Zebrafish (Danio rerio) are rapidly gaining popularity in translational neuroscience and behavioral research. Physiological similarity to mammals, ease of genetic manipulations, sensitivity to pharmacological and genetic factors, robust behavior, low cost, and potential for high-throughput screening contribute to the growing utility of zebrafish models in this field. Understanding zebrafish behavioral phenotypes provides important insights into neural pathways, physiological biomarkers, and genetic underpinnings of normal and pathological brain function. Novel zebrafish paradigms continue to appear with an encouraging pace, thus necessitating a consistent terminology and improved understanding of the behavioral repertoire. What can zebrafish 'do', and how does their altered brain function translate into behavioral actions? To help address these questions, we have developed a detailed catalog of zebrafish behaviors (Zebrafish Behavior Catalog, ZBC) that covers both larval and adult models. Representing a beginning of creating a more comprehensive ethogram of zebrafish behavior, this effort will improve interpretation of published findings, foster cross-species behavioral modeling, and encourage new groups to apply zebrafish neurobehavioral paradigms in their research. In addition, this glossary creates a framework for developing a zebrafish neurobehavioral ontology, ultimately to become part of a unified animal neurobehavioral ontology, which collectively will contribute to better integration of biological data within and across species.

Mice with a malignant hyperthermia mutation (Y522S) in the ryanodine receptor (RyR1) display muscle contractures, rhabdomyolysis, and death in response to elevated environmental temperatures. We demonstrate that this mutation in RyR1 causes Ca(2+) leak, which drives increased generation of reactive nitrogen species (RNS). Subsequent S-nitrosylation of the mutant RyR1 increases its temperature sensitivity for activation, producing muscle contractures upon exposure to elevated temperatures. The Y522S mutation in humans is associated with central core disease. Many mitochondria in the muscle of heterozygous Y522S mice are swollen and misshapen. The mutant muscle displays decreased force production and increased mitochondrial lipid peroxidation with aging. Chronic treatment with N-acetylcysteine protects against mitochondrial oxidative damage and the decline in force generation. We propose a feed-forward cyclic mechanism that increases the temperature sensitivity of RyR1 activation and underlies heat stroke and sudden death. The cycle eventually produces a myopathy with damaged mitochondria.

The skeletal muscle Ca 2؉ -release channel (ryanodine receptor type 1 (RyR1)) is a redox sensor, susceptible to reversible S-nitrosylation, S-glutathionylation, and disulfide oxidation. So far, Cys-3635 remains the only cysteine residue identified as functionally relevant to the redox sensing properties of the channel. We demonstrate that expression of the C3635A-RyR1 mutant in RyR1-null myotubes alters the sensitivity of the ryanodine receptor to activation by voltage, indicating that Cys-3635 is involved in voltage-gated excitation-contraction coupling. However, H 2 O 2 treatment of C3635A-RyR1 channels or wildtype RyR1, following their expression in human embryonic kidney cells, enhances [ 3 H]ryanodine binding to the same extent, suggesting that cysteines other than Cys-3635 are responsible for the oxidative enhancement of channel activity. Using a combination of Western blotting and sulfhydryl-directed fluorescent labeling, we found that two large regions of RyR1 (amino acids 1-2401 and 3120 -4475), previously shown to be involved in disulfide bond formation, are also major sites of both S-nitrosylation and S-glutathionylation. Using selective isotopecoded affinity tag labeling of RyR1 and matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy, we identified, out of the 100 cysteines in each RyR1 subunit, 9 that are endogenously modified (Cys-36, Cys-315, Cys-811, Cys-906, Cys-1591, Cys-2326, Cys-2363, Cys-3193, and Cys-3635) and another 3 residues that were only modified with exogenous redox agents (Cys-253, Cys-1040, and Cys-1303). We also identified the types of redox modification each of these cysteines can undergo. In summary, we have identified a discrete subset of cysteines that are likely to be involved in the functional response of RyR1 to different redox modifications (S-nitrosylation, S-glutathionylation, and oxidation to disulfides). Ca 2ϩ

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Signals between neurons are transduced primarily by receptors, and second messenger and kinase cascades, located in pre- and postsynaptic terminals. Such synaptic signaling pathways include those activated by neurotransmitters, cytokines, neurotrophic factors, and cell-adhesion molecules. Many of these signaling systems are also localized in the growth cones of axons and dendrites, where they control pathfinding and synaptogenesis during development. Although it has been known for decades that such signaling pathways can affect the survival of neurons, by promoting or preventing a form of programmed cell death known as apoptosis, we have discovered that apoptotic biochemical cascades can exert local actions on the functions and structural dynamics of growth cones and synapses. In this article, we provide a brief background on apoptotic biochemical cascades, and present examples of studies in this laboratory that have identified novel apoptotic and anti-apoptotic signaling mechanisms that are activated and act locally in synapses, growth cones, and dendrites to modify their structure and function. Apoptotic synaptic cascades that may play roles in neuronal plasticity include activation of caspases that can cleave certain types of ionotropic glutamate-receptor subunits and thereby modify synaptic plasticity. Caspases may also cleave cytoskeletal protein substrates in growth cones of developing neurons and may thereby regulate neurite outgrowth. Par-4 and the tumor-suppressor protein p53 are pro-apoptotic proteins that may also function in synaptic and developmental plasticity. Examples of anti-apoptotic signals that regulate the plasticity of growth cones and synapses include neurotrophic factor-activated kinase cascades, calcium-mediated actin depolymerization, and activation of the transcription factor NF-kappaB. The emerging data strongly suggest that many of the signaling mechanisms that control apoptosis are also involved in regulating the structural and functional plasticity of neuronal circuits under physiological conditions.