Sex Differences in Context Fear Generalization and Recruitment of Hippocampus and Amygdala during Retrieval

Abstract

Anxiety disorders are commonly associated with increased generalization of fear from a stress- or trauma-associated environment to a neutral context or environment. Differences in context-associated memory in males and females may contribute to increased susceptibility to anxiety disorders in women. Here we examined sex differences in context fear generalization and its neural correlates. We observed stronger context fear conditioning and more generalization of fear to a similar context in females than males. In addition, context preexposure increased fear conditioning in males and decreased generalization in females. Accordingly, males showed stronger cFos activity in dorsal hippocampus during memory retrieval and context generalization, whereas females showed preferential recruitment of basal amygdala. Together, these findings are consistent with previous research showing that hippocampal activity correlates with reduced context fear generalization. Differential competition between hippocampus and amygdala-dependent processes may thus contribute to sex differences in retrieval of context fear and greater generalization of fear-associated memory.

Memory deficits in males and females long after subchronic immune challenge

“…Floor example, after chronic stress, males but not females showed ongoing microglial activation in basolateral amygdala (Bollinger, Collins, Patel, & Wellman, 2017). Alternatively, sex differences in strategy and mechanisms of fear memory formation may mediate differential susceptibility of males to disruption by prior Poly I:C (Keiser et al, 2017;Shansky, 2018). Fear conditioning triggers sex-specific patterns of activation across brain regions (Keiser et al, 2017;Lebron-Milad et al, 2012) and signaling mechanisms (Keiser & Tronson, 2015;Mizuno & Giese, 2010).…”

“…Individual housing in mice prevents fighting-induced stress (Meakin et al, 2013) and is ethologically appropriate for males and females (Becker & Koob, 2016). Individual housing is suitable for testing novel object recognition (Vogel-Ciernia & Wood, 2015) and contextual fear conditioning (Keiser et al, 2017) and follows the University of Michigan Institutional Care and use Committee policies on managing fighting in mice. The facility is ventilated with constant air exchange (60 m 3 / h), temperature (22 ±1°C), and humidity (55±10%) with a standard 12 h light-dark cycle.…”

Enduring and sex-specific changes in hippocampal gene expression after a subchronic immune challenge

“…All mice were individually housed with ad libitum access to standard mouse chow and water as individual housing in mice prevents fighting-induced stress in males (Meakin et al, 2013) and is ethologically appropriate for males and females (Becker and Koob, 2016). The facility is ventilated with constant air exchange (60 m 3 / h), temperature (22 ±1°C), and humidity (55±10%) with a standard 12 h light-dark cycle (Keiser et al, 2017). One month prior to collection of tissue, all animals were tested on context fear conditioning anxiety-like behavior, and depression-like behavior.…”

Assaying Fear Memory Discrimination and Generalization: Methods and Concepts

“…Another point of consideration when designing fear generalization experiments are sex differences. There is now accumulating evidence to support a role for biological sex as an interacting variable in fear discriminant and generalized responses (Asok et al., ; Foilb, Bals, Sarlitto, & Christianson, ; Keiser et al., ; Lynch et al., ). As there is a renewed call for considering sex as a biological variable in behavioral neuroscience (Shansky, ; Shansky & Woolley, ), it is recommended that assays for fear generalization and discrimination are conducted using both male and female animals.…”