Sex and estrous cycle differences in immediate early gene activation in the hippocampus and the dorsal striatum after the cue competition task

Abstract

The hippocampus and dorsal striatum are important structures involved in place and response learning strategies respectively. Both sex and estrous cycle phase differences in learning strategy preference exist following cue competition paradigms. Furthermore, significant effects of sex and learning strategy on hippocampal neural plasticity have been reported. However, associations between learning strategy and immediate early gene (IEG) expression in the hippocampus and dorsal striatum are not completely understood. In the current study we investigated the effects of sex and estrous cycle phase on strategy choice and IEG expression in the hippocampus and dorsal striatum of rats following cue competition training in the Morris water maze. We found that proestrous rats were more likely to choose a place strategy than non-proestrous or male rats. Although male cue strategy users travelled greater distances than the other groups on the first day of training, there were no other sex or strategy differences in the ability to reach a hidden or a visible platform. Female place strategy users exhibited greater zif268 expression and male place strategy users exhibited greater cFos expression compared to all other groups in CA3. Furthermore, cue strategy users had greater expression of cFos in the dorsal striatum than place strategy users. Shorter distances to reach a visible platform were associated with less activation of cFos in CA3 and CA1 of male place strategy users. Our findings indicate multiple differences in brain activation with sex and strategy use, despite limited behavioral differences between the sexes on this cue competition paradigm.

Sex differences in hippocampal cognition and neurogenesis

“…In contrast, female rats relied more on landmark cues during non-proestrous phases (lower levels of estradiol), and a place strategy during the proestrous phase (higher estradiol levels; [145]). This is consistent with other studies showing that higher levels of estradiol are associated with a place strategy and lower levels of estradiol with response strategies in female rats [63,134,146,147]. These sex differences in the preference of the two learning strategies suggest that males and females may rely on different brain regions during spatial training, and may contribute to sex differences in performance during spatial navigation.…”

“…4). Yagi et al [147] found that in the CA3 male place learners showed greater cfos expression, while female place learners showed greater zif268 expression. Intriguingly, there were sex by strategy use differences in activation with female place strategy users showing greater zif268 expression but less cfos expression in the CA3 compared to cue strategy users.…”

“…As described in the previous section ('Sex differences in learning strategy'), males and females have different tendencies to rely on the hippocampus-dependent place strategy or the striatum-dependent response strategy. Indeed, a sex difference favouring males exists in the standard reference memory version of the Morris water maze task; but there is no sex difference observed during a cue competition task in which subjects can use both the place and response strategy to solve the task [147]. Furthermore, the environmental cues within the task can dictate whether sex differences in performance are seen.…”

“…4 Summary for sex and strategy differences in different (zif268, cfos) immediate early gene (IEG) expression in the hippocampus 90 min after memory retrieval in different hippocampus-dependent tasks (data compiled from [109,147]). Female place strategy users have greater zif268 expression in the CA3 compared to female response strategy users and males, while male place strategy users have greater cfos expression in the CA3 compared to all other groups after a cue competition task [147] Studies examining learning after stressful experiences show sex differences in performance [162,163]. Repeated restraint stress (21 days) reduces dendritic complexity in the apical or basal dendrites of CA3 pyramidal neurons of males and females, respectively [73].…”

“…These results suggest that greater number of zif268-expressing CA3 pyramidal neurons in response to memory retrieval in female compared to male rats, may help recruit LTP, as zif268 is strongly associated with LTP. Intriguingly, changes in cfos expression after spatial memory retrieval are seen across the estrous cycle with rats in proestrous having greater cfos expression in the dentate gyrus than rats not in proestrus [147]. While a few studies have examined sex differences in the expression of cfos and zif268, no studies have been conducted using Arc to determine underlying mechanisms of sex differences in spatial learning ability, or Arc expression of newly produced neural dendrites in the dentate gyrus, which is a clear gap in the literature.…”