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.

Figure 1

Females show more generalization of context fear than males. (a) Experimental design. (b) Females showed significantly greater freezing than males in the training context (CxtA), and more generalization to CxtB. Both males and females showed low levels of freezing in CxtC. There was no difference in freezing between different test orders (ABC, white background; BAC, dotted background). (c) Males (striped bars) had higher discrimination scores (DS) than females (white bars). Error bars represent SEM. *P<0.05, **P<0.01, ***P<0.001 cf CxtA. ^#P<0.05, ^##P<0.01 cf females.

Figure 2

Preexposure to CxtA reduces generalization of context fear in females. (a) Experimental design. (b) Preexposure to CxtA effectively reduced context generalization to CxtB in females, only with ABC test order (ABC, white background; BAC, dotted background). Males showed increased freezing in CxtA compared with non-preexposed males (P<0.001). (c) Both males (striped bars) and females (white bars) showed strong discrimination when tested first in CxtA (ABC test order), whereas BAC females showed significantly more generalization. Error bars represent SEM. *P<0.05, ***P<0.001 cf CxtA. ^{^}P<0.05, cf ABC test order.

Figure 3

Preexposure to CxtB increases generalization of context fear in males. (a) Experimental design. (b) There were no sex differences in freezing in context. Both males and females showed generalization between CxtA and CxtB. Test order did not affect freezing or generalization (ABC, white background; BAC, dotted background). (c) Discrimination scores did not differ between males (lined bars) and females (white bars). Error bars represent SEM. *P<0.05, **P<0.01, ***P<0.001 cf CxtA.

Figure 4

Sex differences in dorsal hippocampus and amygdala cFos activity during retrieval and generalization of context fear. (a) Both males and females show increased cFos+ cells in CA1 following test in CxtA. Only males show increases in CA1 during generalization test in CxtB. (b) Males but not females show increased cFos positive cells in CA3 during tests in CxtA and CxtB. (c) In DG, males but not females show increased cFos+ cells during memory retrieval in CxtA. (d) In basal amygdala, females showed increased cFos+ cells after retrieval in CxtA and generalization test in CxtB. All data are normalized to naive levels. ⁺P=0.05, *P<0.05, **P<0.01, ***P<0.001 cf same sex naive. Representative images from each group show cFos+ cells.

Figure 5

No sex differences in dorsal hippocampus and amygdala cFos activity during consolidation of context fear conditioning. (a) Both males and females show more cFos+ cells in CA1 after context fear conditioning. (b, c) Neither males nor females show elevated cFos in CA3 (b) or DG (c) after fear conditioning. (d) Males and females show similar cFos activation in basal amygdala after context fear conditioning. All data are normalized to naive levels. Error bars indicate SEM. BA, basal amygdala; CFC, context fear conditioning; DG, dentate gyrus. *P<0.05, **P<0.01 cf same sex naive.