Living life with an electric touch.

The electric organ discharges (EODs) produced by weakly electric fish have long been a source of scientific intrigue and inspiration. The study of these species has contributed to our understanding of the organization of fixed action patterns, as well as enriching general imaging theory by unveiling the dual impact of an agent's actions on the environment and its own sensory system during the imaging process. This Centenary Review firstly compares how weakly electric fish generate species- and sex-specific stereotyped electric fields by considering: (1) peripheral mechanisms, including the geometry, channel repertoire and innervation of the electrogenic units; (2) the organization of the electric organs (EOs); and (3) neural coordination mechanisms. Secondly, the Review discusses the threefold function of the fish-centered electric fields: (1) to generate electric signals that encode the material, geometry and distance of nearby objects, serving as a short-range sensory modality or 'electric touch'; (2) to mark emitter identity and location; and (3) to convey social messages encoded in stereotypical modulations of the electric field that might be considered as species-specific communication symbols. Finally, this Review considers a range of potential research directions that are likely to be productive in the future.

Visual-stimuli Four-arm Maze test to Assess Cognition and Vision in Mice.

Visual impairments, notably loss of contrast sensitivity and color vision, were documented in Alzheimer's disease (AD) patients yet are critically understudied. This protocol describes a novel visual-stimuli four-arm maze (ViS4M; also called visual x-maze), which is a versatile x-shaped maze equipped with spectrum- and intensity-controlled light-emitting diode (LED) sources and dynamic grayscale objects. The ViS4M is designed to allow the assessment of color and contrast vision along with locomotor and cognitive functions in mice. In the color testing mode, the spectral distributions of the LED lights create four homogenous spaces that differ in chromaticity and luminance, corresponding to the mouse visual system. In the contrast sensitivity test, the four grayscale objects are placed in the middle of each arm, contrasting against the black walls and the white floors of the maze. Upon entering the maze, healthy wild-type (WT) mice tend to spontaneously alternate between arms, even under equiluminant conditions of illumination, suggesting that cognitively and visually intact mice use both color and brightness as cues to navigate the maze. Evaluation of the double-transgenic APPSWE/PS1ΔE9 mouse model of AD (AD+ mice) reveals substantial deficits to alternate in both color and contrast modes at an early age, when hippocampal-based memory and learning is still intact. Profiling of timespan, entries, and transition patterns between the different arms uncovers variable aging and AD-associated impairments in color discrimination and contrast sensitivity. The analysis of arm sequences of alternation reveals different pathways of exploration in young WT, old WT, and AD+ mice, which can be used as color and contrast imprints of functionally intact versus impaired mice. Overall, we describe the utility of a novel visual x-maze test to identify behavioral changes in mice related to cognition, as well as color and contrast vision, with high precision and reproducibility. Graphic abstract: Exploratory behavior of AD+ mice versus age- and sex-matched WT mice is tracked (top left: trajectory from a 5-min video file) in a novel visual-stimuli four-arm maze (ViS4M; also named visual x-maze) equipped with spectrum- and intensity-controlled LED sources or grayscale objects. Consecutive arm entries reveal that APPSWE/PS1ΔE9 (AD+) mice alternate less between arms, as opposed to WT mice. Sequence analysis, according to the three alternation pathways (depicted by white, yellow, and brown arrows) under different conditions of illumination, uncovers specific deficits linked to color vision in AD+ mice, evidenced by a color imprint chart.

Color and contrast vision in mouse models of aging and Alzheimer's disease using a novel visual-stimuli four-arm maze.

We introduce a novel visual-stimuli four-arm maze (ViS4M) equipped with spectrally- and intensity-controlled LED emitters and dynamic grayscale objects that relies on innate exploratory behavior to assess color and contrast vision in mice. Its application to detect visual impairments during normal aging and over the course of Alzheimer's disease (AD) is evaluated in wild-type (WT) and transgenic APPSWE/PS1∆E9 murine models of AD (AD+) across an array of irradiance, chromaticity, and contrast conditions. Substantial color and contrast-mode alternation deficits appear in AD+ mice at an age when hippocampal-based memory and learning is still intact. Profiling of timespan, entries and transition patterns between the different arms uncovers variable AD-associated impairments in contrast sensitivity and color discrimination, reminiscent of tritanomalous defects documented in AD patients. Transition deficits are found in aged WT mice in the absence of alternation decline. Overall, ViS4M is a versatile, controlled device to measure color and contrast-related vision in aged and diseased mice.

Caspase-6 Knockout in the 5xFAD Model of Alzheimer's Disease Reveals Favorable Outcome on Memory and Neurological Hallmarks.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia in the elderly. Caspases, a family of cysteine proteases, are major mediators of apoptosis and inflammation. Caspase-6 is considered to be an up-stream modulator of AD pathogenesis as active caspase-6 is abundant in neuropil threads, neuritic plaques, and neurofibrillary tangles of AD brains. In order to further elucidate the role of caspase-6 activity in the pathogenesis of AD, we produced a double transgenic mouse model, combining the 5xFAD mouse model of AD with caspase-6 knock out (C6-KO) mice. Behavioral examinations of 5xFAD/C6-KO double transgenic mice showed improved performance in spatial learning, memory, and anxiety/risk assessment behavior, as compared to 5xFAD mice. Hippocampal mRNA expression analyses showed significantly reduced levels of inflammatory mediator TNF-α, while the anti-inflammatory cytokine IL-10 was increased in 5xFAD/C6-KO mice. A significant reduction in amyloid-ß plaques could be observed and immunohistochemistry analyses showed reduced levels of activated microglia and astrocytes in 5xFAD/C6-KO, compared to 5xFAD mice. Together, these results indicate a substantial role for caspase-6 in the pathology of the 5xFAD model of AD and suggest further validation of caspase-6 as a potential therapeutic target for AD.

The Role of MAPK's Signaling in Mediating ApoE4-Driven Pathology In Vivo.

BACKGROUND: Alzheimer's Disease (AD) is associated with impairments in key brain Mitogen- Activated Protein Kinase (MAPK) signaling cascades including the p38, c-Jun N-terminal kinase (JNK), ERK and Akt pathways. Apolipoprotein E4 (ApoE4) is the most prevalent genetic risk factor of AD. OBJECTIVES: To investigate the extent to which the MAPK signaling pathway plays a role in mediating the pathological effects of apoE4 and can be reversed by experimental manipulations. METHODS: Measurements of total level and activation of MAPK signaling pathway factors, obtained utilizing immunoblot assay of hippocampal tissues from naïve and viral-treated apoE3 and apoE4 targeted replacement mice. RESULTS: ApoE4 mice showed robust activation of the stress related p38 and JNK pathways and a corresponding decrease in Akt activity, which is coupled to activation of GSK3ß and tau hyperphosphorylation. There was no effect on the ERK pathway. We have previously shown that the apoE4- related pathology, namely; accumulation of Aß, hyper-phosphorylated tau, synaptic impairments and decreased VEGF levels can be reversed by up-regulation of VEGF level utilizing a VEGF-expressing adeno-associated virus. Utilizing this approach, we assessed the extent to which the AD-hallmark and synaptic pathologies of apoE4 are related to the corresponding MAPK signaling effects. This revealed that the reversal of the apoE4-driven pathology via VEGF treatment was associated with a reversal of the p38 and Akt related effects. CONCLUSION: Taken together, these results suggest that the p38 and Akt pathways play a role in mediating the AD-related pathological effects of apoE4 in the hippocampus.

Golden Exosomes Selectively Target Brain Pathologies in Neurodegenerative and Neurodevelopmental Disorders.

Exosomes, nanovesicles that are secreted by different cell types, enable intercellular communication at local or distant sites. Alhough they have been found to cross the blood brain barrier, their migration and homing abilities within the brain remain unstudied. We have recently developed a method for longitudinal and quantitative in vivo neuroimaging of exosomes based on the superior visualization abilities of classical X-ray computed tomography (CT), combined with gold nanoparticles as labeling agents. Here, we used this technique to track the migration and homing patterns of intranasally administrated exosomes derived from bone marrow mesenchymal stem cells (MSC-exo) in different brain pathologies, including stroke, autism, Parkinson's disease, and Alzheimer's disease. We found that MSC-exo specifically targeted and accumulated in pathologically relevant murine models brains regions up to 96 h post administration, while in healthy controls they showed a diffuse migration pattern and clearance by 24 h. The neuro-inflammatory signal in pathological brains was highly correlated with MSC-exo accumulation, suggesting that the homing mechanism is inflammatory-driven. In addition, MSC-exo were selectively uptaken by neuronal cells, but not glial cells, in the pathological regions. Taken together, these findings can significantly promote the application of exosomes for therapy and targeted drug delivery in various brain pathologies.

Encoding phase spectrum for evaluating 'electric qualia'.

The most broadly expressed and studied aspect of sensory transduction is receptor tuning to the power spectral density of the incoming signals. Temporal cues expressed in the phase spectrum are relevant in African and American pulse-emitting electric fish showing electroreceptors sensing the signals carried by the self- and conspecific-generated electric organ discharges. This article concerns the role of electroreceptor phase sensitivity in American pulse Gymnotiformes. These fish show electroreceptors sharply tuned to narrow frequency bands. This led to the common thought that most electrosensory information is contained in the amplitude spectra of the signals. However, behavioral and modeling studies suggest that in their pulses, Gymnotiformes electroreceptors also encode cues embodied in the phase spectrum of natural stimuli. Here, we show that the two main types of tuberous primary afferents of Gymnotus omarorum differentially respond to cues embodied in the amplitude and phase spectra of self-generated electrosensory signals. One afferent type, pulse markers, is mainly driven by the amplitude spectrum, while the other, burst coders, is predominantly sensitive to the phase spectrum. This dual encoding strategy allows the fish to create a sensory manifold where patterns of 'electric color' generated by object impedance and other potential sources of 'colored' images (such as large nearby objects and other electric fish) can be represented.

Combined Gene Therapy to Reduce the Neuronal Damage in the Mouse Model of Focal Ischemic Injury.

Research into stroke is driven by frustration over the limited available therapeutics. Targeting a single aspect of this multifactorial disease contributes to the therapeutic boundaries. To overcome this, we devised a novel multifactorial-cocktail treatment, using lentiviruses encoding excitatory amino acid transporter 2 (EAAT2(, glutamate dehydrogenase 2 (GDH2), and nuclear factor E2-related factor 2 (Nrf2) genes, that acts synergistically to address the effected excito-oxidative axis. Here, we used the vasoconstrictor endothelin-1 (ET-1) to induce focal ischemic injury in mice by direct injection into the striatum. Mice treated with the mixture of these three genes show significant improvement in body balance, motor coordination, and decreased motor asymmetry compared to each gene separately. These results demonstrate that overexpression of the combined EAAT2, GDH2, and NRF2 genes can provide neuroprotection after ischemic injury.

In Vivo Neuroimaging of Exosomes Using Gold Nanoparticles.

Exosomes are emerging as effective therapeutic tools for various pathologies. These extracellular vesicles can bypass biological barriers, including the blood-brain barrier, and can serve as powerful drug and gene therapy transporters. However, the progress of therapy development is impeded by several challenges, including insufficient data on exosome trafficking and biodistribution and the difficulty to image deep brain structures in vivo. Herein, we established a method for noninvasive in vivo neuroimaging and tracking of exosomes, based on glucose-coated gold nanoparticle (GNP) labeling and computed tomography imaging. Labeling of exosomes with the GNPs was achieved directly, as opposed to the typical and less efficient indirect labeling mode through parent cells. On the mechanistic level, we found that the glucose-coated GNPs were uptaken into MSC-derived exosomes via an active, energy-dependent mechanism that is mediated by the glucose transporter GLUT-1 and involves endocytic proteins. Next, we determined optimal parameters of size and administration route; we demonstrated that 5 nm GNPs enabled improved exosome labeling and that intranasal, compared to intravenous, administration led to superior brain accumulation and thus enhanced in vivo neuroimaging. Furthermore, using a mouse model of focal brain ischemia, we noninvasively tracked intranasally administered GNP-labeled exosomes, which showed increased accumulation at the lesion site over 24 h, as compared to nonspecific migration and clearance from control brains over the same period. Thus, this exosome labeling technique can serve as a powerful diagnostic tool for various brain disorders and could potentially enhance exosome-based treatments for neuronal recovery.

Toll-Like Receptor-4 Inhibitor TAK-242 Attenuates Motor Dysfunction and Spinal Cord Pathology in an Amyotrophic Lateral Sclerosis Mouse Model.

Neuroinflammation contributes to amyotrophic lateral sclerosis (ALS) progression. TLR4, a transmembrane protein that plays a central role in activation of the innate immune system, has been shown to induce microglial activation in ALS models. TLR4 is up-regulated in the spinal cords of hSOD1G93A mice. We aimed to examine the effects of specific TLR4 inhibition on disease progression and survival in the hSOD1G93A mouse model of ALS. Immunologic effect of TLR4 inhibition in vitro was measured by the effect of TAK-242 treatment on LPS-induced splenocytes proliferation. hSOD1G93A transgenic mice were treated with TAK-242, a selective TLR4 inhibitor, or vehicle. Survival, body weight, and motor behavior were monitored. To evaluate in vivo immunologic modifications associated with TAK-242 treatment, we measured serum IL-1ß in the plasma, as well as IL-1ß and TNF-α mRNAs in the spinal cord in wild-type mice and in TAK-242-treated and vehicle-treated early symptomatic hSOD1G93A mice. Immunohistochemical analysis of motor neurons, astrocytes, and microglial reactivity in the spinal cords were performed on symptomatic (100 days old) TAK-242-treated and vehicle-treated hSOD1G93A mice. In vitro, splenocytes taken from 100 days old hSOD1G93A mice showed significantly increased proliferation when exposed to LPS (p = 0.0002), a phenomenon that was reduced by TAK-242 (p = 0.0179). TAK-242 treatment did not attenuate body weight loss or significantly affect survival. However, TAK-242-treated hSOD1G93A mice showed temporary clinical delay in disease progression evident in the ladder test and hindlimb reflex measurements. Plasma IL-1ß levels were significantly reduced in TAK-242-treated compared to vehicle-treated hSOD1G93A mice (p = 0.0023). TAK-242 treatment reduced spinal cord astrogliosis and microglial activation and significantly attenuated spinal cord motor neuron loss at early disease stage (p = 0.0259). Compared to wild-type animals, both IL-1ß and TNF-α mRNAs were significantly upregulated in the spinal cords of hSOD1G93A mice. Spinal cord analysis in TAK-242-treated hSOD1G93A mice revealed significant attenuation of TNF-α mRNA (p = 0.0431), but no change in IL-1ß mRNA. TLR4 inhibition delayed disease progression, attenuated spinal cord astroglial and microglial reaction, and reduced spinal motor neuron loss in the ALS hSOD1G93A mouse model. However, this effect did not result in increased survival. To our knowledge, this is the first report on TAK-242 treatment in a neurodegenerative disease model. Further studies are warranted to assess TLR4 as a therapeutic target in ALS.

Cicatrización de úlceras crónicas venosas y diabéticas de miembros inferiores en pacientes tratados con un abordaje holístico / Healing of chronic venous and diabetic ulcers of the lower limbs in patients treated with a holistic approach

Las heridas crónicas son aquellas que no han podido seguir un proceso ordenado de reparación para recuperar la integridad anatómica y funcional luego de cierto tiempo. Las mismas constituyen una epidemia silenciosa con una prevalencia estimada en población general entre 0.18 y 5.9% en países industrializados y entre 3 y 6% en Latinoamérica, siendo el 98% úlceras venosas o diabéticas. Existe escasa evidencia científica en relación a resultados obtenidos con los tratamientos actuales en poblaciones de consulta espontánea. OBJETIVO Evaluar la evolución en el tiempo de la cicatrización de úlceras crónicas de miembros inferiores venosa o diabética tratadas con un abordaje holístico, en una cohorte de pacientes asistidos en un hospital público. MÉTODOS Adultos con úlceras crónicas de miembros inferiores venosas o diabéticas asistentes al consultorio de heridas durante un semestre de 2017. Se aplicó un algoritmo de evaluación y tratamiento (abordaje holístico). RESULTADOS 46 pacientes evaluados; edad promedio 63 años. Las patologías más frecuentes fueron hipertensión, diabetes e insuficiencia venosa crónica. El 72% fueron úlceras diabéticas. Tiempo de evolución promedio 39 meses. Del total de úlceras (n: 51) 33(72%) cicatrizaron al 100% durante 8 meses. Se observó mayor cicatrización en úlceras diabéticas. DISCUSIÓN Con un tratamiento holístico, que incluye educación personalizada, cicatrizó un elevado porcentaje de úlceras tratadas, especialmente diabéticas, pese a ser pacientes con patologías, edad avanzada y largo tiempo de evolución

The bioinspiring potential of weakly electric fish.

Electric fish are privileged animals for bio-inspiring man-built autonomous systems since they have a multimodal sense that allows underwater navigation, object classification and intraspecific communication. Although there are taxon dependent variations adapted to different environments, this multimodal system can be schematically described as having four main components: active electroreception, passive electroreception, lateral line sense and, proprioception. Amongst these sensory modalities, proprioception and electroreception show 'active' systems that extrct information carried by self generated forms of energy. This ensemble of four sensory modalities is present in African mormyriformes and American gymnotiformes. The convergent evolution of similar imaging, peripheral encoding, and central processing mechanisms suggests that these mechanisms may be the most suitable for dealing with electric images in the context of the other and self generated actions. This review deals with the way in which biological organisms address three of the problems that are faced when designing a bioinspired electroreceptive agent: (a) body shape, material and mobility, (b) peripheral encoding of electric images, and (c) early processing of electrosensory signals. Taking into account biological solutions I propose that the new generation of underwater agents should have electroreceptive arms, use complex peripheral sensors for encoding the images and cerebellum like architecture for image feature extraction and implementing sensory-motor transformations.

Identifying self- and nonself-generated signals: lessons from electrosensory systems.

This chapter provides a short review of the mechanisms used by electroreceptive fish to discriminate self- from nonself-generated signals. Electroreception is used by animals to detect objects of electric impedance different from the water, to detect natural electrogenic sources and to communicate signals between conspecifics. Electroreceptive animals may generate electric fields either with the purpose of electrically illuminating the neighborhood or as an epiphenomenon of other functions. In addition, the presence of the fish body as a conductive object in a scene funnels the current flow and, consequently, animal movements also generate signals by changing the body shape or the spatial relationship of the body with the surrounding objects. Therefore, mechanisms for discrimination between self and externally generated signals are very important for constructing a coherent representation of the environment. Some mechanisms facilitate and stream the flow of signals carried by the self-generated electric field. Others are designed to reject unwanted interference coming from self-generated movements or even the self-generated electric field. Finally, more complex operations involving sensory motor integration are used for discriminating between self- and conspecific- generated communication signals. Despite the evolutionary distance between animals endowed with electric sense, mechanisms for self-identification reappear with few differences between species. This suggests that many of the possible strategies are present in vertebrates may be found in these fish. Therefore, we have much to learn about self recognition from the study of electroreception.

Encoding electric signals by Gymnotus omarorum: heuristic modeling of tuberous electroreceptor organs.

The role of different substructures of electroreceptor organs in signal encoding was explored using a heuristic computational model. This model consists of four modules representing the pre-receptor structures, the transducer cells, the synapses and the afferent fiber, respectively. Simulations reproduced previously obtained experimental data. We showed that different electroreceptor types described in the literature can be qualitative modeled with the same set of equations by changing only two parameters, one affecting the filtering properties of the pre-receptor, and the other affecting the transducer module. We studied the responses of different electroreceptor types to natural stimuli using simulations derived from an experimentally-obtained database in which the fish were exposed to resistive or capacitive objects. Our results indicate that phase and frequency spectra are differentially encoded by different subpopulations of tuberous electroreceptors. A different type of receptor responses to the same input is a necessary condition for encoding a multidimensional space of stimuli as in the waveform of the EOD. Our simulation analysis suggested that the electroreceptive mosaic may perform a waveform analysis of electrosensory signals. As in color vision or tactile texture perception, a secondary attribute, "electric color" may be encoded as a parallel activity of various electroreceptor types. This article is part of a Special Issue entitled Neural Coding.

Fish geometry and electric organ discharge determine functional organization of the electrosensory epithelium.

Active electroreception in Gymnotus omarorum is a sensory modality that perceives the changes that nearby objects cause in a self generated electric field. The field is emitted as repetitive stereotyped pulses that stimulate skin electroreceptors. Differently from mormyriformes electric fish, gymnotiformes have an electric organ distributed along a large portion of the body, which fires sequentially. As a consequence shape and amplitude of both, the electric field generated and the image of objects, change during the electric pulse. To study how G. omarorum constructs a perceptual representation, we developed a computational model that allows the determination of the self-generated field and the electric image. We verify and use the model as a tool to explore image formation in diverse experimental circumstances. We show how the electric images of objects change in shape as a function of time and position, relative to the fish's body. We propose a theoretical framework about the organization of the different perceptive tasks made by electroreception: 1) At the head region, where the electrosensory mosaic presents an electric fovea, the field polarizing nearby objects is coherent and collimated. This favors the high resolution sampling of images of small objects and perception of electric color. Besides, the high sensitivity of the fovea allows the detection and tracking of large faraway objects in rostral regions. 2) In the trunk and tail region a multiplicity of sources illuminate different regions of the object, allowing the characterization of the shape and position of a large object. In this region, electroreceptors are of a unique type and capacitive detection should be based in the pattern of the afferents response. 3) Far from the fish, active electroreception is not possible but the collimated field is suitable to be used for electrocommunication and detection of large objects at the sides and caudally.

Timing actions to avoid refractoriness: a simple solution for streaming sensory signals.

Segmenting self- from allo-generated signals is crucial for active sensory processing. We report a dynamic filter used by South American pulse electric fish to distinguish active electro-sensory signals carried by their own electric discharges from other concomitant electrical stimuli (i.e. communication signals). The filter has a sensory component, consisting of an onset type central electro-sensory neuron, and a motor component, consisting of a change in the fish's discharge rate when allo-generated electrical events occur in temporal proximity to the fish's own discharge. We investigated the sensory component of the filter by in vitro mimicking synaptic inputs occurring during behavioral responses to allo-generated interfering signals. We found that active control of the discharge enhances self-generated over allo-generated responses by forcing allo-generated signals into a central refractory period. This hypothesis was confirmed by field potential recordings in freely discharging fish. Similar sensory-motor mechanisms may also contribute to signal segmentation in other sensory systems.

Imaging in electrosensory systems.

This review addresses the biophysical mechanisms of image formation in electrosensory systems. These electrical images are used for navigation and object detection by many species of fish, some amphibians, and some mammals. In the active electrosensory systems of fish these images are formed by the fish's own electric organ discharge. In the passive electrosensory systems of fish, amphibians and mammals the images are formed by external electrical sources. In this review we describe the biophysics of image formation, the effects of the organism's passive electrical properties, the role of exploration, and the influence of context on electroreception. We suggest that the basic principles established in these specialized systems be useful for understanding other more common sensory systems.

Waveform diversity of electric organ discharges: the role of electric organ auto-excitability in Gymnotus spp.

This article shows that differences in the waveforms of the electric organ discharges (EODs) from two taxa are due to the different responsiveness of their electric organs (EOs) to their previous activity (auto-excitability). We compared Gymnotus omarorum endemic to Uruguay (35 degrees South, near a big estuary), which has four components in the head to tail electric field (V(1) to V(4)), with Gymnotus sp. endemic to the south of Brazil, Paraguay and Argentinean Mesopotamia (25 degrees South, inland), which shows a fifth component in addition to the others (V(5)). We found that: (a) the innervation pattern of the electrocytes, (b) the three earlier, neurally driven, EOD components (V(1) to V(3)), and (c) their remnants after curarisation were almost identical in the two taxa. The equivalent electromotive forces of late components (V(4) and V(5)) increased consistently as a function of the external current associated with the preceding component and were abolished by partial curarisation in both taxa. Taken together these data suggest that these components are originated in the responses of the electrocytes to longitudinal currents through the EO. By using a differential load procedure we showed that V(4) in G. omarorum responded to experimental changes in its excitation current with larger amplitude variations than V(4) in Gymnotus sp. We conclude that the differences in the EOD phenotype of the two studied taxa are due to the different EO auto-excitability. This, in turn, is caused either by the different expression of a genetic repertoire of conductance in the electrocyte membrane or in the wall of the tubes forming the EO.

The role of single spiking spherical neurons in a fast sensory pathway.

One difficulty in understanding the brain is that of linking the structure of the neurons with their computational roles in neural circuits. In this paper we address this subject in a relative simple system, the fast electrosensory pathway of an electric fish, where sensory images are coded by the relative latency of a volley of single spikes. The main input to this path is a stream of discrete electric images resulting from the modulation of a self-generated carrier by the environment. At the second order cell level, a window of low responsiveness, reducing potential interference from other stimuli, follows activation of the path. In the present study, we further characterize the input-output relationship at the second order neurons by recording field potentials, and ascertain its cellular basis using in vitro whole cell patch recordings. The field potentials from freely behaving, socially interacting fish were obtained from chronically implanted fish restrained in a mesh pen. In addition, at the end of some experiments the fish was curarized and the fast electrosensory path responses to artificial stimuli were further explored. These in vivo approaches showed that larger stimuli cause larger and longer windows of low responsiveness. The simple spherical geometry of the second order cells allowed us to unveil the membrane mechanisms underlying this phenomenon in vitro. These spherical cells respond with a single spike at the onset of current steps of any amplitude and duration, showing inward and outward rectification, and a long refractory period. We postulate that a low-threshold K+ conductance generates the outward rectification. The most parsimonious interpretation of our data indicates that slow deactivation of this conductance causes the long refractory period. These non-linear properties of the membrane explain the single spiking profile of spherical cells and the low-responsiveness window observed in vivo. Since the electric organ discharges are emitted at intervals slightly longer than the duration of the low-responsiveness window, we propose that the described cellular mechanisms allow fish streaming self-generated images.