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Formation and Function of Neural Circuits Underlying Visual and Locomotor Behaviors Woods Hole Zebrafish Course – August 17, 2013

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Formation and Function of Neural Circuits Underlying Visual and Locomotor Behaviors Woods Hole Zebrafish Course – August 17, 2013 Visual & Motor Behaviors- 8-17-2013 Formation and function of neural circuits underlying visual and locomotor behaviors Woods Hole Zebrafish Course – August 17, 2013 Instructors for visual behaviors sections: Jim Fadool ([email protected]) John Dowling ([email protected]) Instructors for motor behaviors sections: Michael Granato ( [email protected] ) Roshan Jain ([email protected]) Marc Wolman ([email protected]) Overview: In this last part of the course, we focus on the formation and function of neural circuits underlying visual and locomotor behaviors. It is therefore important to ask: What are the advantages of zebrafish for studies of neuronal circuits and behavior? - the transparency of the embryo and larvae, which has made them so useful in screening for developmental defects, also allows for optical studies of their neuronal circuits. - the simplicity of the nervous system (compared to other vertebrate model systems) and the detailed maps of identified spinal cord and hindbrain neurons allow the study of circuits and behavior at a single cell resolution. -the extrauterine development facilitates a number of powerful techniques, including single cell recording, labeling of individual neurons and their projections, application of drugs, and lesion experiments using sharp needles or a laser beam. - the development of genetic constructs such as channelrhodopsin and halorhodopsin allow for optical activation and silencing of neurons. - the availability of mutants and transgenic lines and the ease with which they can be generated. Together, these represent an unparalleled spectrum of techniques available to study the many different aspects of neural circuits and behavior in a single, intact vertebrate. Overall aim of the laboratory demos and exercises. The goal of the laboratory work today is to introduce you to some of the approaches to studies neurons and behavior in zebrafish. Because there is only one day to do this, it will not be possible for you to learn to use all of the approaches on your own. Instead, the exercises will use a combination of demonstrations and hands-on experience with others. You will not be adequately trained in any particular approach, which hardly could be accomplished in one day. Rather, our goals for the day are to: 1) give you a sense of the range of approaches possible for the study of behavior in zebrafish; 2) give you a feeling for the power of the preparation for such studies; and 3) provide you with some of the basics of how the approaches are applied and the questions one can attack with them. This will form a foundation that you can use should you want to apply these approaches in the future. 1 Visual & Motor Behaviors- 8-17-2013 Introduction to visual behaviors and retinal development Retinal development, laminar organization, circuitry and phototransduction are strikingly conserved among most classes of vertebrate. The retina is composed of seven major cell types derived from the neural ectoderm, six neurons and a single glial cell, the Müller cell. The neuronal cell bodies are arranged into three cellular layers separated by two plexiform layers. The photoreceptors cells form the outer most layer of the retina. Bipolar cells, horizontal cells and amacrine cells bodies are positioned in the inner nuclear layer and ganglion cells form the innermost part of the retina. The clarity of the early zebrafish embryo and relatively large size of the eye and lens make screening for morphological defects of the eye relatively straightforward, and have provided significant inroads into the genetic pathways or cellular functions essential to fundamental processes of retinal development. However, the majority of the earlier published mutations affecting the zebrafish are embryonic or larval lethal, whereas inherited diseases of the eye and retina can be congenital (present at birth) or late onset (appearing well after childhood); may affect only the visual system or may be associated with a syndrome. These facts suggest that alternative strategies may uncover more subtle defects affecting the visual system. Zebrafish larvae and adults are highly visual animals. The first visually evoked startle responses are observed 3 dpf. By 4 dpf, many larvae demonstrate an optokinetic reflex (OKR) in response to moving objects, an d by 5 dpf, >95% of zebrafish larvae display smooth pursuit and saccade eye movements in response to illuminated rotating stripes (Easter and Nicola, 1996, 1997). The basic function of the OKR is to keep an object stably positioned on the retina while moving through the environment. The robustness of the OKR, the ability to screen young larvae and the potential to vary the assay to detect multiple types of visual system defects led to use by Brockerhoff et al. (Brockerhoff et al., 1995, 2003) of the OKR as a robust method to identify recessive mutations affecting the visual system in otherwise normal appearing larvae. The assay was subsequently used to screen a collection of 450 mutants previously identified by morphological criteria, of which a total of 25 displayed visual system impairment (Neuhauss, et al., 1999). The assay is rapid, the responses from several larvae can be obtained simultaneously and an entire clutch can be assayed in minutes. Although the rate of isolating mutations affecting the OKR in otherwise normal appearing larvae is several fold less than the frequency of morphological mutants, the benefits are apparent. One potential drawback of any behavioral screen is isolating the origin of the defect to the region of the CNS of interest, in our case, the retina. Therefore, recording of the electroretinogram (ERG) is routinely applied as a secondary screen to distinguish between a retinal defect versus alterations in midbrain nuclei or other structures necessary for the OKR such as the extraocular muscles or the neuromuscular junction. The ERG, however, provides information mainly about the outer retina, but single unit recordings can be made from zebrafish ganglion cells, providing information about inner retinal function. Once an interesting defect is confirmed as retinal in origin, positional cloning and a candidate gene approach are used to identify the mutated gene. Even with the wealth of information gained by the analysis of the existing mutations in zebrafish and other model organisms, novel screens for visual guide behaviors or more subtle cellular alterations continue to reveal mutations not detected by other assays. Like most classes of extant vertebrates, the neurons of the zebrafish the major classes of interneurons, the horizontal, bipolar and amacrine cells can also be subdivided into numerous subpopulations based upon morphological, immunohistochemical and physiological profiles. For example, the zebrafish is diurnal and its retina contains a large number of diverse cone subtypes in addition to rods. The cones are subdivided into four classes based upon spectral sensitivity and morphology. The red- and green-sensitive cones paired as distinct long double cones. The long single cones are blue-sensitive while the short single cones are the ultraviolet (UV)-sensitive cones. The rod cell bodies are located vitread to the cone nuclei, and in the light-adapted retina, the thin rod inner and outer segments project beyond the cones to interdigitate with the apical microvilli of the pigment epithelium. Furthermore, the well-characterized laminar organization of the retina is complemented by the nonrandom or mosaic organization of the neuronal populations within each of the layers (Wässle and Riemann, 1978; Fadool, 2003). The necessity of a mosaic arrangement is self-ecident; gaps in 2 Visual & Motor Behaviors- 8-17-2013 the distribution of cells or random clustering would result in under-representation or over-sampling of information in those regions of the visual field. In the fish retina, this arrangement is most evident in the outer nuclear layer where the position of each cone subtype is precisely arranged relative to the others (Fadool, 2003; Robinson et al., 1993) resulting in a highly ordered crystalline- like mosaic. In adult zebrafish, the mosaic is composed of columns of alternating blue- and UV- sensitive single cones that alternate in turn with columns of red- and green-sensitive double cones. The parallel columns are aligned such that in a horizontal row, the green-sensitive members of the double cones flank the short single cones, whereas the long single cones flank the red-sensitive member of the double cone. Just as the OKR offered a clear advantage over morphological screens for detecting some types of visual deficits in otherwise normal larvae, other well thought out assays can uncover additional phenotypes. The OKR is largely mediated by cone responses therefore it is likely that mutations specifically affecting rods were not detected in the previous larval screens. The growing number of transgenic lines demonstrating retinal-specific expression of fluorescent reporter genes or markers of specific cell types has enable more subtle, cell-specific defects to be uncovered (Perkins et al., 2002; Alvarez-Delfin, et al., 2009). Introduction to circuit formation and locomotor behaviors Understanding how neural circuits form and then function to allow for organisms to interpret their surroundings and behave appropriately is a daunting task. Notwithstanding, dissecting the genetic program that dictates how neural circuits modulate motor behavior through sensory perception, cognitive processing, and motor output is one
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