Octopamine Neuromodulation Regulates Gr32a-Linked Aggression and Courtship Pathways in Drosophila Males

Chemosensory pheromonal information regulates aggression and reproduction in many species, but how pheromonal signals are transduced to reliably produce behavior is not well understood. Here we demonstrate that the pheromonal signals detected by Gr32a-expressing chemosensory neurons to enhance male aggression are filtered through octopamine (OA, invertebrate equivalent of norepinephrine) neurons. Using behavioral assays, we find males lacking both octopamine and Gr32a gustatory receptors exhibit parallel delays in the onset of aggression and reductions in aggression. Physiological and anatomical experiments identify Gr32a to octopamine neuron synaptic and functional connections in the suboesophageal ganglion. Refining the Gr32a-expressing population indicates that mouth Gr32a neurons promote male aggression and form synaptic contacts with OA neurons. By restricting the monoamine neuron target population, we show that three previously identified OA-FruM neurons involved in behavioral choice are among the Gr32a-OA connections. Our findings demonstrate that octopaminergic neuromodulatory neurons function as early as a second-order step in this chemosensory-driven male social behavior pathway

Seismic imaging in Long Valley, California, by surface and borehole techniques: An investigation of active tectonics

The search for silicic magma in the upper crust is converging on the Long Valley Caldera of eastern California, where several lines of geophysical evidence show that an active magma chamber exists at mid‐to lower‐crustal depths. There are also other strong indications that magma may be present at depths no greater than about 5 km below the surface. In this paper, we review the history of the search for magma at Long Valley. We also present the preliminary results from a coordinated suite of seismic experiments, conducted by a consortium of institutions in the summer and fall of 1984, that were designed to refine our knowledge of the upper extent of the magma chamber. Major funding for the experiments was provided by the Geothermal Research Program of the U.S. Geological Survey (USGS) and by the Magma Energy Technology Program of the U.S. Department of Energy (DOE), a program to develop the technology necessary to extract energy directly from crustal magma. Additional funding came from DOE's Office of Basic Energy Sciences and the National Science Foundation (NSF). Also, because extensive use was made of a 0.9‐km‐deep well lent to us by Santa Fe Geothermal, Inc., the project was conducted partly under the auspices of the Continental Scientific Drilling Program (CSDP). As an integrated seismic study of the crust within the caldera that involved the close cooperation of a large number of institutions, the project was moreover viewed as a prototype for future scientific experiments to be conducted under the Program for Array Seismic Studies of the Continental Lithosphere (PASSCAL). The experiment thus represented a unique blend of CSDP and PASSCAL methods, and achieved goals consistent with both programs

Seismic imaging in Long Valley, California, by surface and borehole techniques: An investigation of active tectonics

The search for silicic magma in the upper crust is converging on the Long Valley Caldera of eastern California, where several lines of geophysical evidence show that an active magma chamber exists at mid‐to lower‐crustal depths. There are also other strong indications that magma may be present at depths no greater than about 5 km below the surface. In this paper, we review the history of the search for magma at Long Valley. We also present the preliminary results from a coordinated suite of seismic experiments, conducted by a consortium of institutions in the summer and fall of 1984, that were designed to refine our knowledge of the upper extent of the magma chamber. Major funding for the experiments was provided by the Geothermal Research Program of the U.S. Geological Survey (USGS) and by the Magma Energy Technology Program of the U.S. Department of Energy (DOE), a program to develop the technology necessary to extract energy directly from crustal magma. Additional funding came from DOE's Office of Basic Energy Sciences and the National Science Foundation (NSF). Also, because extensive use was made of a 0.9‐km‐deep well lent to us by Santa Fe Geothermal, Inc., the project was conducted partly under the auspices of the Continental Scientific Drilling Program (CSDP). As an integrated seismic study of the crust within the caldera that involved the close cooperation of a large number of institutions, the project was moreover viewed as a prototype for future scientific experiments to be conducted under the Program for Array Seismic Studies of the Continental Lithosphere (PASSCAL). The experiment thus represented a unique blend of CSDP and PASSCAL methods, and achieved goals consistent with both programs

Chronic Obstructive Pulmonary Disease and Lung Cancer: Underlying Pathophysiology and New Therapeutic Modalities

Chronic obstructive pulmonary disease (COPD) and lung cancer are major lung diseases affecting millions worldwide. Both diseases have links to cigarette smoking and exert a considerable societal burden. People suffering from COPD are at higher risk of developing lung cancer than those without, and are more susceptible to poor outcomes after diagnosis and treatment. Lung cancer and COPD are closely associated, possibly sharing common traits such as an underlying genetic predisposition, epithelial and endothelial cell plasticity, dysfunctional inflammatory mechanisms including the deposition of excessive extracellular matrix, angiogenesis, susceptibility to DNA damage and cellular mutagenesis. In fact, COPD could be the driving factor for lung cancer, providing a conducive environment that propagates its evolution. In the early stages of smoking, body defences provide a combative immune/oxidative response and DNA repair mechanisms are likely to subdue these changes to a certain extent; however, in patients with COPD with lung cancer the consequences could be devastating, potentially contributing to slower postoperative recovery after lung resection and increased resistance to radiotherapy and chemotherapy. Vital to the development of new-targeted therapies is an in-depth understanding of various molecular mechanisms that are associated with both pathologies. In this comprehensive review, we provide a detailed overview of possible underlying factors that link COPD and lung cancer, and current therapeutic advances from both human and preclinical animal models that can effectively mitigate this unholy relationship

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Gr32a-expressing neurons promote aggression via OA signaling.

<p>(<b>A–B</b>) Fights between males with Gr32a-expressing neurons removed by expressing Diptheria Toxin <i>(UAS-DTI;Gr32a-Gal4)</i> and individual transgenic controls, <i>UAS-DTI</i> or <i>Gr32a-Gal4</i>. (<b>A</b>) The latency to first lunge was significantly higher in <i>UAS-DTI/+</i>; <i>Gr32a-Gal4/+</i> males as compared to controls (all statistical tests are Kruskal-Wallis with Dunn's multiple comparison test except where noted, ***<i>p</i><0.001, *<i>p</i><0.05). (<b>B</b>) Number of lunges (represented by each dot) performed in a 30 min period after the first lunge by any control or experimental male in a fighting pair. Males without Gr32a neurons exhibited a significant reduction in lunges as compared to controls (***<i>p</i><0.001, **<i>p</i><0.01). (<b>C</b>) Fights between control male pairs (revertant <i>tβh^M6</i> allele), experimental males without OA (revertant null mutation, <i>tβh^nM18</i>), or experimental males without OA and without Gr32a-expressing neurons (<i>tβh^nM18;UAS-DTI/+</i>; <i>Gr32a-Gal4/+</i>). The latency to first lunge was significantly higher in males without OA and in experimental males compared to control males (**<i>p</i><0.01) and not statistically different between males without OA and experimental <i>tβh^nM18;UAS-DTI/+</i>; <i>Gr32a-Gal4/+</i> males. (<b>D–F</b>) Fights between control male pairs (revertant <i>tβh^M6</i> allele) and three groups of experimental males; without OA = <i>tβh^nM18</i>, without Gr32a receptors = <i>tβh^M6;;Gr32a^−/−</i>, and without OA and Gr32a receptors = <i>tβh^nM18;;Gr32a^−/−</i>). (<b>D</b>) The latency to first lunge was significantly higher in males without OA (<i>tβh^nM18</i>) and in experimental males without OA and the Gr32a receptor (<i>tβh^nM18; Gr32a^−/−</i>) or without only the Gr32 receptor (<i>tβh^M6; Gr32a^−/−</i>) males as compared to control <i>tβh^M6</i> males (One way ANOVA, <i>post hoc</i> Tukey's comparison, *<i>p</i><0.05, **<i>p</i><0.01). (<b>E</b>) The number of lunges by pairs of experimental males were significantly less than exhibited by control males but not when compared to each other (***<i>p</i> = 0.0002, **<i>p</i> = 0.002, *<i>p</i> = 0.01). (<b>F</b>) The average number of wing extensions directed toward the second male in each aggression assay. The number of wing extensions exhibited by males without the Gr32a receptor and without OA, and males without Gr32a receptors were significantly greater than control <i>tβh^M6</i> males (***<i>p</i><0.001) but not males without OA (<i>tβh^nM18</i>). Error bars denote s.e.m.</p

Mouth-specific Gr32a neurons contact OA neurons in the suboesophageal ganglion.

<p>(<b>A</b>) Axons of Gr32a-expressing neurons located in the mouth identified by immunofluorescence to CD8:GFP in <i>tsh-Gal80;UAS-CD8:GFP/Gr32a-Gal4</i> progeny (green, anti-CD8, Invitrogen). Note the absence of axonal projections from the legs via the thoracic ganglion (arrow, compare to <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004356#pgen-1004356-g001" target="_blank">Figure 1A</a>). (<b>B</b>) Higher magnification of Gr32a mouth neurons expressing CD8:GFP. (<b>C</b>) Schematic representation of the GRASP reporter lines combined with the <i>tsh-Gal80</i>;<i>Gr32a-Gal4</i> and <i>Tdc2-lexA</i> driver lines. Gal80 driven by the <i>tsh-Gal80</i> line prevents Gal4 activity and subsequent expression of the <i>UAS-CD4::spGFP1-10</i> GRASP reporter. (<b>D–E</b>) Two different confocal image magnifications of a male brain with the same number of optical sections as in panel A. A reduced amount of GRASP-mediated GFP reconstitution is observed reflecting Gr32a neurons located only in the mouth expressing CD4::spGFP1-10 and OA neurons expressing CD4::spGFP11. GRASP reconstitution is detected by immunofluorescence using rabbit monoclonal GFP antibody (green; Life Technologies). (<b>F–G</b>) <i>tsh-Gal80</i> blocks GFP expression in Gr32a-expressing leg neurons. Less than one neuron per leg of <i>UAS-nlsGFP; teashirt-Gal80/Gr32a-Gal4</i> progeny is observed (arrowhead, 0.38 neurons per front leg, n = 8), versus males without Gal80 expression (arrowhead, 5 neurons per front leg, n = 8). (<b>H–J</b>) Optical sections of a female brain (<i>UAS-syt:HA; tsh-Gal80;UAS-CD8:GFP/Gr32a-Gal4</i>) at higher magnification showing GRASP-mediated GFP reconstituted expression (I), syt:HA localization (H) and clear overlap or close association at synaptic-like puncta in the merged channel (J).</p