Heather A. Bimonte

Estradiol facilitates performance as working memory load increases

A water-escape version of the radial-arm maze was used to assess rat spatial working memory performance. Intact females and ovariectomized females receiving a physiologically low dose, physiologically moderate dose or no estradiol replacement were studied. Subjects were given seven trials a day for 12 days. Females receiving moderate dose estradiol made fewer errors than the other three groups during the latter portion of testing. As trials progressed within a session, the elements of information to be remembered increased. Assessment of individual trials revealed that when the demand on an animals working memory system was limited to one to four elements of information, the three groups with estrogen (including intact females) maintained successful performance, whereas the ovariectomized females made more errors. However, when the demand on an animals working memory system was increased to six elements of information, only the moderate dose estradiol females maintained successful performance. These data suggest that, although moderate levels of estradiol replacement are the most beneficial for working memory function, even low-dose estradiol replacement can act to protect working memory systems from the decline seen with the removal of ovarian hormones.

In two species, females exhibit superior working memory and inferior reference memory on the water radial-arm maze

Male and female mice and rats were tested on a water escape version of the radial-arm maze designed to measure working and reference memory. In both species, females exhibited superior working memory during acquisition, and were better able to handle a higher memory load. However, male mice and rats exhibited better reference memory than females during the asymptotic portion of testing. Our data suggest that females may be better at working memory when both working and reference memory information must be learned simultaneously, and males better at reference memory when it has been differentiated from working memory.

Sex differences in vicarious trial-and-error behavior during radial arm maze learning

We investigated sex differences in VTE behavior in rats during radial arm maze learning. Females made more VTEs than males, although there were no sex differences in learning. Further, VTEs and errors were positively correlated during the latter testing sessions in females, but not in males. This sex difference may be a reflection of differences between the sexes in conflict behavior or cognitive strategy while solving the maze.

Differential learning strategies in spatial and nonspatial versions of the Morris water maze in the C57BL/6J inbred mouse strain

We recently developed a new nonspatial version of the Morris water maze that requires the use of four visually distinct intra-maze patterns to efficiently locate a hidden platform. The nonspatial version was designed to match the spatial version on complexity of cue usage, and differs only on spatiality of cues, thereby allowing more meaningful comparisons between the two versions. Following a previous experiment that demonstrated nonspatial learning with the BXSB inbred mouse strain, C57 inbred mice were tested in this study. They received spatial and nonspatial training in a counter-balanced order so that Test Order and information transfer could be assessed. Subjects that received spatial training first had superior performance in both the spatial and the nonspatial tasks when compared to mice that received nonspatial training first. The mice that received spatial training first used extra-maze cues as a spatial strategy. However, during nonspatial testing they did not use the intra-maze cues to locate the platform; instead, the mice used an egocentric strategy of circling through the platform annulus. Subjects that received spatial testing first were superior on the nonspatial task to those subjects that received nonspatial training first. Moreover, subjects that received nonspatial testing first were unable to learn the spatial version. Overall, C57 mice can learn both the spatial and nonspatial versions of the Morris maze presented here; however, the nonspatial version is more difficult and is solved using an egocentric strategy.

Spatial ability of XY sex-reversed female mice

Perinatal gonadal hormones significantly affect subsequent sex differences in reproductive and non-reproductive behaviors in rodents. However, the influence of the sex chromosomes on these behaviors has been largely ignored. To assess the influence of the non-pseudoautosomal region of the Y chromosome, C57BL/JEi male and female mice and mice from the C57BL/6JEi-Y(POS) consomic strain were given behavioral tests known to distinguish males from females. The C57BL/6JEi-Y(POS) strain contains sex-reversed XY-females which, when compared to their XX-female siblings, allow assessment of the influence of the Y chromosome in a female phenotype. XX-females and XY-females did not differ on open-field activity, the Lashley maze, or active avoidance learning, but XY-females were significantly better than XX-females on the Morris hidden platform spatial maze. These findings suggest that males may have both a genetic and a hormonal mechanism to ensure visuospatial superiority.

Spatial and nonspatial Morris maze learning: impaired behavioral flexibility in mice with ectopias located in the prefrontal cortex.

About half of BXSB/MpJ-Yaa (BXSB) mice have neocortical ectopias (misplaced clusters of neurons located in layer I of cortex). Previous behavioral studies have suggested that ectopic mice have superior spatial, but equivalent nonspatial, reference memory learning. However, since spatial and nonspatial learning were not assessed in the same apparatus and with the same testing procedure, it is unclear if this conclusion is accurate. We have created a new nonspatial Morris maze for mice that differs from the spatial task only in the type of cues that must be utilized to efficiently locate the platform (intra-maze black/white patterns vs. extra-maze room cues) and does not differ in the level of task complexity or the presence of objects within the maze. Ectopic mice were very good in utilizing extra-maze cues when learning the spatial version and in utilizing intra-maze cues when learning the nonspatial version of the Morris maze, while non-ectopics were not, suggesting that ectopics have superior spatial and nonspatial reference memory. Ectopias in BXSB mice are usually located in prefrontal and/or motor cortex. The prefrontal cortex is involved in behavioral flexibility (e.g. being able to easily switch from using spatial to nonspatial cues). Only ectopic mice with ectopias specifically located in the prefrontal region of cortex demonstrated difficulty switching from using extra-maze to intra-maze cues and vice versa. Thus, the presence of one or more ectopias in the prefrontal region of cortex disrupted one of the normal functions of the prefrontal cortex.

Perceptual auditory gap detection deficits in male BXSB mice with cerebrocortical ectopias

Underlying impairments in rapid auditory processing may contribute to disrupted phonological processing, which in turn characterizes developmental language impairment (LI). Identification of a neurobiological feature of LI that is associated with auditory deficits would further support this model. Accordingly, we found that adult male rats with induced cortical malformations were impaired in rapid auditory processing. Since 40–60% of BXSB mice exhibit spontaneous focal cerebrocortical ectopias (as seen in dyslexics brains), we assessed auditory gap detection in adult male BXSB mice. Ectopic mice were significantly worse than non-ectopics in detecting a 5 ms silent gap, but were not significantly impaired at longer gap durations (10–100 ms). Our results confirm that focal cortical malformations are associated with impairments in rapid auditory processing.

Ovarian hormones can organize the rat corpus callosum in adulthood.

The rat corpus callosum (CC) is larger in males than females, and is responsive to hormone manipulations during development. Previous data suggest that CC sensitivity to testosterone ends by postnatal day 8 (P8). In contrast, responsivity to ovarian hormones extends as late as P25. The current series of experiments investigates whether ovarian hormone effects on the callosum are permanent and whether CC sensitivity to ovarian hormones extends beyond P25. We found that P70 ovariectomy (Ovx) did not affect callosal size, suggesting that ovarian hormone exposure sometime prior to P70 is sufficient to feminize the CC, and that once the callosum is feminized, the effects can not be reversed. We also found that P25 ovariectomy enlarged, or defeminized, adult female CC, whereas ovary transfer starting on P55 or P70 counteracted this enlarging effect, resulting in feminized adult CC. Thus, although a previously feminized callosum is not affected by P70 ovarian hormone removal, a not-yet feminized callosum can still be feminized after P70. These findings indicate that there is flexibility in the developmental window within which the female brain is responsive to the active feminization process initiated by ovarian hormones.

Adult ovary transfer counteracts the callosal enlargement resulting from prepubertal ovariectomy.

The rat corpus callosum (CC) is larger in males than females, and is sensitive to hormone manipulations during development. Previous research found that, in rats, CC sensitivity to testosterone ended by postnatal day 8 (P8). In contrast, more recent findings demonstrated that CC responsivity to ovarian hormones continued at least through P70. The current experiment extends these findings by showing that the female callosum is still sensitive to ovarian hormones as late as P130, well into adulthood.

Lack of activational influence of ovarian hormones on the size of the female rat's corpus callosum

The sex difference in the midsagittal area of the adult rat corpus callosum (CC) has been shown to be mediated, in part, by gonadal steroids in early development, with the sensitive period of hormone action in the female extending at least up to postnatal day 25. Given this prolonged sensitivity, the current study attempted to delineate organizational vs. activational influences of gonadal hormones on the female rat CC. In Experiment 1, callosal size was examined across the estrous cycle at 52 and 90 days of age. In Experiment 2, females were ovariectomized at 78 days and CC parameters assessed at 110 days. Last, in Experiment 3, females were ovariectomized at 78 days and sacrificed at 110 days; in addition, sham females were sacrificed during proestrus or estrus. Neither stage of estrous cycle nor adult ovariectomy affected midsagittal CC size. These results provide evidence for organizational effects of ovarian steroids on the female callosum, with the sensitive period of hormone action ending sometime between days 25 and 78.