Effect of acute alarm odor exposure and biological sex on generalized avoidance and glutamatergic signaling in the hippocampus of Wistar rats

Abstract

Post-traumatic stress disorder (PTSD) is characterized by the development of paradoxical memory disturbances including intrusive memories and amnesia for specific details of the traumatic experience. Despite evidence that women are at higher risk to develop PTSD, most animal research has focused on the processes by which male rodents develop adaptive fear memory. As such, the mechanisms contributing to sex differences in the development of PTSD-like memory disturbances are poorly understood. In this investigation, we exposed adult male and female Wistar rats to the synthetic alarm odor 2,4,5-trimethylthiazole (TMT) to assess development of generalized fear behavior and rapid modulation of glutamate uptake and signaling cascades associated with hippocampus-dependent long-term memory. We report that female Wistar rats exposed to alarm odor exhibit context discrimination impairments relative to TMT-exposed male rats, suggesting the intriguing possibility that females are at greater risk in developing generalized fear memories. Mechanistically, alarm odor exposure rapidly modulated signaling cascades consistent with activation of the CREB shut-off cascade in the male, but not the female hippocampus. Moreover, TMT exposure dampened glutamate uptake and affected expression of the glutamate transporter, GLT-1 in the hippocampus. Taken together, these results provide evidence for rapid sex-dependent modulation of CREB signaling in the hippocampus by alarm odor exposure which may contribute to the development of generalized fear.

Increased alcohol self-administration following exposure to the predator odor TMT in high stress-reactive female rats

“…TMT elicits innate fear and stress-related behavioral responses including freezing [34,40], immobility [27]; [36] and avoidance behavior [27]; [35,36,41]. Here, bedding was present in the TMT exposure context so that we could examine an additional stress-reactivity behavior, defensive digging [27].…”

“…It is interpreted as a proactive response to stress [29][30][31], such that it reflects an active coping response or fear-related behavior [32] and predator-stress responsiveness [33]. Freezing behavior is a wellcharacterized fear-like behavior that animals have been shown to engage in during TMT exposure [27,[34][35][36]. The present study sought to examine individual differences in stress-reactive behaviors (digging and immobility) during TMT exposure in male and female Long Evans rats to determine whether these individual differences could predict subsequent increases in context reactivity, hyperarousal and anxiety-like behavior and alcohol self-administration.…”

Increased alcohol self-administration following exposure to the predator odor TMT in active coping female rats

“…It is interpreted as a proactive response to stress [29][30][31], such that it reflects an active coping response or fear-related behavior [32] and predator-stress responsiveness [33]. Freezing behavior is a wellcharacterized fear-like behavior that animals have been shown to engage in during TMT exposure [27,[34][35][36]. The present study sought to examine individual differences in stress-reactive behaviors (digging and immobility) during TMT exposure in male and female Long Evans rats to determine whether these individual differences could predict subsequent increases in context reactivity, hyperarousal and anxiety-like behavior and alcohol self-administration.…”

Smell and Stress Response in the Brain: Review of the Connection between Chemistry and Neuropharmacology

“…In view of molecules that stimulate the olfaction, 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) is the main component of fox feces. Therefore, TMT is a predator odor for rodents, and it causes PTSD as a serious stressor [ 13 , 18 , 68 , 69 , 70 , 71 , 72 , 73 , 74 ]. Miyazono et al [ 75 ] found that a mixture of three pyrazine analogues (P-mix) present at high levels in wolf urine induced fear-related responses in mice, which was attenuated by etizolam, an anxiolytic.…”

“…They suggested that this odor may be involved in 4-methylpentanal and hexanal. On the response to odor stress, gender differences are pointed out [ 13 , 18 , 70 , 78 , 79 ]. Harris et al [ 80 ] demonstrated the social defeat paradigm that works in female mice.…”