Repeated performance of visual tasks leads to long-lasting increased sensitivity to the trained stimulus, a phenomenon termed perceptual learning. A ubiquitous property of visual learning is specificity: performance improvement obtained during training applies only for the trained stimulus features, which are thought to be encoded in sensory brain regions [1-3]. However, recent results show performance decrements with an increasing number of trials within a training session [4, 5]. This selective sensitivity reduction is thought to arise due to sensory adaptation [5, 6]. Here we show, using the standard texture discrimination task [7], that location specificity is a consequence of sensory adaptation; that is, it results from selective reduced sensitivity due to repeated stimulation. Observers practiced the texture task with the target presented at a fixed location within a background texture. To remove adaptation, we added task-irrelevant ("dummy") trials with the texture oriented 45° relative to the target's orientation, known to counteract adaptation [8]. The results indicate location specificity with the standard paradigm, but complete generalization to a new location when adaptation is removed. We suggest that adaptation interferes with invariant pattern-discrimination learning by inducing network-dependent changes in local visual representations.

| INTRODUC TI ONNonapeptides are known to be important players in the regulation of social behaviour across taxa. 1 They evolved from a common ancestral molecule, the arginine vasotocin, after a gene duplication event in early-jawed fish. 2 One copy originated the vasopressin-like peptides, which retained the most primitive functions of the ancestral molecule, namely the regulation of osmotic balance. The other originated the oxytocin (OXT)-like peptides, which have greatly diverged across species, being recruited for diverse homeostatic processes, including parturition and lactation in mammals. Throughout evolution, these nonapeptides have also been involved in the regulation of social behaviours, with vasopressin being more involved in aggression and agonistic behaviours and OXT in affiliative behaviours and sociality. 3 AbstractSociality is a complex phenomenon that involves the individual´s motivation to approach their conspecifics, along with social cognitive functions that enable individuals to interact and survive. The nonapeptide oxytocin (OXT) is known to regulate sociality in many species. However, the role of OXT in specific aspects of sociality is still not well understood. In the present study, we investigated the contribution of the OXT receptor (OXTR) signalling in two different aspects of zebrafish social behaviour: social preference, by measuring their motivation to approach a shoal of conspecifics, and social recognition, by measuring their ability to discriminate between a novel and familiar fish, using a mutant zebrafish lacking a functional OXTR. Although oxtr mutant zebrafish displayed normal attraction to a shoal of conspecifics, they exhibited reduced social recognition. We further investigated whether this effect would be social-domain specific by replacing conspecific fish by objects. Although no differences were observed in object approach, oxtr mutant fish also exhibited impaired object recognition. Our findings suggest that OXTR signalling regulates a more general memory recognition of familiar vs novel entities, not only in social but also in a non-social domain, in zebrafish. K E Y W O R D Sautism spectrum disorders, oxytocin, social preference, social recognition, zebrafish S U PP O RTI N G I N FO R M ATI O NAdditional supporting information may be found online in the Supporting Information section.

Hormones regulate behavior either through activational effects that facilitate the acute expression of specific behaviors or through organizational effects that shape the development of the nervous system thereby altering adult behavior. Much research has implicated the neuropeptide oxytocin (OXT) in acute modulation of various aspects of social behaviors across vertebrate species, and OXT signaling is associated with the developmental social deficits observed in autism spectrum disorders (ASDs); however, little is known about the role of OXT in the neurodevelopment of the social brain. We show that perturbation of OXT neurons during early zebrafish development led to a loss of dopaminergic neurons, associated with visual processing and reward, and blunted the neuronal response to social stimuli in the adult brain. Ultimately, adult fish whose OXT neurons were ablated in early life, displayed altered functional connectivity within social decision-making brain nuclei both in naive state and in response to social stimulus and became less social. We propose that OXT neurons have an organizational role, namely, to shape forebrain neuroarchitecture during development and to acquire an affiliative response toward conspecifics.

The regulation of neuropeptide level at the site of release is essential for proper neurophysiological functions. We focused on a prominent neuropeptide, oxytocin (OXT) in the zebrafish as an in vivo model to visualize and quantify OXT content at the resolution of a single synapse. We found that OXT-loaded synapses were enriched with polymerized actin. Perturbation of actin filaments by either cytochalasin-D or conditional Cofilin expression resulted in decreased synaptic OXT levels. Genetic loss of robo2 or slit3 displayed decreased synaptic OXT content and robo2 mutants displayed reduced mobility of the actin probe Lifeact-EGFP in OXT synapses. Using a novel transgenic reporter allowing real-time monitoring of OXT-loaded vesicles, we show that robo2 mutants display slower rate of vesicles accumulation. OXT-specific expression of dominant-negative Cdc42, which is a key regulator of actin dynamics and a downstream effector of Robo2, led to a dose-dependent increase in OXT content in WT, and a dampened effect in robo2 mutants. Our results link Slit3-Robo2-Cdc42, which controls local actin dynamics, with the maintenance of synaptic neuropeptide levels.

The pituitary adenylate cyclase-activating polypeptide receptor (PAC1, also known as ADCYAP1R1) is associated with post-traumatic stress disorder and modulation of stress response in general. Alternative splicing of PAC1 results in multiple gene products, which differ in their mode of signalling and tissue distribution. However, the roles of distinct splice variants in the regulation of stress behavior is poorly understood. Alternative splicing of a short exon, which is known as the "hop cassette", occurs during brain development and in response to stressful challenges. To examine the function of this variant, we generated a splice-specific zebrafish mutant lacking the hop cassette, which we designated 'hopless'. We show that hopless mutant larvae display increased anxiety-like behavior, including reduced dark exploration and impaired habituation to dark exposure. Conversely, adult hopless mutants displayed superior ability to rebound from an acute stressor, as they exhibited reduced anxiety-like responses to an ensuing novelty stress. We propose that the developmental loss of a specific PAC1 splice variant mimics prolonged mild stress exposure, which in the long term, predisposes the organism's stress response towards a resilient phenotype. Our study presents a unique genetic model demonstrating how early-life state of anxiety paradoxically correlates with reduced stress susceptibility in adulthood. PAC1 (a.k.a. Adcyap1r1) is a G-protein coupled receptor (GPCR) that serves as the high-affinity receptor for the pituitary adenylate cyclase-activating polypeptide (PACAP). PAC1 has pleiotropic functions and was demonstrated to be involved in the regulation of several homeostatic processes including metabolic rate and food consumption 1,2 , circadian rhythm 3 and, in particular, stress response 4,5. Intracerebroventricular injection of PACAP increased phosphorylated cyclic AMP response element binding protein (pCREB) and corticotropin-releasing hormone (CRH) immunoreactivity in the rat paraventricular nucleus 6. PACAP knockout mice display blunted hypothalamic CRH levels in response to restraint challenge 7. PACAP/PAC1 signaling was also associated with hypothalamo-pituitary-adrenal activity and stress-related behaviors in humans and rodents 5,8,9. Furthermore, this pathway was correlated with stress-related risky behaviors in human and rodents 10,11. Overall, these findings support positive stress regulation by PAC1; yet, some reports suggest that it may also act to suppress stress phenotypes 4,12. It has been suggested that genetic vulnerability to post-traumatic stress disorder (PTSD) may depend on PAC1 expression and single-nucleotide polymorphism (SNP) in the PAC1 gene. Ressler et al. demonstrated that a specific PAC1 genotype is strongly correlated with susceptibility to PTSD in women, probably due to perturbed expression of PAC1 resulting in impaired stress responses 13. The same PAC1 SNP was associated with PTSD in African-American females, emotional numbing in traumatized earthquake Chinese survivors, dark-e...

Emotional contagion is the most ancestral form of empathy. We tested to what extent the proximate mechanisms of emotional contagion are evolutionarily conserved by assessing the role of oxytocin, known to regulate empathic behaviors in mammals, in social fear contagion in zebrafish. Using oxytocin and oxytocin receptor mutants, we show that oxytocin is both necessary and sufficient for observer zebrafish to imitate the distressed behavior of conspecific demonstrators. The brain regions associated with emotional contagion in zebrafish are homologous to those involved in the same process in rodents (e.g., striatum, lateral septum), receiving direct projections from oxytocinergic neurons located in the pre-optic area. Together, our results support an evolutionary conserved role for oxytocin as a key regulator of basic empathic behaviors across vertebrates.

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Individuals in a population respond differently to stressful situations. While resilient individuals recover efficiently, others are susceptible to the same stressors. However, it remains challenging to identify resilience in mammalian embryos to determine if stress resilience is established as a trait during development or acquired later in life. Using a new behavioural paradigm in zebrafish larvae, we show that resilience is a trait that is determined and exhibited early in life. Resilient and susceptible individuals retained these traits throughout life and passed them on to the next generation. Resilient larvae showed higher expression of resilience-associated genes and larvae lacking neuropeptide Y and miR218 were significantly under-represented in the resilient population. Unbiased transcriptome analysis revealed that multiple factors of the innate immune complement cascade were downregulated in resilient larvae in response to stressors. Pharmacological inhibition and genetic knockouts of critical complement factors led to an increase in resilience. We conclude that resilience is established early during development as a stable trait, and that neuropeptides and the complement pathway play positive and negative roles in determining resilience respectively.