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Electrifying extinction: how transcranial direct current stimulation sparks fear reduction in mice
Boek - Dissertatie
Post-traumatic stress disorder is a debilitating psychiatric disorder which can arise after experiencing or witnessing a traumatic event. Trauma-based psychotherapy is recommended as a first-line treatment and aims to facilitate the processing of the traumatic event using cognitive and exposure-based techniques. However, not all patients achieve long-term remission and remain symptomatic. This highlights the need for novel treatment strategies to improve the efficacy of trauma-based psychotherapies. In this context, transcranial direct current stimulation (tDCS) received considerable interest lately. In this doctoral thesis, we aim to gain a better understanding into the potential of tDCS to facilitate exposure-based psychotherapy, using the fear extinction paradigm in mice as a preclinical model.
In a first part of this thesis, we elaborate in a technical chapter on how tDCS can be applied in mice and provide an overview of distinct experimental procedures. Whereas the described procedures intrinsically follow the same methodology, they differ in whether mice are awake or under general anesthesia, or whether they can freely move or remain restrained during stimulation. We proposed the tDCS procedure in freely moving mice to limit interactions with anaesthetic compounds and to avoid restrained stress. While we show that it is feasible to conduct tDCS in freely moving, the tDCS procedure and stimulation parameters could be further optimized upon experimental needs. Nevertheless, interactions with anaesthetic compounds or stress cannot be fully avoided. Moreover, further validation of the freely moving tDCS procedure, and direct comparison between the distinct procedures may be useful.
For the tDCS experiments conducted in this thesis, mice were single housed to avoid cage mates to damage the cranial implant. However, single housing of mice is a highly debated topic. In a second part of the thesis, we sought to explore whether prolonged single housing of male mice affects animal welfare and stress-related behavioral and physiological outcome measures. We therefore studied the effects of single housing on exploratory activity, anxiety-like behavior, fear memory processing and HPA-axis activity and compared the effects to pair housing or pair housing with a cage divider. Interestingly, the results of this study did not provide evidence for robust differences in exploratory activity, anxiety and fear memory processing in male mice that were single housed, pair housed or pair housed with a cage divider. As such, the results suggest no impact of single housing on stress-related behavioral and physiological outcome measures. The latter is an important finding for our tDCS experiments, in which the effects of tDCS on similar outcome measures were studied.
In the last part of the thesis, we scrutinized the potential of tDCS over the prefrontal cortex to facilitate exposure-based psychotherapy using the auditory fear extinction paradigm in mice. In a first series of experiments, we focused on the effects of a single session of anodal tDCS (0,2 mA, 20 min) on auditory fear extinction, when performed immediately before or after extinction training. In both experimental conditions, no significant effect of anodal tDCS on the short- and long-term retention of auditory fear extinction was observed. Moreover, we cannot draw conclusions regarding the role of the timing of tDCS relative to extinction training. Since more robust and long-lasting effects could be expected with a repeated stimulation protocol, we further explored the effects of repeated anodal tDCS (0.2 mA, 20 min, 2x/day). In this second series of experiments, we used several protocols of auditory fear conditioning and extinction to investigate the boundary conditions under which a facilitation of fear extinction could be observed. When the intensity of fear conditioning was high, a significant effect of repeated anodal tDCS on the acquisition of extinction and the short-term retention of auditory fear extinction was observed. These findings suggest that repeated anodal tDCS can augment the acquisition rate and short-term retention of auditory fear extinction in mice. Moreover, under the same conditions of conditioning, we found that tDCS may have long-lasting effects on generalized fear responses induced by contextual cues. Although these findings are promising, the mechanism-of-action underlying these effects should be further scrutinized.
Altogether, we showed for the first time that repeated anodal tDCS over the prefrontal cortex can facilitate auditory fear extinction in mice. Additional studies are necessary to identify the stimulation parameters that may yield long-term effects on the retention of fear extinction, to explore whether similar results can be obtained in a model of impaired extinction and to evaluate the clinical relevance for PTSD treatment.
In a first part of this thesis, we elaborate in a technical chapter on how tDCS can be applied in mice and provide an overview of distinct experimental procedures. Whereas the described procedures intrinsically follow the same methodology, they differ in whether mice are awake or under general anesthesia, or whether they can freely move or remain restrained during stimulation. We proposed the tDCS procedure in freely moving mice to limit interactions with anaesthetic compounds and to avoid restrained stress. While we show that it is feasible to conduct tDCS in freely moving, the tDCS procedure and stimulation parameters could be further optimized upon experimental needs. Nevertheless, interactions with anaesthetic compounds or stress cannot be fully avoided. Moreover, further validation of the freely moving tDCS procedure, and direct comparison between the distinct procedures may be useful.
For the tDCS experiments conducted in this thesis, mice were single housed to avoid cage mates to damage the cranial implant. However, single housing of mice is a highly debated topic. In a second part of the thesis, we sought to explore whether prolonged single housing of male mice affects animal welfare and stress-related behavioral and physiological outcome measures. We therefore studied the effects of single housing on exploratory activity, anxiety-like behavior, fear memory processing and HPA-axis activity and compared the effects to pair housing or pair housing with a cage divider. Interestingly, the results of this study did not provide evidence for robust differences in exploratory activity, anxiety and fear memory processing in male mice that were single housed, pair housed or pair housed with a cage divider. As such, the results suggest no impact of single housing on stress-related behavioral and physiological outcome measures. The latter is an important finding for our tDCS experiments, in which the effects of tDCS on similar outcome measures were studied.
In the last part of the thesis, we scrutinized the potential of tDCS over the prefrontal cortex to facilitate exposure-based psychotherapy using the auditory fear extinction paradigm in mice. In a first series of experiments, we focused on the effects of a single session of anodal tDCS (0,2 mA, 20 min) on auditory fear extinction, when performed immediately before or after extinction training. In both experimental conditions, no significant effect of anodal tDCS on the short- and long-term retention of auditory fear extinction was observed. Moreover, we cannot draw conclusions regarding the role of the timing of tDCS relative to extinction training. Since more robust and long-lasting effects could be expected with a repeated stimulation protocol, we further explored the effects of repeated anodal tDCS (0.2 mA, 20 min, 2x/day). In this second series of experiments, we used several protocols of auditory fear conditioning and extinction to investigate the boundary conditions under which a facilitation of fear extinction could be observed. When the intensity of fear conditioning was high, a significant effect of repeated anodal tDCS on the acquisition of extinction and the short-term retention of auditory fear extinction was observed. These findings suggest that repeated anodal tDCS can augment the acquisition rate and short-term retention of auditory fear extinction in mice. Moreover, under the same conditions of conditioning, we found that tDCS may have long-lasting effects on generalized fear responses induced by contextual cues. Although these findings are promising, the mechanism-of-action underlying these effects should be further scrutinized.
Altogether, we showed for the first time that repeated anodal tDCS over the prefrontal cortex can facilitate auditory fear extinction in mice. Additional studies are necessary to identify the stimulation parameters that may yield long-term effects on the retention of fear extinction, to explore whether similar results can be obtained in a model of impaired extinction and to evaluate the clinical relevance for PTSD treatment.
Aantal pagina's: 270
Jaar van publicatie:2023
Toegankelijkheid:Open