RESUMEN
Genomic studies have identified hundreds of candidate genes near loci associated with risk for schizophrenia. To define candidates and their functions, we mutated zebrafish orthologs of 132 human schizophrenia-associated genes. We created a phenotype atlas consisting of whole-brain activity maps, brain structural differences, and profiles of behavioral abnormalities. Phenotypes were diverse but specific, including altered forebrain development and decreased prepulse inhibition. Exploration of these datasets identified promising candidates in more than 10 gene-rich regions, including the magnesium transporter cnnm2 and the translational repressor gigyf2, and revealed shared anatomical sites of activity differences, including the pallium, hypothalamus, and tectum. Single-cell RNA sequencing uncovered an essential role for the understudied transcription factor znf536 in the development of forebrain neurons implicated in social behavior and stress. This phenotypic landscape of schizophrenia-associated genes prioritizes more than 30 candidates for further study and provides hypotheses to bridge the divide between genetic association and biological mechanism.
Asunto(s)
Esquizofrenia/genética , Esquizofrenia/fisiopatología , Animales , Encéfalo , Corteza Cerebral , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Pez Cebra/genéticaRESUMEN
The Australian lycaenid butterfly Jalmenus evagoras has iridescent wings that are sexually dimorphic, spectrally and in their degree of polarization, suggesting that these properties are likely to be important in mate recognition. We first describe the results of a field experiment showing that free-flying individuals of J. evagoras discriminate between visual stimuli that vary in polarization content in blue wavelengths but not in others. We then present detailed reflectance spectrophotometry measurements of the polarization content of male and female wings, showing that female wings exhibit blue-shifted reflectance, with a lower degree of polarization relative to male wings. Finally, we describe a novel method for measuring alignment of ommatidial arrays: by measuring variation of depolarized eyeshine intensity from patches of ommatidia as a function of eye rotation, we show that (a) individual rhabdoms contain mutually perpendicular microvilli; (b) many rhabdoms in the array have their microvilli misaligned with respect to neighboring rhabdoms by as much as 45 deg; and (c) the misaligned ommatidia are useful for robust polarization detection. By mapping the distribution of the ommatidial misalignments in eye patches of J. evagoras, we show that males and females exhibit differences in the extent to which ommatidia are aligned. Both the number of misaligned ommatidia suitable for robust polarization detection and the number of aligned ommatidia suitable for edge detection vary with respect to both sex and eye patch elevation. Thus, J. evagoras exhibits finely tuned ommatidial arrays suitable for perception of polarized signals, likely to match sex-specific life history differences in the utility of polarized signals.
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Mariposas Diurnas , Animales , Masculino , Femenino , Humanos , Australia , Visión Ocular , Células Fotorreceptoras de InvertebradosRESUMEN
Many animals have the potential to discriminate nonspectral colors. For humans, purple is the clearest example of a nonspectral color. It is perceived when two color cone types in the retina (blue and red) with nonadjacent spectral sensitivity curves are predominantly stimulated. Purple is considered nonspectral because no monochromatic light (such as from a rainbow) can evoke this simultaneous stimulation. Except in primates and bees, few behavioral experiments have directly examined nonspectral color discrimination, and little is known about nonspectral color perception in animals with more than three types of color photoreceptors. Birds have four color cone types (compared to three in humans) and might perceive additional nonspectral colors such as UV+red and UV+green. Can birds discriminate nonspectral colors, and are these colors behaviorally and ecologically relevant? Here, using comprehensive behavioral experiments, we show that wild hummingbirds can discriminate a variety of nonspectral colors. We also show that hummingbirds, relative to humans, likely perceive a greater proportion of natural colors as nonspectral. Our analysis of plumage and plant spectra reveals many colors that would be perceived as nonspectral by birds but not by humans: Birds' extra cone type allows them not just to see UV light but also to discriminate additional nonspectral colors. Our results support the idea that birds can distinguish colors throughout tetrachromatic color space and indicate that nonspectral color perception is vital for signaling and foraging. Since tetrachromacy appears to have evolved early in vertebrates, this capacity for rich nonspectral color perception is likely widespread.
Asunto(s)
Aves/fisiología , Percepción de Color/fisiología , Visión de Colores/fisiología , Animales , Estimulación Luminosa , RetinaRESUMEN
In the cerebral cortex, local circuits consist of tens of thousands of neurons, each of which makes thousands of synaptic connections. Perhaps the biggest impediment to understanding these networks is that we have no wiring diagrams of their interconnections. Even if we had a partial or complete wiring diagram, however, understanding the network would also require information about each neuron's function. Here we show that the relationship between structure and function can be studied in the cortex with a combination of in vivo physiology and network anatomy. We used two-photon calcium imaging to characterize a functional property--the preferred stimulus orientation--of a group of neurons in the mouse primary visual cortex. Large-scale electron microscopy of serial thin sections was then used to trace a portion of these neurons' local network. Consistent with a prediction from recent physiological experiments, inhibitory interneurons received convergent anatomical input from nearby excitatory neurons with a broad range of preferred orientations, although weak biases could not be rejected.
Asunto(s)
Red Nerviosa/anatomía & histología , Red Nerviosa/citología , Neuronas/fisiología , Corteza Visual/anatomía & histología , Corteza Visual/citología , Animales , Señalización del Calcio , Interneuronas/fisiología , Masculino , Ratones , Microscopía Electrónica de Transmisión , Microscopía Fluorescente , Microtomía , Red Nerviosa/fisiología , Red Nerviosa/ultraestructura , Inhibición Neural/fisiología , Neuronas/ultraestructura , Células Piramidales/fisiología , Células Piramidales/ultraestructura , Sinapsis/fisiología , Corteza Visual/fisiología , Corteza Visual/ultraestructuraRESUMEN
Animals modulate their arousal state to ensure that their sensory responsiveness and locomotor activity match environmental demands. Neuropeptides can regulate arousal, but studies of their roles in vertebrates have been constrained by the vast array of neuropeptides and their pleiotropic effects. To overcome these limitations, we systematically dissected the neuropeptidergic modulation of arousal in larval zebrafish. We quantified spontaneous locomotor activity and responsiveness to sensory stimuli after genetically induced expression of seven evolutionarily conserved neuropeptides, including adenylate cyclase activating polypeptide 1b (adcyap1b), cocaine-related and amphetamine-related transcript (cart), cholecystokinin (cck), calcitonin gene-related peptide (cgrp), galanin, hypocretin, and nociceptin. Our study reveals that arousal behaviors are dissociable: neuropeptide expression uncoupled spontaneous activity from sensory responsiveness, and uncovered modality-specific effects upon sensory responsiveness. Principal components analysis and phenotypic clustering revealed both shared and divergent features of neuropeptidergic functions: hypocretin and cgrp stimulated spontaneous locomotor activity, whereas galanin and nociceptin attenuated these behaviors. In contrast, cart and adcyap1b enhanced sensory responsiveness yet had minimal impacts on spontaneous activity, and cck expression induced the opposite effects. Furthermore, hypocretin and nociceptin induced modality-specific differences in responsiveness to changes in illumination. Our study provides the first systematic and high-throughput analysis of neuropeptidergic modulation of arousal, demonstrates that arousal can be partitioned into independent behavioral components, and reveals novel and conserved functions of neuropeptides in regulating arousal.
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Nivel de Alerta/fisiología , Regulación de la Expresión Génica/fisiología , Actividad Motora/fisiología , Neuropéptidos/metabolismo , Animales , Animales Modificados Genéticamente , Nivel de Alerta/genética , Péptido Relacionado con Gen de Calcitonina/metabolismo , Colecistoquinina/metabolismo , Adaptación a la Oscuridad/efectos de los fármacos , Adaptación a la Oscuridad/genética , Adaptación a la Oscuridad/fisiología , Femenino , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/efectos de la radiación , Calor , Larva , Luz , Masculino , Actividad Motora/genética , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/metabolismo , Neuropéptidos/genética , Péptidos Opioides/metabolismo , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Análisis de Componente Principal , Pez Cebra , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , NociceptinaRESUMEN
We present an economical imaging system with integrated hardware and software to capture multispectral images of Lepidoptera with high efficiency. This method facilitates the comparison of colors and shapes among species at fine and broad taxonomic scales and may be adapted for other insect orders with greater three-dimensionality. Our system can image both the dorsal and ventral sides of pinned specimens. Together with our processing pipeline, the descriptive data can be used to systematically investigate multispectral colors and shapes based on full-wing reconstruction and a universally applicable ground plan that objectively quantifies wing patterns for species with different wing shapes (including tails) and venation systems. Basic morphological measurements, such as body length, thorax width, and antenna size are automatically generated. This system can increase exponentially the amount and quality of trait data extracted from museum specimens.
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Museos , Registros , Fenotipo , Programas InformáticosRESUMEN
High-throughput behavioral phenotyping is critical to genetic or chemical screening approaches. Zebrafish larvae are amenable to high-throughput behavioral screening because of their rapid development, small size, and conserved vertebrate brain architecture. Existing commercial behavioral phenotyping systems are expensive and not easily modified for new assays. Here, we describe a modular, highly adaptable, and low-cost system. Along with detailed assembly and operation instructions, we provide data acquisition software and a robust, parallel analysis pipeline. We validate our approach by analyzing stimulus response profiles in larval zebrafish, confirming prepulse inhibition phenotypes of two previously isolated mutants, and highlighting best practices for growing larvae prior to behavioral testing. Our new design thus allows rapid construction and streamlined operation of many large-scale behavioral setups with minimal resources and fabrication expertise, with broad applications to other aquatic organisms.
RESUMEN
Inputs from olfactory sensory neuron (OSN) axons expressing the same type of odorant receptor (OR) converge in the glomerulus of the main olfactory bulb. A key marker of mature OSNs is olfactory marker protein (OMP), whose deletion has been associated with deficits in OSN signal transduction and odor discrimination. Here, we investigate glomerular odor responses and anatomical architecture in mice in which one or both alleles of OMP are replaced by the fluorescent synaptic activity reporter, synaptopHluorin. Functionally heterogeneous glomeruli, that is, ones with microdomains with distinct odor responses, are rare in OMP+/- mice, but occur frequently in OMP-/- mice. Genetic targeting of single ORs reveals that these microdomains arise from co-innervation of individual glomeruli by OSNs expressing different ORs. This glomerular mistargeting is locally restricted to a few glomerular diameters. Our studies document functional heterogeneity in sensory input within individual glomeruli and uncover its anatomical correlate, revealing an unexpected role for OMP in the formation and refinement of the glomerular map.
Asunto(s)
Bulbo Olfatorio/metabolismo , Proteína Marcadora Olfativa/metabolismo , Neuronas Receptoras Olfatorias/metabolismo , Receptores Odorantes/metabolismo , Alelos , Animales , Heterogeneidad Genética , Inmunohistoquímica , Ratones , Ratones Noqueados , Ratones Mutantes , Proteína Marcadora Olfativa/genética , Receptores Odorantes/genéticaRESUMEN
Brain circuits endow behavioral flexibility. Here, we study circuits encoding flexible chemotaxis in C. elegans, where the animal navigates up or down NaCl gradients (positive or negative chemotaxis) to reach the salt concentration of previous growth (the set point). The ASER sensory neuron mediates positive and negative chemotaxis by regulating the frequency and direction of reorientation movements in response to salt gradients. Both salt gradients and set point memory are encoded in ASER temporal activity patterns. Distinct temporal activity patterns in interneurons immediately downstream of ASER encode chemotactic movement decisions. Different interneuron combinations regulate positive versus negative chemotaxis. We conclude that sensorimotor pathways are segregated immediately after the primary sensory neuron in the chemotaxis circuit, and sensory representation is rapidly transformed to motor representation at the first interneuron layer. Our study reveals compact encoding of perception, memory, and locomotion in an experience-dependent navigational behavior in C. elegans.
Asunto(s)
Quimiotaxis/fisiología , Memoria/fisiología , Percepción/fisiología , Animales , Caenorhabditis elegans , Calcio/metabolismo , Células Quimiorreceptoras/fisiología , Interneuronas/fisiologíaRESUMEN
We explored the map of odor space created by glomeruli on the olfactory bulb of both rat and mouse. Identified glomeruli could be matched across animals by their response profile to hundreds of odors. Their layout in different individuals varied by only approximately 1 glomerular spacing, corresponding to a precision of 1 part in 1,000. Across species, mouse and rat share many glomeruli with apparently identical odor tuning, arranged in a similar layout. In mapping the position of a glomerulus to its odor tuning, we found only a coarse relationship with a precision of approximately 5 spacings. No chemotopic order was apparent on a finer scale and nearby glomeruli were almost as diverse in their odor sensitivity as distant ones. This local diversity of sensory tuning stands in marked distinction from other brain maps. Given the reliable placement of the glomeruli, it represents a feature, not a flaw, of the olfactory bulb.
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Mapeo Encefálico , Bulbo Olfatorio/citología , Bulbo Olfatorio/fisiología , Vías Olfatorias/citología , Vías Olfatorias/fisiología , Olfato/fisiología , Animales , Femenino , Proteínas Fluorescentes Verdes/genética , Masculino , Ratones , Ratones Mutantes , Modelos Neurológicos , Odorantes , Neuronas Receptoras Olfatorias/citología , Neuronas Receptoras Olfatorias/fisiología , Ratas , Ratas Long-Evans , Ratas Wistar , Receptores Odorantes/genética , Receptores Odorantes/metabolismoRESUMEN
Center-surround receptive fields are a fundamental unit of brain organization. It has been proposed that olfactory bulb mitral cells exhibit this functional circuitry, with excitation from one glomerulus and inhibition from a broad field of glomeruli within reach of the lateral dendrites. We investigated this hypothesis using a combination of in vivo intrinsic imaging, single-unit recording, and a large panel of odors. Assuming a broad inhibitory field, a mitral cell would be influenced by >100 contiguous glomeruli and should respond to many odors. Instead, the observed response rate was an order of magnitude lower. A quantitative model indicates that mitral cell responses can be explained by just a handful of glomeruli. These glomeruli are spatially dispersed on the bulb and represent a broad range of odor sensitivities. We conclude that mitral cells do not have center-surround receptive fields. Instead, each mitral cell performs a specific computation combining a small and diverse set of glomerular inputs.