Sherman, E. R. | bioRxiv Science

bioRxiv2024

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

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. HIGHLIGHTS-Auditory cue at low salience revealed attentional bias unrelated to maze behaviour -Low salience cue recruited activation of the BNST -Alarm call vocaliser rats had deficit in extinction consolidation -GlyT1 inhibition enhanced extinction consolidation

neuroscience↗

bioRxiv2022

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

Fear and anxiety are adaptive states that allow humans and animals alike to respond appropriately to threatening cues in their environment. Commonly used tasks for studying behaviour akin to fear and anxiety in rodent models are pavlovian threat conditioning and the elevated plus maze (EPM) respectively. In threat conditioning the rodents learn to associate an aversive event with a specific stimulus or context. The learnt association between the two stimuli (the memory) can then be recalled by re-exposing the subject to the conditioned stimulus. The elevated plus maze is argued to measure the agoraphobic avoidance of the brightly lit open maze arms in crepuscular rodents. These two tasks have been used extensively, yet research into whether they interact is scarce. We investigated whether recall of an aversive memory, across contextual, odour or auditory modalities, would potentiate anxiety-like behaviour in the elevated plus maze. The data did not support that memory recall, even over a series of timepoints, could influence EPM behaviour. Furthermore, there was no correlation between EPM behaviour and conditioned freezing in independent cohorts tested in the EPM before or after auditory threat conditioning. Further analysis found the production of 22kHz ultrasonic vocalisations revealed the strongest responders to a conditioned threat cue. These results are of particular importance for consideration when using the EPM and threat conditioning to identify individual differences, and the possibility to use the tasks in batteries of tests without cross-task interference.

neuroscience↗