Genetic Control of Collective Behavior in Zebrafish.

Many animals, including humans, have evolved to live and move in groups. In humans, disrupted social interactions are a fundamental feature of many psychiatric disorders. However, we know little about how genes regulate social behavior. Zebrafish may serve as a powerful model to explore this question. By comparing the behavior of wild-type fish with 90 mutant lines, we show that mutations of genes associated with human psychiatric disorders can alter the collective behavior of adult zebrafish. We identify three categories of behavioral variation across mutants: "scattered," in which fish show reduced cohesion; "coordinated," in which fish swim more in aligned schools; and "huddled," in which fish form dense but disordered groups. Changes in individual interaction rules can explain these differences. This work demonstrates how emergent patterns in animal groups can be altered by genetic changes in individuals and establishes a framework for understanding the fundamentals of social information processing.

αKlotho Regulates Age-Associated Vascular Calcification and Lifespan in Zebrafish.

The hormone αKlotho regulates lifespan in mice, as knockouts die early of what appears to be accelerated aging due to hyperphosphatemia and soft tissue calcification. In contrast, the overexpression of αKlotho increases lifespan. Given the severe mouse phenotype, we generated zebrafish mutants for αklotho as well as its binding partner fibroblast growth factor-23 (fgf23). Both mutations cause shortened lifespan in zebrafish, with abrupt onset of behavioral and degenerative physical changes at around 5 months of age. There is a calcification of vessels throughout the body, most dramatically in the outflow tract of the heart, the bulbus arteriosus (BA). This calcification is associated with an ectopic activation of osteoclast differentiation pathways. These findings suggest that the gradual loss of αKlotho found in normal aging might give rise to ectopic calcification.

Mating Suppresses Alarm Response in Zebrafish.

Mating and flight from threats are innate behaviors that enhance species survival [1, 2]. Stimuli to these behaviors often are contemporaneous and conflicting [3, 4]. Both how such conflicts are resolved and where in the brain such decisions are made are poorly understood. For teleosts, olfactory stimuli are key elements of mating and threat responses [5-7]. For example, zebrafish manifest a stereotypical escape response when exposed to an alarm substance released from injured conspecific skin ("skin extract") [8, 9]. We find that when mating, fish ignore this threatening stimulus. Water conditioned by the mating fish ("mating water") suffices to suppress much of the alarm-response behavior. By 2-photon imaging of calcium transients [10], we mapped the regions of the brain responding to skin extract and to mating water. In the telencephalon, we found regions where the responses overlap, one region (medial Dp) to be predominantly activated by skin extract, and another, Vs, to be predominantly activated by mating water. When mating water and skin extract were applied simultaneously, the alarm-specific response was suppressed, while the mating-water-specific response was retained, corresponding to the dominance of mating over flight behavior. The choice made, for reproduction over escape, is opposite to that of mammals, presumably reflecting how the balance affects species survival.

Abnormal Behavior of Zebrafish Mutant in Dopamine Transporter Is Rescued by Clozapine.

Dopamine transporter (SLC6A3) deficiency causes infantile Parkinson disease, for which there is no effective therapy. We have explored the effects of genetically deleting SLC6A3 in zebrafish. Unlike the wild-type, slc6a3-/- fish hover near the tank bottom, with a repetitive digging-like behavior. slc6a3-/- fish manifest pruning and cellular loss of particular tyrosine hydroxylase-immunoreactive neurons in the midbrain. Clozapine, an effective therapeutic for treatment-resistant schizophrenia, rescues the abnormal behavior of slc6a3-/- fish. Clozapine also reverses the abnormalities in the A8 region of the mutant midbrain. By RNA sequencing analysis, clozapine increases the expression of erythropoietin pathway genes. Transgenic over-expression of erythropoietin in neurons of slc6a3-/- fish partially rescues the mutant behavior, suggesting a potential mechanistic basis for clozapine's efficacy.