Environmental variables that ameliorate extinction learning deficits in the 129S1/SvlmJ mouse strain

Cazares, Victor A.; Rodriguez, Genesis; Parent, Rachel; Ouillette, Lara; Glanowska, Katarzyna M.; Moore, Stanford; Murphy, Geoffrey G.

doi:10.1111/gbb.12575

Cited by 12 publications

(9 citation statements)

References 56 publications

(191 reference statements)

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“…This is furthermore corroborated by the finding that the baseline distance traveled was lower in S1 than BL6 mice, which indicates decreased home cage activity at the beginning of the light period. In agreement with this finding, reduced spontaneous locomotion and home cage activity in the S1 strain has been reported before (34)(35)(36). We did not observe spontaneous freezing in the S1 animals (data not shown, but also see no pre-CS habituation during fear conditioning) as food intake measurements were conducted in the home cage to minimize anxiogenic effects during the test.…”

Section: Discussionsupporting

confidence: 93%

Ghrelin receptor agonist MK0677 and overnight fasting do not rescue deficient fear extinction in 129S1/SvImJ mice

Fritz

Pierre²,

Bundel³

et al. 2023

Front. Psychiatry

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The hunger hormone ghrelin has been implicated in the modulation of anxiety- and fear-related behaviors in rodents and humans, while its dysregulation may be associated with psychiatric illness. Along these lines, the ghrelin system has been suggested as a potential target to facilitate fear extinction, which is the main mechanism underlying cognitive behavioral therapy. So far, this hypothesis has not been tested in individuals that have difficulties to extinguish fear. Thus, we investigated pharmacological (ghrelin receptor agonist MK0677) and non-pharmacological (overnight fasting) strategies to target the ghrelin system in the 129S1/SvImJ (S1) mouse strain, which models the endophenotype of impaired fear extinction that has been associated with treatment resistance in anxiety and PTSD patients. MK0677 induced food intake and overnight fasting increased plasma ghrelin levels in S1 mice, suggesting that the ghrelin system is responsive in the S1 strain. However, neither systemic administration of MK0677 nor overnight fasting had an effect on fear extinction in S1 mice. Similarly, our groups previously reported that both interventions did not attenuate fear in extinction-competent C57BL/6J mice. In summary, our findings are in contrast to several studies reporting beneficial effects of GHSR agonism and overnight fasting on fear- and anxiety-related behaviors in rodents. Rather, our data agree with accumulating evidence of divergent behavioral effects of ghrelin system activation and underscore the hypothesis that potential benefits of targeting the ghrelin system in fear extinction may be dependent on factors (e.g., previous stress exposure) that are not yet fully understood.

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Section: Discussionsupporting

confidence: 93%

Ghrelin receptor agonist MK0677 and overnight fasting do not rescue deficient fear extinction in 129S1/SvImJ mice

Fritz

Pierre²,

Bundel³

et al. 2023

Front. Psychiatry

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“…Disturbed sleep has been proposed as a possible confounding factor in the process of fear extinction and, thus, a risk factor for anxiety- and trauma-related disorders 29 , 31 , 54 , 55 . To investigate whether the S1 mouse strain, for which a severe impairment of fear extinction learning has been previously described by different groups 34 , 36 , 37 , 41 – 43 , 56 , shows aberrant sleep patterns at baseline, we examined circadian sleep/wake behaviors of S1 mice in comparison to those of typically extinction-competent BL6 mice. Within the present study, we uncovered profound differences between both mouse strains regarding the diurnal distribution of sleep and wakefulness, but also sleep architecture, spectral EEG features and sleep spindle events.…”

Section: Discussionmentioning

confidence: 99%

“…C57BL/6 (BL6)] 33 , 34 , represents a prototype of this clinical feature 35 . The maladaptive fear phenotype of the S1 mouse strain is furthermore characterized by deficits in safety learning and high susceptibility to fear generalization to ambiguous contexts or cues 36 , 37 , which are also characteristics of anxiety-related disorders 38 , 39 . Moreover, compared to BL6, S1 mice show an anxiety-like phenotype as well as reduced novelty- and reward seeking and an altered neuroendocrine stress response 40 .…”

Section: Introductionmentioning

confidence: 99%

Altered sleep behavior in a genetic mouse model of impaired fear extinction

Fritz

Kreuzer

Altunkaya

et al. 2021

Sci Rep

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Sleep disturbances are a common complaint of anxiety patients and constitute a hallmark feature of post-traumatic stress disorder (PTSD). Emerging evidence suggests that poor sleep is not only a secondary symptom of anxiety- and trauma-related disorders but represents a risk factor in their development, for example by interfering with emotional memory processing. Fear extinction is a critical mechanism for the attenuation of fearful and traumatic memories and multiple studies suggest that healthy sleep is crucial for the formation of extinction memories. However, fear extinction is often impaired in anxiety- and trauma-related disorders—an endophenotype that is perfectly modelled in the 129S1/SvImJ inbred mouse strain. To investigate whether these mice exhibit altered sleep at baseline that could predispose them towards maladaptive fear processing, we compared their circadian sleep/wake patterns to those of typically extinction-competent C57BL/6 mice. We found significant differences regarding diurnal distribution of sleep and wakefulness, but also sleep architecture, spectral features and sleep spindle events. With regard to sleep disturbances reported by anxiety- and PTSD patients, our findings strengthen the 129S1/SvImJ mouse models’ face validity and highlight it as a platform to investigate novel, sleep-focused diagnostic and therapeutic strategies. Whether the identified alterations causally contribute to its pathological anxiety/PTSD-like phenotype will, however, have to be addressed in future studies.

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“…For example, despite lack of extinction C57Bl/6J and 129S1/SvlmJ mice, cued threat memory seems to “fade” with time in males but not in females, as evidenced by reduced freezing during spontaneous recovery compared to the last extinction block. While beyond the scope of the present study, we hope that our findings will guide future work exploring the maximal perimeters required for assessment of threat memory dynamics within each strain (i.e., Cazares et al, 2019; Wimer et al, 1968) in order to better assess of the impacts of sex and estrous cycle. Finally, our experimental design focused on the contributions of estrous cycle to endophenotypes relevant to negative valence systems and offers little insight to sex hormone regulation of behavior in males.…”

Section: Discussionmentioning

confidence: 99%

Sex differences in avoidance behavior and cued threat memory dynamics in mice: Interactions between estrous cycle and genetic background

Ryherd,

Bunce,

Edwards

et al. 2023

Preprint

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Anxiety disorders are the most prevalent mental illnesses worldwide, exhibit high heritability, and affect twice as many women as men. To evaluate potential interactions between genetic background and cycling ovarian hormones on sex differences in susceptibility to negative valence behaviors relevant to anxiety disorders, we assayed avoidance behavior and cued threat memory dynamics in gonadally-intact adult male and female mice across four common inbred mouse strains: C57Bl/6J, 129S1/SVlmJ, DBA/2J, and BALB/cJ. Independent of sex, C57Bl/6J mice exhibited low avoidance but high threat memory, 129S1/SvlmJ mice high avoidance and high threat memory, DBA/2J mice low avoidance and low threat memory, and BALB/cJ mice high avoidance but low threat memory. Within-strain comparisons revealed reduced avoidance behavior in the high hormone phase of the estrous cycle (proestrus) compared to all other estrous phases in all strains except DBA/2J, which did not exhibit cycle-dependent behavioral fluctuations. Robust and opposing sex differences in threat conditioning and extinction training were found in the C57Bl/6J and 129S1/SvlmJ lines, whereas no sex differences were observed in the DBA/2J or BALB/cJ lines. C57Bl/6J males exhibited enhanced acute threat memory, whereas 129S1/SvlmJ females exhibited enhanced sustained threat memory, compared to their sex-matched littermates. These effects were not mediated by estrous cycle stage or sex differences in active versus passive defensive behavioral responses. Our data demonstrate that core features of behavioral endophenotypes relevant to anxiety disorders, such as avoidance and threat memory, are genetically driven yet dissociable and can be influenced further by cycling ovarian hormones.

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Environmental variables that ameliorate extinction learning deficits in the 129S1/SvlmJ mouse strain

Cited by 12 publications

References 56 publications

Ghrelin receptor agonist MK0677 and overnight fasting do not rescue deficient fear extinction in 129S1/SvImJ mice

Ghrelin receptor agonist MK0677 and overnight fasting do not rescue deficient fear extinction in 129S1/SvImJ mice

Altered sleep behavior in a genetic mouse model of impaired fear extinction

Sex differences in avoidance behavior and cued threat memory dynamics in mice: Interactions between estrous cycle and genetic background

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