declined in a rostrocaudal manner. In diencephalon, AptCB1R RNA probe weakly stained the central‐posterior (CP) and prepacemaker (PPn) nuclei. In mesencephalon, AptCB1R mRNA is expressed in deep layers of the dorsal (electrosensory) torus semicircularis (TSd). In hindbrain, AptCB1R RNA probe weakly labeled inhibitory interneurons in the electrosensory lateral line lobe (ELL). Unlike mammals, only few cerebellar granule cells expressed AptCB1R transcripts and these were located in the center of eminentia granularis pars posterior (EGp), a cerebellar region involved in feedback to ELL. J. Comp. Neurol. 521:949–975, 2013.

Organization of the gymnotiform fish pallium in relation to learning and memory: I. Cytoarchitectonics and cellular morphology

The present article examines the anatomical organization of the dorsal telencephalon of two gymnotiform fish: Gymnotus sp. and Apteronotus leptorhynchus. These electric fish use elaborate electrical displays for agonistic and sexual communication. Our study emphasizes mainly pallial divisions: dorsolateral (DL), dorsodorsal (DD), and dorsocentral (DC), previously implicated in social learning dependent on electric signals. We found that the pallial cytoarchitectonics of gymnotiformes are similar to those reported for the commonly studied goldfish, except that DC is larger and better differentiated in gymnotiformes. We identified a new telencephalic region (Dx), located between DL and DC, and describe the morphological and some biochemical properties of its neurons. Most neurons in DL, DD, and DC are glutamatergic with spiny dendrites. However, the size of these cells as well as the orientation and extent of their dendrites vary systematically across these regions. In addition, both DD and DL contained numerous small GABAergic interneurons as well as well‐developed GABAergic plexuses. One important and novel observation is that the dendrites of the spiny neurons within all three regions remain confined to their respective territories. We confirm that DL and DC express very high levels of NMDA receptor subunits as well as CaMKIIα, a key downstream effector of this receptor. In contrast, this enzyme is nearly absent in DD, while NMDA receptors are robustly expressed, suggesting different rules for synaptic plasticity across these regions. Remarkably, GABAergic pallial neurons do not express CaMKIIα, in agreement with previously reported results in the cortex of rats. J. Comp. Neurol. 520:3390–3413, 2012.

Signal cancellation and contrast invariance in electrosensory systems

When processing sensory input, it is of vital importance for the neural systems to be able to discriminate a novel stimulus from the background of redundant, unimportant signals. Neural mechanisms responsible for prediction and cancellation of redundant information could be an efficient way to achieve such discrimination. While the concrete mechanisms that the brain employs for this task are presently unknown, a network able to perform this cancellation is thought to exist in the electrosensory lateral line lobe (ELL) of weakly electric fish [1]. This fish emits a high-frequency (600-1000 Hz) sinusoidal electric organ discharge (EOD) into its environment to sense its surroundings and communicate to conspecifics. Small objects such as prey create spatially localized amplitude modulations (AMs) of the EOD, whereas tail bending or communication signals induce spatially global AMs [2]. These AMs are detected by electroreceptors that densely cover the body of the fish, and provide feedforward input to pyramidal cells in the ELL. It is known that a subpopulation of such pyramidal cells, the superficial pyramidal (SP) cells, remove low-frequency predictable global signals (i.e. tail bending) from their input to maximize detection of novel local stimuli (i.e. prey) [1]. This is presumably achieved using a feedback pathway involving the granule cell layer (a cerebellarlike structure known as EGp). These granule cells connect to SP cells via parallel fibers (PFs) which may be acting as delay lines segregated into frequency channels to destructively interfere with the global stimulus. Recent in vitro studies found a novel burst timingdependent learning rule which would be able to shape this feedback [3]. Following a previous work [4], we study the cancellation of low-frequency simple redundant signals, i.e. sine waves, in the ELL of the weakly electric fish. The study combines in vitro data, in vivo electrophysiology recordings from neurons in the ELL and numerical modeling to address this issue. More precisely, we model the neural network responsible for signal cancellation in the ELL of the fish, and compare our predictions with electrophysiology data recorded in vivo [4]. In the model, we assume the presence of: 1) stimulus-driven feedback to the SP neurons, 2) a large variety of temporal delays in the PFs transmitting such feedback, and 3) burstinduced long-term plasticity. We show that the modeled network is able to efficiently cancel global redundant signals by shaping the feedback as a negative image of the global signal arriving to the SP cells. Such negative image is generated via the burst-induced anti-Hebbian learning rule in the PF-SP cell synapses, while the full period of the signal is covered by the incoming feedback due to the wide range of PF delays present in the network. The cancellation is found to be in agreement with in vivo recordings, and it is strong for signals with frequencies up to 16 Hz, enabling a clearer background above which to detect relevant non-repetitive stimuli such as prey signals (and thus to better capture the prey). Due to the importance of the phase-relationship between the feedback and the stimulus, the mechanism is found to be frequency-specific, suggesting the presence of multiple frequency channels as observed in vivo [4]. Interestingly, our model predicts that the cancellation is maintained for signals with different AM strengths (i.e. contrasts). Such contrast-invariance is highly desirable since natural signals would display different contrasts depending, for instance, on the distance between the fish and the origin of the EOD perturbation. * Correspondence: jmejias@uottawa.ca Department of Physics, University of Ottawa, Ottawa, K1N 6N5 Ontario, Canada Full list of author information is available at the end of the article Mejias et al. BMC Neuroscience 2012, 13(Suppl 1):F2 http://www.biomedcentral.com/1471-2202/13/S1/F2

Cryptic laminar and columnar organization in the dorsolateral pallium of a weakly electric fish

In the weakly electric gymnotiform fish, Apteronotus leptorhynchus, the dorsolateral pallium (DL) receives diencephalic inputs representing electrosensory input utilized for communication and navigation. Cell counts reveal that, similar to thalamocortical projections, many more cells are present in DL than in the diencephalic nucleus that provides it with sensory input. DL is implicated in learning and memory and considered homologous to medial and/or dorsal pallium. The gymnotiform DL has an apparently simple architecture with a random distribution of simple multipolar neurons. We used multiple neurotracer injections in order to study the microcircuitry of DL. Surprisingly, we demonstrated that the intrinsic connectivity of DL is highly organized. It consists of orthogonal laminar and vertical excitatory synaptic connections. The laminar synaptic connections are symmetric sparse, random, and drop off exponentially with distance; they parcellate DL into narrow (60 μm) overlapping cryptic layers. At distances greater than 100 μm, the laminar connections generate a strongly connected directed graph architecture within DL. The vertical connectivity suggests that DL is also organized into cryptic columns; these connections are highly asymmetric, with superficial DL cells preferentially projecting towards deeper cells. Our experimental analyses suggest that the overlapping cryptic columns have a width of 100 μm, in agreement with the minimal distance for strong connectivity. The architecture of DL and the expansive representation of its input, taken together with the strong expression of N‐methyl‐D‐aspartate (NMDA) receptors by its cells, are consistent with theoretical ideas concerning the cortical computations of pattern separation and memory storage via bump attractors. J. Comp. Neurol. 524:408–428, 2016.