Reactivity to conditioned threat cues is distinct from exploratory drive in the elevated plus maze

Hilton, Robert; Simpson, Susannah R.; Sherman, Emily R.; Raby-Smith, Will; Azvine, Keemia; Arribas, Maite; Zhou, Jiaqi; Deiana, Serena; Hengerer, Bastian; Cahill, Emma

doi:10.1111/ejn.15870

Cited by 10 publications

(6 citation statements)

References 36 publications

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“…We did not find any relation of vigilance screen behaviour to behaviour in the elevated plus maze, a task widely used to model the avoidance symptoms of anxiety disorders. We recently demonstrated a relative independence of measures from aversive conditioning and the EPM exploration (18), which supports that these tasks reveal different behavioural strategies for dealing with potential threats. Rats have been successfully studied as models for affective state biases in choice behaviours (21–23).…”

Section: Discussionmentioning

confidence: 59%

“…The following day, a vigilance screen was performed where one group were presented with the tone CS twice at a low volume (Low Vol) to reduce its salience. The levels of time spent in the closed arm during the EPM test did not significantly correlate with behaviour at the later Vigilance Screen (P=0.9870), suggesting the two tests measure distinct reactions to threats (18). At the first presentation of the Low Vol CS, freezing responses were significantly lower as a group than those presented a Norm Vol CS as expected (P=0.0083, Fig1c).…”

Section: Resultsmentioning

confidence: 95%

“…The elevated plus maze (EPM) was carried out as described previously (18). In brief, rats were tested for exploration of the open arms for a period of 5 mins each.…”

Section: Elevated Plus Mazementioning

confidence: 99%

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Influence of aversive cue detection sensitivity on extinction in adult male rats

Cahill,

Sherman,

Jollans

et al. 2024

Preprint

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Threat detection prompts reactions classified either as fear (obvious, predictable, immediate threat) or anxiety (ambiguous, sustained, distant threat). Hypervigilance is a state of sensitivity to threatening stimuli and an attentional bias symptomatic of anxiety disorders. In rodents, threat detection can be measured by freezing behaviour and production of ultrasonic vocalisation (USV) alarm calls. The amygdala is classically associated with fear-like responses, whereas the bed nucleus of the stria terminalis (BNST) has been proposed to be preferentially recruited by anxiogenic stimuli. The conditioned responses triggered by aversive cues can be extinguished through repeated exposure of a subject to the threat stimulus but without any aversive reinforcement. The extent of extinction acquisition and consolidation are notedly variable across individuals. It has been reported that NMDA-type glutamate receptor co-agonists, like D-cycloserine, can enhance extinction consolidation. In the experiments herein, the salience of a threat cue was modified to compare the relative activation of the brain vigilance networks to an obvious cue, and to test whether sensitivity to the aversive cue at such a vigilance screen might predict subsequent ability to extinguish conditioned responses. We demonstrated activation of the BNST by a low salience aversive cue. Rats that had the propensity to make alarm ultrasonic vocalisation calls reacted more strongly to aversive cues and had deficits in conditioned freezing extinction. Finally, we demonstrated the potential to enhance extinction consolidation by targeting glycine transmission. Taken together these results demonstrate how threat detection and responses are sensitive to cue salience and can be manipulated by combined pharmacological and behavioural interventions.

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Section: Discussionmentioning

confidence: 59%

Section: Resultsmentioning

confidence: 95%

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Influence of aversive cue detection sensitivity on extinction in adult male rats

Cahill,

Sherman,

Jollans

et al. 2024

Preprint

Self Cite

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“…Research has shown that the recall of aversive memories, such as those associated with conditioned threat cues, can potentiate anxiety-like behavior in rodents. This suggests that subtle cues, reminiscent of microaggressions, can have significant impacts on behavior [111]. By incorporating these cues into rodent models, researchers can better mimic the nuanced social stressors experienced by humans.…”

Section: Study Microaggressions Through Subtle Threat Cuesmentioning

confidence: 99%

Bridging Species and Disciplines: Incorporating Sociological Frameworks into Animal Models of Addiction

Fields

2024

Multidisciplinary Approach for Better Understanding of Addictive Behaviour [Working Title]

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This chapter explores the integration of sociological concepts and frameworks into animal models of addictive behaviors, aiming to enhance cross-species validity and deepen understanding of addiction’s multifaceted biopsychosocial roots. Through an interdisciplinary approach merging sociology and behavioral neuroscience, the investigation examines how experiences of discrimination and constrained agency may contribute to addiction vulnerability. Specifically, chronic social defeat stress’s impact on drug-seeking behaviors is explored, drawing parallels between rodent models and human experiences of racial battle fatigue resulting from daily racial microaggressions. The chapter also delves into how lack of autonomy, social isolation, and perceived loss of control due to discrimination may precipitate substance use as a coping mechanism. Additionally, the influence of social hierarchies, bonding patterns, and intergenerational epigenetic effects on resilience versus susceptibility to addiction is considered. Current methodologies are critically evaluated, with a proposal to enhance ecological validity in animal experiments to better simulate nuanced sociocultural stressors associated with addiction risk. Emphasizing the urgent need for cross-disciplinary collaborations between rodent researchers and social scientists, the chapter advocates for the incorporation of relevant sociological concepts into behavioral assays. Ultimately, the integration of diverse perspectives is crucial for comprehensively addressing the psychosocial and neurobiological dynamics underlying addiction across mammalian species and for developing more effective and equitable prevention and treatment approaches.

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“…Distinct motivations to freeze are evident across assays; freezing on one task will not necessarily predict freezing on another. For example, freezing during context conditioning does not predict freezing on an elevated plus maze (Ahn et al, 2013 ; Hilton et al, 2023 ). Thus, the same mechanisms that lead to freezing during fear conditioning do not necessarily contribute to freezing on more exploratory-based behavioral assays, supporting the observation that multiple neural circuits can trigger this behavioral state (Zelikowsky et al, 2018 ).…”

Section: Box 1: Considerations For Interpreting Measures Of Fear and ...mentioning

confidence: 99%

Understanding the heterogeneity of anxiety using a translational neuroscience approach

Drzewiecki,

Fox

2024

Cogn Affect Behav Neurosci

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Anxiety disorders affect millions of people worldwide and present a challenge in neuroscience research because of their substantial heterogeneity in clinical presentation. While a great deal of progress has been made in understanding the neurobiology of fear and anxiety, these insights have not led to effective treatments. Understanding the relationship between phenotypic heterogeneity and the underlying biology is a critical first step in solving this problem. We show translation, reverse translation, and computational modeling can contribute to a refined, cross-species understanding of fear and anxiety as well as anxiety disorders. More specifically, we outline how animal models can be leveraged to develop testable hypotheses in humans by using targeted, cross-species approaches and ethologically informed behavioral paradigms. We discuss reverse translational approaches that can guide and prioritize animal research in nontraditional research species. Finally, we advocate for the use of computational models to harmonize cross-species and cross-methodology research into anxiety. Together, this translational neuroscience approach will help to bridge the widening gap between how we currently conceptualize and diagnose anxiety disorders, as well as aid in the discovery of better treatments for these conditions.

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Reactivity to conditioned threat cues is distinct from exploratory drive in the elevated plus maze

Abstract: The funder did not have any additional role in study design, data collection and analysis, decision to publish, or preparation of the article. There are no patents, products in development, or marketed products to declare.

Cited by 10 publications

References 36 publications

Influence of aversive cue detection sensitivity on extinction in adult male rats

Influence of aversive cue detection sensitivity on extinction in adult male rats

Bridging Species and Disciplines: Incorporating Sociological Frameworks into Animal Models of Addiction

Understanding the heterogeneity of anxiety using a translational neuroscience approach

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