RESUMO
GRIA1 encodes the GluA1 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors, which are ligand-gated ion channels that act as excitatory receptors for the neurotransmitter L-glutamate (Glu). AMPA receptors (AMPARs) are homo- or heteromeric protein complexes with four subunits, each encoded by different genes, GRIA1 to GRIA4. Although GluA1-containing AMPARs have a crucial role in brain function, the human phenotype associated with deleterious GRIA1 sequence variants has not been established. Subjects with de novo missense and nonsense GRIA1 variants were identified through international collaboration. Detailed phenotypic and genetic assessments of the subjects were carried out and the pathogenicity of the variants was evaluated in vitro to characterize changes in AMPAR function and expression. In addition, two Xenopus gria1 CRISPR-Cas9 F0 models were established to characterize the in vivo consequences. Seven unrelated individuals with rare GRIA1 variants were identified. One individual carried a homozygous nonsense variant (p.Arg377Ter), and six had heterozygous missense variations (p.Arg345Gln, p.Ala636Thr, p.Ile627Thr, and p.Gly745Asp), of which the p.Ala636Thr variant was recurrent in three individuals. The cohort revealed subjects to have a recurrent neurodevelopmental disorder mostly affecting cognition and speech. Functional evaluation of major GluA1-containing AMPAR subtypes carrying the GRIA1 variant mutations showed that three of the four missense variants profoundly perturb receptor function. The homozygous stop-gain variant completely destroys the expression of GluA1-containing AMPARs. The Xenopus gria1 models show transient motor deficits, an intermittent seizure phenotype, and a significant impairment to working memory in mutants. These data support a developmental disorder caused by both heterozygous and homozygous variants in GRIA1 affecting AMPAR function.
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Transtornos do Neurodesenvolvimento , Receptores de AMPA , Estudos de Coortes , Heterozigoto , Humanos , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/genética , Receptores de AMPA/genéticaRESUMO
Sex is an important biological variable that is widely recognized in studies of alcohol-related effects. Complementing clinical and preclinical rodent research, the zebrafish (Danio rerio) is the second most used laboratory species, and a powerful model organism in biomedicine. Like clinical and rodent models, zebrafish demonstrate overt sex differences in alcohol-related responses. Collectively, this evidence shows that the zebrafish becomes a sensitive model species to further probe in-depth sex differences commonly reported in alcohol research.
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Etanol , Peixe-Zebra , Animais , Feminino , Masculino , Caracteres Sexuais , Modelos Animais de DoençasRESUMO
Salient landmarks enhance route learning. We hypothesised that semantically salient nostalgic landmarks would improve route learning compared to non-nostalgic landmarks. In two experiments, participants learned a route through a computer-generated maze using directional arrows and wall-mounted pictures. On the test trial, the arrows were removed, and participants completed the maze using only the pictures. In the nostalgia condition, pictures were of popular music artists and TV characters from 5 to 10 years ago. In the control condition, they were recent pictures of these same artists and characters. In Experiment 1, in the test trial, participants in the nostalgia condition completed the maze faster than controls. Experiment 2 conceptually replicated these findings and extended them by exploring boundary conditions. Participants had to learn two mazes sequentially. In Maze 1, we placed nostalgic/control landmarks only at non-decision points (whereas we placed them at decision points in Experiment 1). In Maze 2, we placed nostalgic/control landmarks at decision points during acquisition but removed them in the test trial (whereas they were present in the test trial in Experiment 1). In both mazes, participants in the nostalgia (compared to control) condition completed the test trial faster.
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Aprendizagem , Música , HumanosRESUMO
Spatial anxiety (i.e., feelings of apprehension and fear about navigating everyday environments) can adversely impact people's ability to reach desired locations and explore unfamiliar places. Prior research has either assessed spatial anxiety as an individual-difference variable or measured it as an outcome, but there are currently no experimental inductions to investigate its causal effects. To address this lacuna, we developed a novel protocol for inducing spatial anxiety within a virtual environment. Participants first learnt a route using directional arrows. Next, we removed the directional arrows and randomly assigned participants to navigate either the same route (n = 22; control condition) or a variation of this route in which we surreptitiously introduced unfamiliar paths and landmarks (n = 22; spatial-anxiety condition). The manipulation successfully induced transient (i.e., state-level) spatial anxiety and task stress but did not significantly reduce task enjoyment. Our findings lay the foundation for an experimental paradigm that will facilitate future work on the causal effects of spatial anxiety in navigational contexts. The experimental task is freely available via the Open Science Framework ( https://osf.io/uq4v7/ ).
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Navegação Espacial , Humanos , Aprendizagem , Ansiedade , IndividualidadeRESUMO
Behavioural needs are highly motivated actions critical to a species survival and reproduction. Prolonged restriction of these behaviours can lead to stereotypic behaviours (SB) in captive animals, and this is particularly common in ungulate species. While risk factors for SB have been suggested for some ungulates, no study has integrated these findings to identify which aspects of ungulates' wild behavioural biology and captive husbandry are potential drivers for SB across this clade. We collated SB data from 15 236 individuals across 38 ungulate species from 95 sources, and determined species wild/free-ranging behaviour from 559 additional studies. Bayesian-phylogenetic statistical methods showed that ungulate behavioural needs relating to foraging and mating are particularly affected by captive environments, with promiscuous and browsing species showing the greatest prevalence of SB. Concentrate-only diets and lack of ad libitum feed substrates were also associated with high SB prevalence. This study identifies which ungulates are better suited to captive environments and which species require targeted husbandry, enrichment and breeding protocols in order to meet their behavioural needs. Our approach of applying Bayesian-phylogenetic inference to factors influencing SB within a clade can be used to identify other intrinsic and extrinsic risk factors of reduced animal health and welfare.
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Mamíferos , Comportamento Estereotipado , Animais , Teorema de Bayes , Filogenia , Fatores de RiscoRESUMO
Early life stress (ELS) is defined as a short or chronic period of trauma, environmental or social deprivation, which can affect different neurochemical and behavioral patterns during adulthood. Zebrafish (Danio rerio) have been widely used as a model system to understand human neurodevelopmental disorders and display translationally relevant behavioral and stress-regulating systems. In this study, we aimed to investigate the effects of moderate ELS by exposing young animals (6-weeks postfertilization), for 3 consecutive days, to three stressors, and analyzing the impact of this on adult zebrafish behavior (16-week postfertilization). The ELS impact in adults was assessed through analysis of performance on tests of unconditioned memory (free movement pattern Y-maze test), exploratory and anxiety-related task (novel tank diving test), and social cohesion (shoaling test). Here, we show for the first time that moderate ELS increases the number of alternations in turn-direction compared to repetitions in the unconditioned Y-maze task, suggesting increased working memory, but has no effect on shoal cohesion, locomotor profile, or anxiety-like behavior. Overall, our data suggest that moderate ELS may be linked to adaptive flexibility which contributes to build "resilience" in adult zebrafish by improving working memory performance.
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Experiências Adversas da Infância , Peixe-Zebra , Adulto , Animais , Ansiedade , Comportamento Animal , Humanos , Memória de Curto Prazo , Coesão Social , Privação SocialRESUMO
Numerous neurodegenerative and psychiatric disorders are associated with deficits in executive functions such as working memory and cognitive flexibility. Progress in developing effective treatments for disorders may benefit from targeting these cognitive impairments, the success of which is predicated on the development of animal models with validated behavioural assays. Zebrafish offer a promising model for studying complex brain disorders, but tasks assessing executive function are lacking. The Free-movement pattern (FMP) Y-maze combines aspects of the common Y-maze assay, which exploits the inherent motivation of an organism to explore an unknown environment, with analysis based on a series of sequential two-choice discriminations. We validate the task as a measure of working memory and executive function by comparing task performance parameters in adult zebrafish treated with a range of glutamatergic, cholinergic and dopaminergic drugs known to impair working memory and cognitive flexibility. We demonstrate the cross-species validity of the task by assessing performance parameters in adapted versions of the task for mice and Drosophila, and finally a virtual version in humans, and identify remarkable commonalities between vertebrate species' navigation of the maze. Together, our results demonstrate that the FMP Y-maze is a sensitive assay for assessing working memory and cognitive flexibility across species from invertebrates to humans, providing a simple and widely applicable behavioural assay with exceptional translational relevance.
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Função Executiva , Memória de Curto Prazo , Animais , Encéfalo , Aprendizagem em Labirinto , Camundongos , Motivação , Peixe-ZebraRESUMO
Zebrafish (Danio rerio) are widely used as a translational model for human neuropsychiatric conditions. Many studies have not considered sex differences in their analyses. Here, we studied sex differences of adult zebrafish in two behavioral domains: Anxiety and Memory. To assess whether sex influences anxiety-like responses, we used two different behavioral protocols, the novel tank diving task and the light-dark test. To assess sex differences in learning and memory tasks, we explored two memory domains, short-term spatial memory (free movement pattern Y-maze task) and short-term fear memory (Pavlovian fear-conditioning task). Although we did not find any significant difference in learning and memory tasks, female zebrafish showed robust increases in anxiety-like behavioral endpoints in both anxiety tests. Overall, our data suggest that zebrafish is a sensitive model to work with sex differences when modeling anxiety-related disorders and this should be an important factor to consider in different experimental designs.
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Comportamento Animal , Peixe-Zebra , Animais , Ansiedade , Medo , Feminino , Humanos , Masculino , Memória de Curto PrazoRESUMO
Impulse control disorders (ICDs) are characterized by generalized difficulty controlling emotions and behaviors. ICDs are a broad group of the central nervous system (CNS) disorders including conduct disorder, intermittent explosive, oppositional-defiant disorder, antisocial personality disorder, kleptomania, pyromania and other illnesses. Although they all share a common feature (aberrant impulsivity), their pathobiology is complex and poorly understood. There are also currently no ICD-specific therapies to treat these illnesses. Animal models are a valuable tool for studying ICD pathobiology and potential therapies. The zebrafish (Danio rerio) has become a useful model organism to study CNS disorders due to high genetic and physiological homology to mammals, and sensitivity to various pharmacological and genetic manipulations. Here, we summarize experimental models of impulsivity and ICD in zebrafish and highlight their growing translational significance. We also emphasize the need for further development of zebrafish ICD models to improve our understanding of their pathogenesis and to search for novel therapeutic treatments.
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Doenças do Sistema Nervoso Central , Transtornos Disruptivos, de Controle do Impulso e da Conduta , Animais , Transtornos Disruptivos, de Controle do Impulso e da Conduta/terapia , Comportamento Impulsivo , Modelos Animais , Peixe-ZebraRESUMO
Once considered a uniquely human attribute, behavioral laterality has proven to be ubiquitous among non-human animals, and is associated with several neurophenotypes in rodents and fishes. Zebrafish (Danio rerio) is a versatile vertebrate model system widely used in translational neuropsychiatric research owing to their highly conserved genetic homology, well-characterized physiological responses, and extensive behavioral repertoire. Although spontaneous left- and right-biased responses, and associated behavioral domains (e.g., stress reactivity, aggression, and learning), have previously been observed in other teleost species, no information relating to whether spontaneous motor left-right-bias responses of zebrafish predicts other behavioral domains has been described. Thus, we aimed to investigate the existence and incidence of natural left-right bias in adult zebrafish, exploiting an unconditioned continuous free movement pattern (FMP) Y-maze task, and to explore the relationship of biasedness on performance within different behavioral domains. This included learning about threat cues in a Pavlovian fear conditioning test, and locomotion and anxiety-related behavior in the novel tank diving test. Although laterality did not change locomotion or anxiety-related behaviors, we found that biased animals displayed a different search strategy in the Y-maze, making them easily discernable from their unbiased counterparts, and increased learning associated to fear cues. In conclusion, we showed, for the first time, that zebrafish exhibit a natural manifestation of motor behavioral lateralization which can influence aversive learning responses.
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Lateralidade Funcional , Peixe-Zebra , Animais , Ansiedade , Aprendizagem da Esquiva , Comportamento Animal , Medo , Memória de Curto PrazoRESUMO
The purpose of the study reported in this Research Communication was to evaluate alterations in concentration of total antioxidant capacity (TAC) of plasma, plasma total thiols as markers of oxidative protein damage and malondialdehyde (as a final product of lipid peroxidation) in samples obtained at different stages of the lactation cycle and dry period of dairy cows. We found that TAC was significantly lower in the primiparous cows compared to multiparous cows. This study clearly demonstrates a need for monitoring primiparous cows during the production cycle, especially when they are faced with severe metabolic conditions. Furthermore, TAC may be a sensitive, reliable and useful indicator for measurement of cumulative effects of antioxidants as an addition to metabolic profile tests, which are currently used to analyse dairy cattle health.
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Antioxidantes/análise , Bovinos/fisiologia , Lactação/fisiologia , Animais , Biomarcadores/sangue , Feminino , Peroxidação de Lipídeos , Malondialdeído/sangue , Oxirredução , Paridade , Período Pós-Parto , Compostos de Sulfidrila/sangueRESUMO
Exposure to alcohol during early central nervous system development has been shown variously to affect aspects of physiological and behavioural development. In extreme cases, this can extend to craniofacial defects, severe developmental delay and mental retardation. At more moderate levels, subtle differences in brain morphology and behaviour have been observed. One clear effect of developmental alcohol exposure is an increase in the propensity to develop alcoholism and other addictions. The mechanisms by which this occurs, however, are not currently understood. In this study, we tested the hypothesis that adult zebrafish chronically exposed to moderate levels of ethanol during early brain ontogenesis would show an increase in conditioned place preference for alcohol and an increased propensity towards habit formation, a key component of drug addiction in humans. We found support for both of these hypotheses and found that the exposed fish had changes in mRNA expression patterns for dopamine receptor, nicotinic acetylcholine receptor and µ-opioid receptor encoding genes. Collectively, these data show an explicit link between the increased proclivity for addiction and addiction-related behaviour following exposure to ethanol during early brain development and alterations in the neural circuits underlying habit learning.
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Alcoolismo , Encéfalo/efeitos dos fármacos , Depressores do Sistema Nervoso Central/farmacologia , Desenvolvimento Embrionário , Etanol/farmacologia , Efeitos Tardios da Exposição Pré-Natal , RNA Mensageiro/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/embriologia , Comportamento de Escolha/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Gravidez , RNA Mensageiro/metabolismo , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores Dopaminérgicos/genética , Receptores Nicotínicos/efeitos dos fármacos , Receptores Nicotínicos/genética , Receptores Opioides mu/efeitos dos fármacos , Receptores Opioides mu/genética , Peixe-ZebraRESUMO
Zebrafish are a dynamic research model in the domains of neuropsychopharmacology, biological psychiatry and behaviour. Working with larvae ≤4 days post-fertilisation (dpf) offers an avenue for high-throughput investigation whilst aligning with the 3Rs principles of animal research. The light/dark assay, which is the most widely used behavioural assay for larval neuropharmacology research, lacks experimental reliability and standardisation. This study aimed to formulate a robust, reproducible and standardised light/dark behavioural assay using 4 dpf zebrafish larvae. Considerable between-batch and inter-individual variability was found, which we rectified with a normalisation approach to ensure a reliable foundation for analysis. We then identified that 5-min light/dark transition periods are optimal for locomotor activity. We also found that a 30-min acclimation in the light was found to produce significantly increased dark phase larval locomotion. Next, we confirmed the pharmacological predictivity of the standardised assay using ethanol which, as predicted, caused hyperlocomotion at low concentrations and hypolocomotion at high concentrations. Finally, the assay was validated by assessing the behavioural phenotype of hyperactive transgenic (adgrl3.1-/-) larvae, which was rescued with psychostimulant medications. Our standardised assay not only provides a clear experimental and analytical framework to work with 4 dpf larvae, but also facilitates between-laboratory collaboration using our normalisation approach.
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Comportamento Animal , Larva , Locomoção , Peixe-Zebra , Animais , Peixe-Zebra/fisiologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Animais Geneticamente Modificados , Etanol/farmacologia , Reprodutibilidade dos Testes , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Fotoperíodo , Luz , Estimulantes do Sistema Nervoso Central/farmacologiaRESUMO
Boredom, a complex emotional state with implications for mental health and well-being, has garnered attention across disciplines, yet remains relatively understudied in psychiatric research. Here, we explored the intricate relationship between trait-impulsivity, stress, and boredom across two studies. Participants completed self-report measures of trait-impulsivity and boredom and boredom-inducing tasks. Study 1, involving 80 participants (42 women and 38 men, aged 20-63), replicates previous findings, by demonstrating that impulsive individuals report greater boredom following a boring task. Study 2 then extends this, using 20 participants (9 women and 12 men, aged 18-24), to show that hypothalamic-pituitary-adrenal (HPA) axis activity, specifically heightened salivary cortisol responses, mediate the link between impulsivity and boredom following a boring task. Collectively, these results demonstrate that HPA axis activity may underline the relationship between trait-impulsivity and boredom by extending previous work and offering a novel insight into potential mechanisms. These findings offer promise for personalised interventions, designed for high impulsivity individuals, to alleviate the negative impacts of boredom and potentially break the identified feedback loop.
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Tédio , Hidrocortisona , Sistema Hipotálamo-Hipofisário , Comportamento Impulsivo , Sistema Hipófise-Suprarrenal , Saliva , Humanos , Masculino , Comportamento Impulsivo/fisiologia , Feminino , Adulto , Adulto Jovem , Sistema Hipotálamo-Hipofisário/metabolismo , Hidrocortisona/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Saliva/metabolismo , Saliva/química , Adolescente , Pessoa de Meia-Idade , Autorrelato , Estresse Psicológico/fisiopatologia , Estresse Psicológico/metabolismo , Personalidade/fisiologiaRESUMO
INTRODUCTION: Both sleep deprivation and hypoxia have been shown to impair executive function. Conversely, moderate intensity exercise is known to improve executive function. In a multi-experiment study, we tested the hypotheses that moderate intensity exercise would ameliorate any decline in executive function after i) three consecutive nights of partial sleep deprivation (PSD) (Experiment 1) and ii) the isolated and combined effects of a single night of total sleep deprivation (TSD) and acute hypoxia (Experiment 2). METHODS: Using a rigorous randomised controlled crossover design, 12 healthy participants volunteered in each experiment (24 total, 5 females). In both experiments seven executive function tasks (2-choice reaction time, logical relations, manikin, mathematical processing, 1-back, 2-back, 3-back) were completed at rest and during 20 min semi-recumbent, moderate intensity cycling. Tasks were completed in the following conditions: before and after three consecutive nights of PSD and habitual sleep (Experiment 1) and in normoxia and acute hypoxia (FIO2 = 0.12) following one night of habitual sleep and one night of TSD (Experiment 2). RESULTS: Although the effects of three nights of PSD on executive functions were inconsistent, one night of TSD (regardless of hypoxic status) reduced executive functions. Significantly, regardless of sleep or hypoxic status, executive functions are improved during an acute bout of moderate intensity exercise. CONCLUSION: These novel data indicate that moderate intensity exercise improves executive function performance after both PSD and TSD, regardless of hypoxic status. The key determinants and/or mechanism(s) responsible for this improvement still need to be elucidated. Future work should seek to identify these mechanisms and translate these significant findings into occupational and skilled performance settings.
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Função Executiva , Privação do Sono , Feminino , Humanos , Cognição , Hipóxia , Sono , Exercício Físico , Estudos Cross-Over , MasculinoRESUMO
In three experiments, we examined whether overshadowing of geometric cues by a discrete landmark (beacon) is due to the relative saliences of the cues. Using a virtual water maze task, human participants were required to locate a platform marked by a beacon in a distinctively shaped pool. In Experiment 1, the beacon overshadowed geometric cues in a trapezium, but not in an isosceles triangle. The longer escape latencies during acquisition in the trapezium control group with no beacon suggest that the geometric cues in the trapezium were less salient than those in the triangle. In Experiment 2, we evaluated whether generalization decrement, caused by the removal of the beacon at test, could account for overshadowing. An additional beacon was placed in an alternative corner. For the control groups, the beacons were identical; for the overshadow groups, they were visually unique. Overshadowing was again found in the trapezium. In Experiment 3, we tested whether the absence of overshadowing in the triangle was due to the geometric cues being more salient than the beacon. Following training, the beacon was relocated to a different corner. Participants approached the beacon rather than the trained platform corner, suggesting that the beacon was more salient. These results suggest that associative processes do not fully explain cue competition in the spatial domain.
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Aprendizagem por Associação , Sinais (Psicologia) , Aprendizagem por Discriminação , Aprendizagem em Labirinto , Reconhecimento Visual de Modelos , Adulto , Feminino , Humanos , Masculino , Percepção Espacial , Interface Usuário-ComputadorRESUMO
We explored (1) self-reported changes in alcohol use during the pandemic in the UK and (2) the extent to which self-reported inhibitory control and/or stress were associated with any change in drinking behaviour. We used a UK-based cross-sectional online survey administered to four nationally representative birth cohorts (N = 13,453). A significant minority of 30- (29.08%) and 50-year-olds (26.67%) reported drinking more, and between 32.23 and 45.02% of respondents reported feeling more stressed depending on the cohort. Stress was associated with hazardous drinking among 30-year-olds (OR = 3.77, 95% CI 1.15 to 12.28). Impatience was associated with both increased alcohol use (1.14, 95% CI 1.06, 1.24) and hazardous drinking (1.20, 95% CI 1.05, 1.38) among 19-year-olds. Risk-taking was associated with hazardous drinking for 30-year-olds (OR = 1.18, 95% CI 1.05, 1.32). These data highlight concerns for those at risk of alcohol misuse and alcohol-related harm during COVID-19 lockdowns. Supplementary Information: The online version contains supplementary material available at 10.1007/s11469-021-00599-8.
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Early-life adversity impacts on anxiety-related behaviors in adulthood. The effects of such adversity not only affect the animal itself, but can be passed on transgenerationally. Pervasive effects of experimentally-induced early-life stress (ELS) have been documented in adult zebrafish but it is not clear if this can be passed on via the germline. Here, we investigated the effects of ELS across three generations, by analyzing the responses of adult animals exposed to ELS in two different anxiety-related tasks, as well as in social behavior, memory, and cognition. Animals exposed to ELS (at 7 days-post-fertilization) showed a marked attenuation of specific anxiety-related behaviors (F0) as adults, and these alterations were maintained across two subsequent generations (F1 and F2). This suggest zebrafish may be a useful model organism to study the transgenerational effects of ELS, and how this pertains to (for example) neuropsychiatric disorders. In addition, our data may naturally provoke questions regarding consideration of the environment of laboratory-housed zebrafish at early developmental stages. In particular, more work may be necessary to determine how different environmental stressors could affect data variability across laboratories.
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Estresse Psicológico , Peixe-Zebra , Animais , Ansiedade , Comportamento Animal , Cognição , Comportamento SocialRESUMO
The acquisition of executive skills such as working memory, decision-making and adaptive responding occur at different stages of central nervous system development. Zebrafish (Danio rerio) are increasingly used in behavioural neuroscience for complex behavioural tasks, and there is a critical need to understand the ontogeny of their executive functions. Zebrafish across developmental stages (4, 7, 14, 30 and 90 days post fertilisation (dpf)), were assessed to track development of working memory (WM) and behavioural flexibility (BF) using the free movement pattern Y-maze (FMP Y-maze). Several differences in both WM and BF were identified during the transition from yolk-dependent to independent feeding. Specifically, WM is evident in all age groups, even from 4 dpf. However, BF is not developed until larvae start free feeding, and show significant improvement thereafter, with young adults (90 dpf) demonstrating the most well-defined BF. We demonstrate, for the first time, objective WM processes in 4 dpf zebrafish larvae. This suggests that those wishing to study WM in zebrafish may be able to do so from 4 dpf, thus drastically increasing throughput. In addition, we show that zebrafish follow distinct stages of cognitive development and age-related changes during the early developmental period. Finally, our findings indicate distinct WM and BF mechanisms, which may be useful to study for translational purposes.
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Stress, trait impulsivity, and emotional dysregulation are independent predictors of alcohol use and misuse, but little is known about the potential mechanisms that link these risk factors together. To address this issue, we carried out an exploratory cross-sectional study, on UK-based participants. Our preregistered, hypothesised theoretical framework was that emotional dysregulation mediates the association between cumulative lifetime stressor exposure and lifetime alcohol use. We also hypothesised that heightened impulsivity would strengthen these relations. As hypothesised, emotional dysregulation fully mediated the relation between cumulative lifetime stressor exposure and lifetime alcohol use. Several facets of impulsivity moderated these associations. For example, as levels of negative urgency increased, the associations between cumulative lifetime stressor exposure and emotional dysregulation, emotional dysregulation and lifetime alcohol use, and lifetime stress exposure and lifetime alcohol use, via emotional dysregulation, strengthened. These preliminary findings propose a theoretically framed model which integrates several prominent risk-factors for alcohol misuse, extending prior research and generating interesting and novel lines of enquiry for longitudinal and cross-cultural analyses. The findings also highlight the potential clinical utility of screening for lifetime stress exposure while tailoring personalised treatment interventions.