Long-term behavioral change as a result of acute ethanol exposure in zebrafish: Evidence for a role for sonic hedgehog but not retinoic acid signaling

Abstract

BACKGROUND Developmental exposure to ethanol is recognized to produce long-term neurobehavioral impairment in multiple animal models. However, the molecular mechanisms underlying these deficits remain poorly understood. The present study was undertaken to ascertain whether two well-characterized targets of prenatal alcohol exposure, sonic hedgehog (Shh) and retinoic acid (RA), that induce the hallmark morphological phenotypes of fetal alcohol spectrum disorders (FASD), are involved in the generation of behavioral alterations as a result of alcohol exposure. METHODS Zebrafish embryos were exposed to ethanol (0%, 1%, 3%) at either 8–10 or 24–27 hours post-fertilization (hpf) and then evaluated during adolescence in the novel tank dive test to assess anxiety and risk-taking behavior. Overt signs of dysmorphogenesis were also scored and behavioral and morphological changes were compared for embryos treated with alcohol alone or in combination with subthreshold doses of shh or alhh1a3 morpholinos (MOs). RESULTS Ethanol treated fish displayed altered tank diving behavior that was not exacerbated by combined MO treatment. While treatment of embryos with either shha mRNA or RA prior to ethanol exposure only ameliorated the altered tank diving response in the case of shha mRNA overexpression, dysmorphogenesis was rescued by both treatments. CONCLUSION These results suggest that the effects of ethanol exposure on changes in anxiety and risk-taking behavior in adolescent zebrafish is manifested by a blunting of Shh, but not RA, signaling during early development.

Fetal alcohol spectrum disorder predisposes to metabolic abnormalities in adulthood

“…Multiple studies have demonstrated that EAE affects zebrafish swimming behaviors (35)(36)(37)(38). To determine whether reduced locomotion was present in adults after EAE, we assessed activity level (35,(39)(40)(41)(42)(43)(44). Adult fish were subjected to a 10-minute habituation period, followed by a monitored locomotion assay.…”

Ethanol and cannabinoids interact to alter behavior in a zebrafish fetal alcohol spectrum disorder model

“…Previous studies in our laboratory analyzed novel tank diving behavior of juvenile fish exposed to 1% ethanol and demonstrated that binge‐like ethanol exposures cause alteration in behavior that is a correlate of anxiolytic (risk‐taking) behavior (Bailey et al, ; Burton et al, ). Other laboratories have also observed anxiolytic behaviors in larval and adult fish exposed to low‐dose CB1R agonists, and anxiogenic behavior when exposed to high‐dose agonists (Akhtar et al, ; Stewart & Kalueff, ).…”

“…This suggests that signaling along the entire pathway may be inhibited. Interestingly, several studies have shown that the morphological and behavioral abnormalities associated with embryonic ethanol exposure in zebrafish could be rescued with shh mRNA overexpression (Burton, Zhang, Boa‐Amponsem, Mackinnon, & Cole, ; Loucks & Ahlgren, ; Zhang et al, ; Zhang, Turton, Mackinnon, Sulik, & Cole, ).…”

“…Zebrafish have become a useful animal behavioral model as they exhibit behavioral complexity similar to mammals (Stewart & Kalueff, ). Many behavioral deficits are observed after a brief exposure of zebrafish embryos or larvae to ethanol, with anxiety and social behavior affected by embryonic ethanol exposure (Bailey et al, ; Burton et al, ; Buske & Gerlai, ; Fernandes & Gerlai, ; Fernandes, Rampersad, & Gerlai, ). CBs produce similar effects in rodents, including anxiogenic and hypolocomotor effects, impaired object recognition, spatial learning, working memory, and social interaction (Buske & Gerlai, ).…”

Social deficits following embryonic ethanol exposure arise in post‐larval zebrafish

“…There are a growing number of behavioral assays in zebrafish that are relevant to the study of FASD (Burton et al . ). Social deficits are common in FASD (Kelly, Day & Streissguth ; Rasmussen et al .…”