Conserved serotonergic background of experience-dependent challenge-responding in zebrafish (Danio rerio)

Abstract

Forming effective responses to threatening stimuli requires the adequate and coordinated emergence of stress-related internal states. Such ability depends on early-life experiences and, in connection, the adequate formation of neuromodulatory systems, particularly serotonergic signaling. Here, we assess the serotonergic background of experience-dependent behavioral responsiveness employing a zebrafish (Danio rerio) model. For the first time, we have characterized a period during the behavioral metamorphosis in which zebrafish are highly reactive to their environment. Absence of social stimuli during this phase established by isolated rearing fundamentally altered the behavioral phenotype of post-metamorphic zebrafish in a challenge-specific manner, partially due to a decline in responsiveness and an inability to develop stress-associated arousal state. In line with this, isolation differently affected whole-brain 5-HT signaling in resting and stress-induced conditions, an effect that was present at the level of the dorsal pallium and was negatively associated with responsiveness. Administration of the 5HT1AR partial agonist buspirone prevented the isolation-induced serotonin response to novelty in the forebrain and rescued stress-induced arousal along with challenge-induced behaviors, which altogether indicates a functional connection between these changes. In summary, there is a consistent negative association between behavioral responsiveness and serotonergic signaling in zebrafish, which is well recognizable through the modifying effects of developmental perturbation and pharmacological manipulations as well. Our results imply a conserved serotonergic mechanism that context-dependently modulates environmental reactivity and is highly sensitive to experiences acquired during a specific early-life time-window, a phenomenon that was previously only suggested in mammals.Significance statementThe ability to respond to challenges is a fundamental factor in survival. We show that zebrafish that lack appropriate social stimuli in a sensitive developmental period show exacerbated alertness in non-stressful conditions while failing to react adequately to stressors. This shift is reflected inversely by central serotonergic signaling, a system that is implicated in numerous mental disorders in humans. Serotonergic changes in brain regions modulating responsivity and behavioral impairment were both prevented by the pharmacological blockade of serotonergic function. These results imply a serotonergic mechanism in zebrafish that transmits early-life experiences to the later phenotype by shaping stress-dependent behavioral reactivity, a phenomenon that was previously only suggested in mammals. Zebrafish provide new insights into early-life-dependent neuromodulation of behavioral stress-responses.

Altered GABAergic, glutamatergic and endocannabinoid signaling is accompanied by neuroinflammatory response in a zebrafish model of social withdrawal behavior

“…Increased number of riskassessment behaviors were also observed in BTBR mice, an animal model of ASD also characterized by impaired sociability and high anxiety (Chao et al, 2018). In line with the above, adult zebrafish that were subjected to social isolation during their early-life stages displayed a characteristic dark avoidance behavior that could not be interpreted as an anxiolytic response, suggesting the inability to develop stress-associated arousal state (Varga et al, 2020). Our perspective that MK-801-treated zebrafish are characterized by a heightened anxiety-state, is further reinforced by their diminished weight gain, a response that is reported in rodents and zebrafish after prolonged stress exposure (Riaz et al, 2015;Fulcher et al, 2017).…”

The Effects of Early Life Stress on the Brain and Behaviour: Insights From Zebrafish Models

“…Interestingly, in another study, developmentally isolated fish (isolated 0-7 dpf) were observed to have significantly reduced levels of DOPAC, but not dopamine, serotonin or 5-HIAA, when compared with socialreared fish in adulthood (Shams et al, 2018). Further, Varga et al (2020) observed that social isolation of fish during a critical period of behavioural metamorphosis that occurs in the juvenile stage affects later behavioural responsiveness and serotonergic signalling in the dorsal pallium. Blockade of 5-hydroxytryptamine (5-HT) signalling was sufficient to prevent the serotonin-associated brain changes and behavioural deficits, suggesting that a serotonergic mechanism, sensitive to environmental manipulation during a specific time window, modulates context-dependent behaviours in later life.…”