Social isolation modulates appetite and avoidance behavior via a common oxytocinergic circuit in larval zebrafish.

Animal brains have evolved to encode social stimuli and transform these representations into advantageous behavioral responses. The commonalities and differences of these representations across species are not well-understood. Here, we show that social isolation activates an oxytocinergic (OXT), nociceptive circuit in the larval zebrafish hypothalamus and that chemical cues released from conspecific animals are potent modulators of this circuit's activity.

Zebrafish oxytocin neurons drive nocifensive behavior via brainstem premotor targets.

Animals have evolved specialized neural circuits to defend themselves from pain- and injury-causing stimuli. Using a combination of optical, behavioral and genetic approaches in the larval zebrafish, we describe a novel role for hypothalamic oxytocin (OXT) neurons in the processing of noxious stimuli. In vivo imaging revealed that a large and distributed fraction of zebrafish OXT neurons respond strongly to noxious inputs, including the activation of damage-sensing TRPA1 receptors.

Analysis of axonal trafficking via a novel live-imaging technique reveals distinct hedgehog transport kinetics.

The () eye is an ideal model to study development, intracellular signaling, behavior, and neurodegenerative disease. Interestingly, dynamic data are not commonly employed to investigate eye-specific disease models. Using axonal transport of the morphogen Hedgehog (Hh), which is integral to eye-brain development and implicated in stem cell maintenance and neoplastic disease, we demonstrate the ability to comprehensively quantify and characterize its trafficking in various neuron types and a neurodegeneration model in live early third-instar larval We find that neuronal Hh, whose kinetics have not been reported previously, favors fast anterograde transport and varies in speed and flux with respect to axonal position.

A novel proteolytic event controls Hedgehog intracellular sorting and distribution to receptive fields.

The patterning activity of a morphogen depends on secretion and dispersal mechanisms that shape its distribution to the cells of a receptive field. In the case of the protein Hedgehog (Hh), these mechanisms of secretion and transmission remain unclear. In the developing visual system, Hh is partitioned for release at opposite poles of photoreceptor neurons.

Mitochondrial chaperone TRAP1 activates the mitochondrial UPR and extends healthspan in Drosophila.

The molecular mechanisms influencing healthspan are unclear but mitochondrial function, resistance to oxidative stress and proteostasis are recurring themes. Tumor necrosis factor Receptor Associated Protein 1 (TRAP1), the mitochondrial analog of Hsp75, regulates levels of reactive oxygen species in vitro and is found expressed at higher levels in tumor cells where it is thought to play a pro-survival role. While TRAP1-directed compartmentalized protein folding is a promising target for cancer therapy, its role at the organismal level is unclear.

Reph, a regulator of Eph receptor expression in the Drosophila melanogaster optic lobe.

Receptors of the Eph family of tyrosine kinases and their Ephrin ligands are involved in developmental processes as diverse as angiogenesis, axon guidance and cell migration. However, our understanding of the Eph signaling pathway is incomplete, and could benefit from an analysis by genetic methods. To this end, we performed a genetic modifier screen for mutations that affect Eph signaling in Drosophila melanogaster.

Determinants of the Drosophila odorant receptor pattern.

In most olfactory systems studied to date, neurons that express the same odorant receptor (Or) gene are scattered across sensory epithelia, intermingled with neurons that express different Or genes. In Drosophila, olfactory sensilla that express the same Or gene are dispersed on the antenna and the maxillary palp. Here we show that Or identity is specified in a spatially stereotyped pattern by the cell-autonomous activity of the transcriptional regulators Engrailed and Dachshund.

Endocytic pathway is required for Drosophila Toll innate immune signaling.

The Toll signaling pathway is required for the innate immune response against fungi and Gram-positive bacteria in Drosophila. Here we show that the endosomal proteins Myopic (Mop) and Hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) are required for the activation of the Toll signaling pathway. This requirement is observed in cultured cells and in flies, and epistasis experiments show that the Mop protein functions upstream of the MyD88 adaptor and the Pelle kinase.

Optimizing Drosophila olfactory learning with a semi-automated training device.

Drosophila olfactory aversive conditioning has served as a powerful model system with which to elucidate the molecular and neuronal mechanisms underlying memory formation. In the typical protocol, flies are exposed to a constant odor stream while receiving a pulsed electric shock in the conditioning tube of a manual apparatus. We have devised a simple, low-cost semi-automated conditioning apparatus that computationally controls the delivery of odor and shock.

The full-length unprocessed hedgehog protein is an active signaling molecule.

The hedgehog (HH) family of ligands plays an important instructional role in metazoan development. HH proteins are initially produced as approximately 45-kDa full-length proteins, which undergo an intramolecular cleavage to generate an amino-terminal product that subsequently becomes cholesterol-modified (HH-Np). It is well accepted that this cholesterol-modified amino-terminal cleavage product is responsible for all HH-dependent signaling events.

Amino acid metabolic origin as an evolutionary influence on protein sequence in yeast.

The metabolic cycle of Saccharomyces cerevisiae consists of alternating oxidative (respiration) and reductive (glycolysis) energy-yielding reactions. The intracellular concentrations of amino acid precursors generated by these reactions oscillate accordingly, attaining maximal concentration during the middle of their respective yeast metabolic cycle phases. Typically, the amino acids themselves are most abundant at the end of their precursor's phase.

Evolutionarily conserved optimization of amino acid biosynthesis.

The "cognate bias hypothesis" states that early in evolutionary history the biosynthetic enzymes for amino acid x gradually lost residues of x, thereby reducing the threshold for deleterious effects of x scarcity. The resulting reduction in cognate amino acid composition of the enzymes comprising a particular amino acid biosynthetic pathway is predicted to confer a selective growth advantage on cells. Bioinformatic evidence from protein-sequence data of two bacterial species previously demonstrated reduced cognate bias in amino acid biosynthetic pathways.

A trace of silence: memory and microRNA at the synapse.

Identifying the neural circuits that mediate particular behaviors and uncovering their plasticity is an endeavor at the heart of neuroscience. This effort is allied with the elucidation of plasticity mechanisms, because the molecular determinants of plasticity can be markers for the neurons and synapses that are modified by experience. Of particular interest is protein synthesis localized to the synapse, which might establish and maintain the stable modification of neuronal properties, including the pattern and strength of synaptic connections.

A C-terminal motif targets Hedgehog to axons, coordinating assembly of the Drosophila eye and brain.

The developmental signal Hedgehog is distributed to two receptive fields by the photoreceptor neurons of the developing Drosophila retina. Delivery to the retina propagates ommatidial development across a precursor field. Transport along photoreceptor axons induces the development of postsynaptic neurons in the brain.

Synaptic protein synthesis associated with memory is regulated by the RISC pathway in Drosophila.

Long-lasting forms of memory require protein synthesis, but how the pattern of synthesis is related to the storage of a memory has not been determined. Here we show that neural activity directs the mRNA of the Drosophila Ca(2+), Calcium/Calmodulin-dependent Kinase II (CaMKII), to postsynaptic sites, where it is rapidly translated. These features of CaMKII synthesis are recapitulated during the induction of a long-term memory and produce patterns of local protein synthesis specific to the memory.

Nonvesicular release of acetylcholine is required for axon targeting in the Drosophila visual system.

We report evidence for a developmental role of acetylcholine in axon pathfinding in the Drosophila visual system. Acetylcholine was detected on photoreceptor axons during their navigation to target sites in the brain, a time well before the formation of functional synapses. The pattern of photoreceptor axon projections was severely disrupted when acetylcholine synthesis or metabolism was altered or eliminated, or when transgenic alpha-bungarotoxin, a nicotinic acetylcholine receptor antagonist, was expressed in the developing eye or brain.

An axon scaffold induced by retinal axons directs glia to destinations in the Drosophila optic lobe.

In the developing Drosophila visual system, glia migrate into stereotyped positions within the photoreceptor axon target fields and provide positional information for photoreceptor axon guidance. Glial migration conversely depends on photoreceptor axons, as glia precursors stall in their progenitor zones when retinal innervation is eliminated. Our results support the view that this requirement for retinal innervation reflects a role of photoreceptor axons in the establishment of an axonal scaffold that guides glial cell migration.

Eph receptor tyrosine kinase-mediated formation of a topographic map in the Drosophila visual system.

Roles for Eph receptor tyrosine kinase signaling in the formation of topographic patterns of axonal connectivity have been well established in vertebrate visual systems. Here we describe a role for a Drosophila Eph receptor tyrosine kinase (EPH) in the control of photoreceptor axon and cortical axon topography in the developing visual system. Although uniform across the developing eye, EPH is expressed in a concentration gradient appropriate for conveying positional information during cortical axon guidance in the second-order optic ganglion, the medulla.

Combgap relays wingless signal reception to the determination of cortical cell fate in the Drosophila visual system.

The dorsoventral axis of the Drosophila visual cortex is patterned by nonautonomous signals expressed at its dorsal and ventral margins. wingless (wg) expression at the margins induces decapentaplegic (dpp), optomotor blind (omb), and aristaless in adjacent domains. We show that Combgap, a zinc finger protein, represses Wg target gene expression in the visual cortex.

Axonal signals in the assembly of neural circuitry.

Recent work in Drosophila and rodents has revealed that proteins transported along axons and delivered to pathway and target cell populations play important roles in the construction of neural circuitry. Interestingly, the parallels between these systems may extend to the identities of some of the molecules involved.

A retinal axon fascicle uses spitz, an EGF receptor ligand, to construct a synaptic cartridge in the brain of Drosophila.

Photoreceptor axons arriving in the Drosophila brain organize their postsynaptic target field into a precise array of five neuron "cartridge" ensembles. Here we show that Hedgehog, an initial inductive signal transported along retinal axons from the developing eye, induces postsynaptic precursor cells to express the Drosophila homolog of the epidermal growth factor receptor (EGFR). The EGFR ligand Spitz, a signal for ommatidial assembly in the compound eye, is transported to retinal axon termini in the brain where it acts as a local cue for the recruitment of five cells into a cartridge ensemble.

Signals transmitted along retinal axons in Drosophila: Hedgehog signal reception and the cell circuitry of lamina cartridge assembly.

The arrival of retinal axons in the brain of Drosophila triggers the assembly of glial and neuronal precursors into a 'neurocrystalline' array of lamina synaptic 'cartridges'. Hedgehog, a secreted protein, is an inductive signal delivered by retinal axons for the initial steps of lamina differentiation. In the development of many tissues, Hedgehog acts in a signal relay cascade via the induction of secondary secreted factors.

Hedgehog, transmitted along retinal axons, triggers neurogenesis in the developing visual centers of the Drosophila brain.

The development of the visual centers of the Drosophila brain is tightly regulated by the ingrowth of retinal axons from the developing eye. In the first optic ganglion, the lamina, arriving retinal axons trigger the precursors of their synaptic partners to complete a final cell division and commence neural differentiation. The secreted product of the hedgehog gene regulates the temporal assembly of photoreceptor precursor cells into ommatidial clusters in the compound eye.