Biology subjects

Gliksberg, M.

Publications and source records attributed to Gliksberg, M..

5 recordsLinked to original sources

bioRxiv2022

Stress resilience is established during development and is regulated by complement factors

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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/478444v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@359261org.highwire.dtl.DTLVardef@11d1e62org.highwire.dtl.DTLVardef@b5d346org.highwire.dtl.DTLVardef@141bae1_HPS_FORMAT_FIGEXP M_FIG C_FIG Why some individual individuals recover better than others from stressful situations is unclear. We show that resilience to stress is established during zebrafish development as a stable and heritable trait. Resilience is augmented by brain-derived neuropeptides and attenuated by innate immune complement factors specifically expressed in the liver. HighlightsO_LIWildtype zebrafish larvae show differences in their dynamics of recovering from stress, with some being more resilient than others. C_LIO_LIResilience is a stable and heritable trait. C_LIO_LIResilient fish show specific stress-responsive transcriptional changes. C_LIO_LINeuropeptide Y and miRNA218 positively affect resilience, while innate immune complement factors attenuate resilience. C_LI

neuroscience↗

bioRxiv2021

Oxytocin regulation of social transmission of fear in zebrafish reveals its evolutionary conserved role in emotional contagion

Emotional contagion is the most ancestral form of empathy that relies on simple perception-action mechanisms, on top of which more complex forms of empathic behaviors, such as consolation and helping, have evolved. Here we tested to what extent the proximate mechanisms of emotional contagion are evolutionary conserved by assessing the role of oxytocin, known to regulate empathic behaviors in mammals, in social fear contagion in zebrafish, which represents an evolutionary divergent line to that of tetrapods, within vertebrates. Using mutants for the ligand of the fish oxytocin nonapeptide and both of its receptors in zebrafish we showed that oxytocin is necessary for observer zebrafish to copy the distressed behavior of conspecific demonstrators. Exogeneous administration of oxytocin to the ligand mutant rescued the ability of observers to express social fear transmission, indicating that oxytocin is not only necessary but also sufficient for emotional contagion. The brain regions in the ventral telencephalon that are associated with emotional contagion in zebrafish are homologous to those known to be involved in the same process in rodents (e.g. striatum, lateral septum), and receive direct projections from oxytocinergic neurons located in the pre-optic area. Finally, we ruled out the hypothesis that social transmission of fear in zebrafish merely relies on behavior contagion by motor imitation, and we showed that it rather relies on emotion discrimination. Together our results support an evolutionary conserved role for oxytocin as a key regulator of basic empathic behaviors across vertebrates. One-Sentence SummaryOxytocin is necessary and sufficient for social fear contagion in zebrafish supporting an evolutionary conserved role for oxytocin in emotional contagion among vertebrates.

animal behavior and cognition↗

bioRxiv2020

Developmental effects of oxytocin neurons on social affiliation and processing of social information

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, 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 towards conspecifics. Significance StatementSocial behavior is developed over the lifetime of an organism and the neuropeptide oxytocin modulates social behaviors across vertebrate species, and is associated with neuro-developmental social deficits such as autism. However, whether oxytocin plays a role in the developmental maturation of neural systems that are necessary for social behavior remains poorly explored. We show that proper behavioral and neural response to social stimuli depends on a developmental process orchestrated by oxytocin neurons. Animals whose oxytocin system is ablated in early life show blunted neuronal and behavioral responses to social stimuli as well as wide ranging disruptions in the functional connectivity of the Social Brain. We provide a window into the mechanisms underlying oxytocin-dependent developmental processes that implement adult sociality.

neuroscience↗

bioRxiv2020

Splice-specific deficiency of the PTSD-associated gene PAC1 leads to a paradoxical age-dependent stress behavior

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 organisms 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.

animal behavior and cognition↗

bioRxiv2019

Robo2 regulates synaptic oxytocin content by affecting actin state

The regulation of neuropeptide level at the site of release is essential for proper neurophysiological functions. We focused on a prominent neuropeptide, oxytocin (OXT), and used 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 surrounded by polymerized actin. Perturbation of actin filaments by cytochalasin-D resulted in decreased synaptic OXT levels. Live imaging of the actin probe, Lifeact-EGFP, showed reduced mobility in OXT synapses in robo2 mutants, which displayed decreased synaptic OXT content. Using a novel transgenic reporter line allowing real-time monitoring of OXT-loaded vesicles, we showed 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 Robo2-Cdc42 signalling, which controls local actin dynamics, with the maintenance of synaptic neuropeptide levels.

developmental biology↗