Sex differences in behavioral responses during a conditioned flight paradigm

Borkar, Chandrashekhar D.; Дорофейкова, Мария; Le, Quan-Son Eric; Vutukuri, Rithvik; Vo, Catherine; Hereford, Daniel; Resendez, Alexis; Basavanhalli, Samhita; Sifnugel, Natalia; Fadok, Jonathan P.

doi:10.1016/j.bbr.2020.112623

Cited by 37 publications

(26 citation statements)

References 43 publications

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“…This could be due to scoring differences as original reports used an automated detection method (Gruene et al, 2015). Conversely, other work shows that female mice actually exhibit increased freezing in the SCS paradigm, though the average speed of male and female mice during the SCS did not differ (Borkar et al, 2020). We do report here that female rats frequently show increased freezing during SCS habituation and conditioning, although the effects were small and not always present across experiments.…”

Section: Discussionmentioning

confidence: 90%

Behavioral and brain mechanisms mediating conditioned flight behavior in rats

Totty

Warren

Huddleston

et al. 2021

Preprint

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Environmental contexts and associative learning can inform animals of potential threats, though it is currently unknown how contexts bias defensive transitions. Here we investigated context-dependent flight responses in the Pavlovian serial-compound stimulus (SCS) paradigm. We show here that SCS-evoked flight behavior in male and female rats is dependent on contextual fear. Flight was reduced in the conditioning context after context extinction and could be evoked in a different shock-associated context. Although flight was exclusive to white noise stimuli, it was nonetheless associative insofar as rats that received an equal number of unpaired USs did not show flight-like behavior. Finally, we found that inactivation of either the central nucleus of the amygdala (CeA) or bed nucleus of the stria terminalis (BNST) attenuated both contextual fear and flight responses. This work demonstrates that contextual fear summates with cued and innate fear to drive a high fear state and freeze-to-flight transitions.

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Section: Discussionmentioning

confidence: 90%

Behavioral and brain mechanisms mediating conditioned flight behavior in rats

Totty

Warren

Huddleston

et al. 2021

Preprint

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“…For example, depending on strain and precise experimental protocol, no sex difference in contextual fear conditioning (208); stronger context fear conditioning and more generalization to a similar context have been reported in females compared to males (209), whilst extinction of conditioned freezing to a tone was faster in males than in females (210). Using a serial compound conditioned stimulus (tone and white noise that elicits clear transitions between freezing and flight behaviors within individual subjects) females exhibited more freezing behavior than males although there was no difference between the sexes in flight behavior (211).…”

Section: Conditioned Fear and Fear Potentiated Startlementioning

confidence: 98%

Effect of Estrous Cycle on Behavior of Females in Rodent Tests of Anxiety

2021

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Anxiety disorders are more prevalent in women than in men. In women the menstrual cycle introduces another variable; indeed, some conditions e.g., premenstrual syndrome, are menstrual cycle specific. Animal models of fear and anxiety, which form the basis for research into drug treatments, have been developed almost exclusively, using males. There remains a paucity of work using females and the available literature presents a confusing picture. One confound is the estrous cycle in females, which some authors consider, but many do not. Importantly, there are no accepted standardized criteria for defining cycle phase, which is important given the rapidly changing hormonal profile during the 4-day cycle of rodents. Moreover, since many behavioral tests that involve a learning component or that consider extinction of a previously acquired association require several days to complete; the outcome may depend on the phase of the cycle on the days of training as well as on test days. In this article we consider responsiveness of females compared to males in a number of commonly used behavioral tests of anxiety and fear that were developed in male rodents. We conclude that females perform in a qualitatively similar manner to males in most tests although there may be sex and strain differences in sensitivity. Tests based on unconditioned threatening stimuli are significantly influenced by estrous cycle phase with animals displaying increased responsiveness in the late diestrus phase of the cycle (similar to the premenstrual phase in women). Tests that utilize conditioned fear paradigms, which involve a learning component appear to be less impacted by the estrous cycle although sex and cycle-related differences in responding can still be detected. Ethologically-relevant tests appear to have more translational value in females. However, even when sex differences in behavior are not detected, the same outward behavioral response may be mediated by different brain mechanisms. In order to progress basic research in the field of female psychiatry and psychopharmacology, there is a pressing need to validate and standardize experimental protocols for using female animal models of anxiety-related states.

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“…The understanding of individual differences in fear responses in females is also confounded by sex differences in phenotypic expression of fear. While Pavlovian fear conditioning and extinction in rodents are traditionally measured in terms of freezing, emerging studies show that females display a different repertoire of fear responses compared to their male counterparts (LeDoux, 1994;Shumake et al, 2014;Gruene et al, 2015a,b;Borkar et al, 2020). Female rodents usually exhibit less freezing than males during cued fear learning, conventionally understood as impaired learning, but this interpretation may be confounded by more recent data showing females exhibit darting responses to fear more often than males (Baran et al, 2009;Gruene et al, 2015a;Colom-Lapetina et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Individual Differences in Conditioned Fear and Extinction in Female Rats

Tryon

Kellis

Kaigler

et al. 2021

Front. Behav. Neurosci.

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The inability to extinguish a traumatic memory is a key aspect of post-traumatic stress disorder (PTSD). While PTSD affects 10–20% of individuals who experience a trauma, women are particularly susceptible to developing the disorder. Despite this notable female vulnerability, few studies have investigated this particular resistance to fear extinction observed in females. Similar to humans, rodent models of Pavlovian fear learning and extinction show a wide range of individual differences in fear learning and extinction, although female rodents are considerably understudied. Therefore, the present study examined individual differences in fear responses, including freezing behavior and ultrasonic vocalizations (USVs), of female Long–Evans rats during acquisition of fear conditioning and cued fear extinction. Similar to prior studies in males, female rats displayed individual variation in freezing during cued fear extinction and were divided into extinction competent (EC) and extinction resistant (ER) phenotypes. Differences in freezing between ER and EC females were accompanied by shifts in rearing during extinction, but no darting was seen in any trial. Freezing behavior during fear learning did not differ between the EC and ER females. Vocalizations emitted in the 22 and 50 kHz ranges during fear learning and extinction were also examined. Unlike vocalizations seen in previous studies in males, very few 22 kHz distress vocalizations were emitted by female rats during fear acquisition and extinction, with no difference between ER and EC groups. Interestingly, all female rats produced significant levels of 50 kHz USVs, and EC females emitted significantly more 50 kHz USVs than ER rats. This difference in 50 kHz USVs was most apparent during initial exposure to the testing environment. These results suggest that like males, female rodents show individual differences in both freezing and USVs during fear extinction, although females appear to vocalize more in the 50 kHz range, especially during initial periods of exposure to the testing environment, and emit very few of the 22 kHz distress calls that are typically observed in males during fear learning or extinction paradigms. Overall, these findings show that female rodents display fear behavior repertoires divergent from males.

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Sex differences in behavioral responses during a conditioned flight paradigm

Cited by 37 publications

References 43 publications

Behavioral and brain mechanisms mediating conditioned flight behavior in rats

Behavioral and brain mechanisms mediating conditioned flight behavior in rats

Effect of Estrous Cycle on Behavior of Females in Rodent Tests of Anxiety

Individual Differences in Conditioned Fear and Extinction in Female Rats

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