Gustatory stimuli have at least 2 kinds of function: They can support immediate, reflexive responses (such as substrate choice and feeding) and they can drive internal reinforcement. We provide behavioral analyses of these functions with respect to sweet taste in larval Drosophila. The idea is to use the dose–effect characteristics as behavioral “fingerprints” to dissociate reflexive and reinforcing functions. For glucose and trehalose, we uncover relatively weak preference. In contrast, for fructose and sucrose, preference responses are strong and the effects on feeding pronounced. Specifically, larvae are attracted to, and feeding is stimulated most strongly for, intermediate concentrations of either sugar: Using very high concentrations (4 M) results in weakened preference and suppression of feeding. In contrast to such an optimum function regarding choice and feeding, an asymptotic dose–effect function is found for reinforcement learning: Learning scores reach asymptote at 2 M and remain stable for a 4-M concentration. A similar parametric discrepancy between the reflexive (choice and feeding) and reinforcing function is also seen for sodium chloride (Niewalda T, Singhal S, Fiala A, Saumweber T, Wegener S, Gerber B, in preparation). We discuss whether these discrepancies are based either on inhibition from high-osmolarity sensors upon specifically the reflexive pathways or whether different sensory pathways, with different effective dose–response characteristics, may have preferential access to drive either reflex responses or modulatory neurons mediating internal reinforcement, respectively.

The ability to learn is universal among animals; we investigate associative learning between odors and "tastants" in larval Drosophila melanogaster. As biologically important gustatory stimuli, like sugars, salts, or bitter substances have many behavioral functions, we investigate not only their reinforcing function, but also their response-modulating and response-releasing function. Concerning the response-releasing function, larvae are attracted by fructose and repelled by sodium chloride and quinine; also, fructose increases, but salt and quinine suppress feeding. However, none of these stimuli has a nonassociative, modulatory effect on olfactory choice behavior. Finally, only fructose but neither salt nor quinine has a reinforcing effect in associative olfactory learning. This implies that the response-releasing, response-modulating and reinforcing functions of these tastants are dissociated on the behavioral level. These results open the door to analyze how this dissociation is brought about on the cellular and molecular level; this should be facilitated by the cellular simplicity and genetic accessibility of the Drosophila larva.

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Intraneuronal deposition of aggregated proteins in tauopathies, Parkinson disease, or familial encephalopathy with neuroserpin inclusion bodies (FENIB) leads to impaired protein homeostasis (proteostasis). FENIB represents a conformational dementia, caused by intraneuronal polymerization of mutant variants of the serine protease inhibitor neuroserpin. In contrast to the aggregation process, the kinetic relationship between neuronal proteostasis and aggregation are poorly understood. To address aggregate formation dynamics, we studied FENIB in Caenorhabditis elegans and mice. Point mutations causing FENIB also result in aggregation of the neuroserpin homolog SRP-2 most likely within the ER lumen in worms, recapitulating morphological and biochemical features of the human disease. Intriguingly, we identified conserved protein quality control pathways to modulate protein aggregation both in worms and mice. Specifically, downregulation of the unfolded protein response (UPR) pathways in the worm favors mutant SRP-2 accumulation, while mice overexpressing a polymerizing mutant of neuroserpin undergo transient induction of the UPR in young but not in aged mice. Thus, we find that perturbations of proteostasis through impairment of the heat shock response or altered UPR signaling enhance neuroserpin accumulation in vivo. Moreover, accumulation of neuroserpin polymers in mice is associated with an age-related induction of the UPR suggesting a novel interaction between aging and ER overload. These data suggest that targets aimed at increasing UPR capacity in neurons are valuable tools for therapeutic intervention.

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Wear particles of total joint replacements may lead to an inflammatory response driven by cells of the monocyte/macrophage lineage. Today, there is a general agreement that the continuous release of wear particles by the implant has a critical impact on periprosthetic osteolysis, which can eventually lead to aseptic loosening of the implant. The focus of this study lay on the determination of the polarization of macrophages (M0) toward the pro-inflammatory M1 phenotype or the anti-inflammatory M2-like phenotype upon exposure to differently sized TiO2 particles. The analysis was done with an in vitro model using THP-1 monocytes. It offers a direct characterization of the polarization profile of the macrophages exposed to nano- (<100 nm, measured hydrodynamic diameter: 518.5 nm) and micro- (<5 μm, measured hydrodynamic diameter: 2213 nm) sized TiO2 particles in different concentrations (4 × 104 −4 × 106 particles/mL). The polarization profile was analyzed by the quantitative assessment of relative gene expression levels as well as by the determination of specific proteins by enzyme linked immunosorbent assay (ELISA). Analysis by qRT-PCR revealed significantly elevated levels of pro-inflammatory markers such as TNF-α and CD197 at the highest concentration of stimulation by the microsized particles. This was confirmed on the protein level in the cytokine expression profile of TNF-α. Furthermore, no significant differences were found for the markers CCL22 and CD206, which are specific for the M2-like phenotype. In contrast, stimulation by nanoparticles did not induce macrophage polarization toward M1 or M2-like phenotype in any applied concentration. We conclude that the size of the particle is a determinant factor in driving the biological response of macrophages and an increased understanding of this relationship may potentially guide the design of new biomaterials.

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