Sexually divergent expression of active and passive conditioned fear responses in rats

Gruene, Tina; Flick, Katelyn M; Stefano, Alexis; Shea, Stephen D.; Shansky, Rebecca M.

doi:10.7554/elife.11352

Cited by 324 publications

(358 citation statements)

References 24 publications

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“…However, failure of training to correlate with extinction in SEFL females introduces the possibility they are expressing their response to foot shock through non-freezing behaviors. For instance, darting is described as a coping mechanism that correlates with extinction retention in female rats (67). Alternatively, females could be displaying active avoidance/escape behaviors.…”

Section: Discussionmentioning

confidence: 99%

Susceptibility and Resilience to Posttraumatic Stress Disorder–like Behaviors in Inbred Mice

Sillivan

Joseph

Jamieson

et al. 2017

Biological Psychiatry

100

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Background The limited neurobiological understanding of PTSD has been partially attributed to the need for improved animal models. Stress-enhanced fear learning (SEFL) in rodents recapitulates many PTSD-associated behaviors, including stress-susceptible (SS) and –resilient (SR) subgroups in outbred rats. Identification of subgroups requires additional behavioral phenotyping, a confound to mechanistic studies. Methods We employed a SEFL paradigm in inbred male and female C57BL/6 that combines acute stress with fear conditioning to precipitate “traumatic” memories. Extinction and long-term retention of extinction were examined after SEFL. Further characterization of SEFL effects on male mice was performed with additional behavioral tests, determination of regional activation by Fos immunofluorescence and RNA-sequencing of the basolateral amygdala (BLA). Results Stressed animals displayed persistently elevated freezing during extinction. While more uniform in females, SEFL produced male subgroups with differential susceptibility that were identified without post-training phenotyping. Additional phenotyping of males revealed PTSD-associated behaviors, including extinction-resistant fear memory, hyperarousal, generalization and dysregulated corticosterone in SS males. Altered Fos activation was also seen in the infralimbic cortex and BLA of SS males after remote memory retrieval. Key behavioral outcomes, including susceptibility, were replicated by two independent laboratories. RNA-sequencing of the BLA revealed transcriptional divergence between the male subgroups, including genes with reported polymorphic association to PTSD patients. Conclusions This SEFL model provides a tool for development of PTSD therapeutics that is compatible with the growing number of mouse-specific resources. Furthermore, use of an inbred strain allows for investigation into epigenetic mechanisms that are expected to critically regulate susceptibility and resilience.

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Section: Discussionmentioning

confidence: 99%

Susceptibility and Resilience to Posttraumatic Stress Disorder–like Behaviors in Inbred Mice

Sillivan

Joseph

Jamieson

et al. 2017

Biological Psychiatry

100

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“…The answer to this question may lie with evidence that female and male rodents exhibit different behavioral repertoires when presented with a threat. Several studies have shown that females show superior performance when active responses are measured whether it be classical eyeblink conditioning (Wood and Shors 1998;), fear conditioning (Gruene et al 2015b), or avoidance tasks (Steenbergen et al 1990;Dalla et al 2008). Thus, it is possible that the tendency for females to engage in more active fear responses obscures reliable sex differences in conditioning and/or extinction when freezing behavior is the only measure.…”

Section: Discussionmentioning

confidence: 99%

“…In the case of freezing behavior, differences in activity levels between males and females might complicate the interpretation of experiments which use inactivity as an index of fear. This issue is highlighted by a recent observation that female rats exhibit an active conditioned fear response (i.e., darting) that is not frequently seen in males (Gruene et al 2015b). To further characterize the effect of sex on measures of fear conditioning and extinction, in the current study we compared levels of fear conditioning and extinction in males and females using both freezing behavior and fearpotentiated startle as measures.…”

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confidence: 97%

Response-specific sex difference in the retention of fear extinction

Voulo

Parsons

2017

Learn. Mem.

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Fear conditioning studies in rodents allow us to assess vulnerability factors which might underlie fear-based psychopathology such as post-traumatic stress disorder (PTSD). Despite PTSD being more prevalent in females than males, very few fear conditioning studies in rodents have tested females. Our study assessed fear conditioning and extinction in male and female rats using both fear-potentiated startle and freezing behavior as measures. Rats were trained to fear cues that predicted the occurrence of shock and then subsequently exposed to an extinction training procedure where the cue was presented repeatedly in the absence of shock. Retention of the extinction memory was assessed the next day. Our results showed that females exhibited less retention of fear extinction, but only when measured by fear-potentiated startle. Our results highlight the importance of using multiple indices of fear behavior, particularly when comparing sexes on measures of extinction learning.Not all individuals who experience trauma during their lifetime will develop post-traumatic stress disorder (PTSD). One of the greatest risk factors for developing this disorder is being female, with the lifetime prevalence rate twice as high for women as it is for men (Kessler et al. 1995;Kilpatrick et al. 2013). Fear conditioning studies in rodents allow us to study the behavioral and neural mechanisms that may underlie PTSD (Parsons and Ressler 2013), yet very few fear conditioning studies in rodents have used females as subjects (Lebron-Milad and Milad 2012). Despite the increased prevalence of PTSD and other fear and anxiety-based disorders in females, nonhuman animal studies testing for sex differences in fear conditioning have largely failed to capture this difference.Fear conditioning studies typically use a procedure in which a discrete cue (e.g., auditory stimulus) signals the occurrence of an aversive stimulus, usually a brief shock. Under normal circumstances, animals learn to fear the discrete cue associated with shock and will also learn to fear the context (i.e., place) in which shock occurs. A handful of studies have directly compared animals of both sexes on tests of cued and contextual fear conditioning. Some of these reports have shown that while males and females exhibit equivalent levels of fear conditioning to discrete cues (Maren et al. 1994;Baran et al. 2009;Milad et al. 2009a;Barker and Galea 2010;Gruene et al. 2015a;Fenton et al. 2016), males often show evidence of better contextual conditioning (Maren et al. 1994;Chang et al. 2009;Barker and Galea 2010). Other studies have tested for sex differences in fear extinction learning, a form of learning through which animals learn to inhibit responding to cues that once signaled an aversive event. Over the last several years, the study of fear extinction has received considerable attention (Milad and Quirk 2012) due in part to the fact that humans with PTSD display impaired extinction (Milad et al. 2009b;Norrholm et al. 2011). Recent findings in rodents are mixed with regard t...

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“…It should be noted that, when considering fear as expressed by freezing, these studies have been restricted to males. Recent studies indicate that females employ active avoidance responses and males shift to these when the size of the chamber is increased (Gruene et al, 2015).…”

Section: Emotional Contagion: Social Modulation Of Fear and Painmentioning

confidence: 99%