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. 2022 Sep;29(9):340–348. doi: 10.1101/lm.053499.121

Changes in sex differences in neuroanatomical structure and cognitive behavior across the life span

Janice M Juraska 1,✉
PMCID: PMC9488018  PMID: 36206396

Abstract

Sex differences occur in the structure and function of the rat cerebral cortex and hippocampus, which can change from the juvenile period through old age. Although the evidence is incomplete, it appears that in at least some portions of the cortex these differences develop due to the rise of ovarian hormones at puberty and are potentially not dependent on the perinatal rise in testosterone, which is essential for sexual differentiation of the hypothalamus and sexual behavior. During aging of female rats, the presence of continued ovarian hormone secretion after cessation of the estrous cycle also influences sex differences in neuroanatomical structure and cognitive behavior, resulting in nullification or reversal of sex differences seen in younger adults. Sex differences can be altered by experience in a stimulating environment during the juvenile/adolescent period, and sex differences in performance even can be affected by the parameters of a task. Thus, broad generalizations about differences such as “spatial ability” are to be avoided. It is clear that to understand how the brain produces behavior, sex and hormones have to be taken into account.

Studying the remarkable plasticity of the nervous system was still in its infancy in the 1970s, when I was in graduate school. I was surprised that in all of the excitement only male animals were being used and I was determined to correct this, but with a few exceptions, I was routinely discouraged. It is only recently that it has been become accepted that understanding any phenomenon needs to include both sexes. Why has it taken so long? I posit that there are at least two, somewhat contradictory, explanations.

(1) It was thought that females had more behavioral variability because of the hormonal cycle and thus are impractical to work with since their inclusion would more than double the needed number of subjects. Although cyclic effects occur in learning, the effects are relatively small (Warren and Juraska 1997; Sbisa et al. 2017), and the behavior of females is not more variable than males (for review, see Beery 2018). In spite of the relatively minor differences in behavior due to the cycle, LTP is profoundly influenced by the cycle and by puberty (Warren et al. 1995; for a more recent contribution, see Gall et al. 2021). The underlying mechanisms show greater sex differences than behavior itself.

(2) At a level that seldom was acknowledged, it was assumed that the laws of learning, and thus plasticity, were generalizable across species so that studying nonhuman animals would tell us all that we need to know (shadows of Hull and Skinner). Given this notion, it was thought that surely any laws that extend across species would apply to females as well. Very broadly, this is true—we all classically condition. It is in the details of the behavior and especially in the neural mechanisms that differences between the sexes can arise (see the contributions from the laboratories of Frick [Koss et al. 2018] and Jarome [Farrell et al. 2021]), indicating that there is more than one way for the brain to achieve a behavior.

Sex is indeed complicated, but that does not mean that it should be ignored. It has long been known that there are sex differences in the incidence of various psychiatric conditions and neurological diseases, which are de facto evidence that sex is an important part of neural functioning including in higher-order cognition. More recently, accumulating evidence suggests that the mechanisms underlying learning and memory can be different between the sexes. I am not reviewing this, since several other authors in this special issue have made important and recent contributions to this topic. Here I review sex differences in the cellular structure of the cerebral cortex and hippocampus and their behavioral functions with a focus on studies from my laboratory using the rat model, in particular Long-Evans hooded rats. Much of this work is decades old, but it still can inform the present emphasis on sex differences. I highlight life span changes in sex differences in both neuroanatomical structure and cognitive behavior and the added complication that environmental factors can interact with sex differences, which makes them difficult to study and even harder to generalize. The cortex and hippocampus, essential for most learning and memory, are particularly plastic and susceptible to environmental influences.

The developmental origin of sex differences in the visual and medial prefrontal cortices

This section reviews the current state of what is known about the early development of sex differences in the number of neurons in the cortex, in particular our work on the visual cortex and the medial prefrontal cortex (mPFC). It also covers the limitations in investigating the early hormonal basis for the sex differences due to the hazards of anesthesia during surgery, as well as possible interference with later ovarian output from early exposure to androgens. The establishment of the number of neurons is of special interest because, unlike dendrites and synapses that can readily change throughout life, neurogenesis does not occur in the cortex after birth, and this number sets the size of the target for the development of synapses from ingrowing axons.

The largest sex differences in the rat brain are in the hypothalamus, and they are intimately involved in aspects of reproduction. It has been known for decades (MacLusky and Naftolin 1981; Arnold and Gorski 1984) that most of these differences occur early in perinatal development due to the secretion of testosterone in males, which at least in male rodents is aromatized to estrogen inside cells. This process has not been established in the cortex and hippocampus. There is evidence that androgen, not estrogen, influences the rate of cell death in the visual cortex (Nuñez et al. 2000a), and both androgen and estrogen in the hippocampus can influence the rate of neurogenesis and cell death (Zhang et al. 2008). Whether this ultimately results in a sex difference in cell number after these developmental processes end is not known.

We had found that adult males have more neurons in the binocular visual cortex than females in adulthood. This was done with stereological techniques: density multiplied by the volume of the visual cortex areas (Reid and Juraska 1992). We needed to find how this difference was established. The techniques that traditionally have allowed an exploration of sexual differentiation in subcortical areas are the removal of the testes right after birth to deprive males of testosterone and, conversely, giving females testosterone at birth to mimic males. Both of these have confounds, especially for the cortex and hippocampus. In males, it comes from the work of Olney's laboratory at Washington University (e.g., Ikonomidou et al. 1999; Jevtovic-Todorovic et al. 2003) demonstrating that apoptosis is increased by anesthetics early in development. How much anesthesia affects the hypothalamus and other areas in the diencephalon, where sexual differentiation has been examined with neonatal removal of the gonads, is not known. However, we found that cryoanesthesia on the day after birth decreases the number of neurons and the volume of the visual cortex of rats (Nuñez et al. 1998), as well as the size of the hippocampus and performance in the water maze (Nuñez et al. 2000b). These effects occur in both sexes, but males are more profoundly affected in the cortex such that cryoanesthesia abolishes the sex differences in the volume and in the number of neurons that we have documented in the visual cortex (Nuñez et al. 1998). We also found that sex differences in the volume of the visual cortex were abolished with exposure to halothane, a fast-acting inhalant anesthetic, at postnatal day (P) 1 (Nuñez and Juraska 2000). In general, neonatal anesthetics are deleterious for both sexes, but the effect is greater in males (Rothstein et al. 2008; Cabrera et al. 2020).

To avoid doing surgery, we implanted males with flutamide pellets, a testosterone blocker, on the day of birth, and females were implanted with either testosterone or dihydrotestosterone at this time. At P20, all animals of both sexes had their gonads (ovaries or testes) removed (GDX), except a subset of control animals (with placebo pellets) that was left intact. Both the monocular and binocular subregions of the visual cortex were examined in adulthood (P85–P90), and the number of neurons was quantified (Fig. 1). A significant sex difference was found in controls, replicating our previous results. We found that blocking testosterone with flutamide or GDX only at P20 was without effect in males. In females, all treatments—testosterone, dihydrotestosterone, and GDX—only at P20 resulted in more neurons in adulthood, indistinguishable from the number in males (Nuñez et al. 2002).

Figure 1.

Figure 1.

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The number of neurons in the primary visual cortex (Oc1M and Oc1B) in adult rats. Except for the intact males and females, all other groups were gonadectomized at P20. The significant comparisons are from intact females. (*) P < 0.05, (**) P < 0.01. Reprinted with permission from Nuñez et al. (2002) (© 2002 Wiley Periodicals, Inc.).

The flutamide group in males failed to support testosterone as an influence on the ultimate number of neurons in the visual cortex even though in previous work dihydrotestosterone (not estrogen) did change the rate of cell loss in females (Nuñez et al. 2000a). A possible explanation is that perinatal androgens may not be acting directly on the cortex, but rather they may cause the ovaries to be anovulatory (Barraclough 1961) and disrupt gonadotropin release (Gorski and Wagner 1965). This would presumably stop puberty in females, which in turn would stop the loss of neurons in the cortex, which may be the mechanism for sexual differentiation. Thus, the traditional effects of neonatal gonadectomy in males and exposure to testosterone in females may be acting indirectly by increasing neuron loss due to anesthesia in males and stopping puberty in females.

This pattern also is found in the mPFC, where sex differences (male > female) in intact adult rats did not occur if the female was ovariectomized in the juvenile period before puberty (Fig. 2; Koss et al. 2015). As in the visual cortex, GDX of males before puberty was without effect. Thus, sex differences in the number of neurons in at least these diverse areas of the cortex may be set by puberty. Further work should include females given dihydrotestosterone or estrogen at birth without later GDX, followed by checking whether the ovaries are working through signs of puberty and measurement of adult estrogen levels. Then, in adulthood, quantification of neuron number in the visual cortex and mPFC should be stereologically performed. Establishing sex differences in neuron number in the adult hippocampal CA fields followed by hormonal manipulations in development and prepubertal GDX is also needed.

Figure 2.

Figure 2.

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The number of neurons in the mPFC in adult rats. Gonadectomy (GDX) had occurred at P20. (*) P < 05. Reprinted with permission from Koss et al. (2015) (© 2015 Wiley Periodicals, Inc.).

The importance of the ovarian steroids at puberty for sex differences in neuron number in the cortex also has implications for the mechanism by which giving females testosterone at birth results in masculinized behavior in learning tasks (e.g., Meaney and Stewart 1981; Williams and Meck 1991; Isgor and Sengelaub 2003). However, female puberty as the mechanism for sexual differentiation may not generalize to all cortical areas or the hippocampus, and experiments are needed to establish that. In fact, there are behavioral data that indicate that sex differences in a five-choice serial reaction time task are not affected by GDX before puberty, but females show performance like males when given testosterone on P1–P2 (Darling et al. 2020). This particular task is heavily dependent on the orbital prefrontal cortex (Eagle and Baunez 2010), which may follow a different route for sexual differentiation.

Can the sex difference in neuron number in the mPFC be altered during development from developmental exposure to common environmental chemicals such as the endocrine disruptors, the phthalates? Although the phthalates bind with many hormone receptors, they have notable affinity for androgen receptors (Howdeshell et al. 2017). We have investigated the effects of a mixture of phthalates that is relevant to human exposure being derived by back-calculating from urine metabolites from pregnant women in the Champaign/Urbana area (Pacyga et al. 2021) and the dose being based on a body surface area normalization method for rats (Reagan-Shaw et al. 2008). The mixture was comprised of 35% DEP, 21% DEHP, 15% DBP, 15% DiNP, 8% DiBP, and 5% BBP. Rat dams daily ate the phthalates on cookies during pregnancy through P10 of lactation. As adults, both male and female offspring were found to have fewer neurons and synapses in the same proportion such that the sex differences in the number of neurons and synapses were the same in all groups (Fig. 3; Kougias et al. 2018). In addition, performance on an extradimensional set shift task, which is known to involve the mPFC, was similarly disrupted by phthalate exposure in both sexes, and the sex differences in performance persisted in the phthalate-exposed groups (Kougias et al. 2018). More recently, we have found an increase in the number of apoptotic cells in the mPFC at embryonic day 18 and at P10 in both sexes following phthalate exposure (Sellinger et al. 2021). The persistence of sex differences following perinatal exposure to a known antiandrogenic endocrine disruptor is indirect evidence that androgens are not major contributors to the sexual differentiation of the mPFC.

Figure 3.

Figure 3.

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The number of mPFC perineuronal nets (PNNs) in females. There was a significant increase in the number of PNNs across the mPFC between P30 and P60. The lighter-colored bars indicate females that were prepubertal, while the darker bars indicate postpubertal females. There was a decrease in the number of PNNs at puberty that persisted through P43 before reaching adult-like levels at P60. (*) P < 0.05, (**) P < 0.01. Reprinted by permission from Springer Nature Customer Service Center GmbH, Springer Nature: Drzewiecki et al. (2020).

Thus, work from my laboratory does not indicate a role for hormones in the early development of the number of neurons in the mPFC and visual cortex, although more evidence for this unconventional idea is needed. Also, it is not known how much this generalizes to other areas of the cortex or to other telencephalic structures. Studies are made more difficult because of the effects of anesthetics in increasing cell death in males, while early exposure to androgens can interfere with ovarian function. As already mentioned, sexual differentiation of the visual cortex and mPFC appears to occur due to puberty in females. This is further discussed in the next sections.

Sex differences in adolescence

This section deals with the sex differences in both neuroanatomical structure and behavior in adolescence, especially those involving the mPFC. Our work on the role of puberty in the formation of adult sex differences, some of which was already referenced in the previous section, is further described. Then, our earlier work on the role of the environment in influencing the structure and function of the adolescent brain is also reviewed.

Structure

The sex differences in neuron number, at least in the two areas of the cerebral cortex that we examined, are set in adolescence and do not change during adulthood. Whether this also occurs in the hippocampus (outside of the dentate gyrus) has not been established. Dendrites, dendritic spines, and synapses are actively growing and pruning during adolescence in both the cortex and hippocampus. In this process, sex differences can appear that are temporary in juveniles, such as sex differences (female > male) in the number of dendritic branches in the hippocampal dentate granule cells (Juraska 1990), in the length of dendritic branches in the visual cortex (Seymoure and Juraska 1992), and in the number of axons in the splenium of the corpus callosum (Kim and Juraska 1997). All of these differences either reverse or disappear by young adulthood, which indicates that adolescence, between the juvenile and adult phases, is important in setting up sex differences in adulthood.

We also have evidence that puberty in females is the primary agent for sex differences in two disparate areas of the cortex. Evidence was cited above in “The Developmental Origin of Sex Differences in the Visual and Medial Prefrontal Cortices” that juvenile ovariectomy results in female rats having the same number of neurons as males in both the visual cortex and mPFC (Nuñez et al. 2002; Koss et al. 2015). We have found that the female mPFC has a significant loss of neurons between the day of puberty, average postnatal day (P) 35, and P45 (Willing and Juraska 2015), and in addition, synapses in the mPFC are lost in the same time frame (Drzewiecki et al. 2016). By comparing males on the average day of puberty (P45) versus those that had reached puberty or not, there are indications of loss of neurons and synapses in males at puberty but not the large effect seen in females. While neurons are being pruned, the extracellular structure surrounding a subset of neuronal cell bodies, perineuronal nets (PNNs), increases during adolescence in both males and females (Baker et al. 2017; Drzewiecki et al. 2020). PNNs stabilize the fast-spiking property of parvalbumin neurons, allowing more inhibition in cortical circuits and presumably leading to the maturation of behavior at the expense of some plasticity and the closure of critical periods (Hensch 2005). We have found that females have a peak number of PNNs just before puberty at P35 that abruptly drops at puberty, at which point the increase to adulthood resumes (Fig. 3; Drzewiecki et al. 2020). Interestingly, these same female rats have a peak in estrogen receptor β, as assessed with RNAscope, which drops to adult levels at puberty (Drzewiecki et al. 2021). Whether the drop in PNNs is related to the coincidental drop in estrogen receptor β is unknown at this time. What the increasing levels of PNNs across adolescence mean for behavioral performance in tasks involving the mPFC is unclear at this time, and we are currently investigating this question. Thus, females have more profound structural changes during adolescence than males—especially at puberty—that alter many of the sex differences seen in juvenile/prepubertal rats.

Behavior

Does behavioral ability mirror the changes in sex differences seen in structure during adolescence? There is a limited set of tasks that can be used since adolescence is at best ∼1 mo long, from P27 to P56, with the influence of puberty complicating interpretation. This limited time makes it especially difficult to test more complex tasks that involve the mPFC. We have run a delayed alternation task, which involves both the mPFC and hippocampus, using age-matched adolescent rats. It took adolescent females longer to reach criterion, with more perseverative errors during initial spontaneous alternation training, but by adulthood this difference was gone. There were no sex differences in performance during a series of delays, although adolescents of both sexes performed more poorly at two of the six delays compared with adults (Koss et al. 2011).

One problem with testing male and female rats at the same age during adolescence is that they reach puberty at different time points. On average, we have found that females reach puberty at P35 and males reach puberty at P42–P45. Considerable pruning occurs at puberty, especially in females, which may change how the animal approaches a task, and sex differences in changes in strategy in water maze performance have been found between juvenile and postpubertal rats (Grissom et al. 2013; Rodríguez et al. 2013). Grissom et al. (2013) found that the types of strategy were associated with the ratio of muscarinic binding between the hippocampus and striatum, indicating that these neural areas also change around puberty.

We tested male and female rats matched for puberty rather than age on the water maze and added a cognitive flexibility component to involve the mPFC by moving the platform after initial training. Puberty did not affect the three blocks of trials (four trials/block) to learn to find the hidden platform. After the initial training, when the platform was moved for trial blocks four and five, the path length revealed that postpubertal rats of both sexes performed better than prepubertal rats (Fig. 4; Willing et al. 2016). It should be noted that the postpubertal females were 3–5 d younger than the prepubertal males, indicating that pubertal status rather than age is predominantly important for performance in adolescence.

Figure 4.

Figure 4.

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Path length to reach the novel platform location in the water maze. Results from females appear in A and results from males appear in B. Path length was significantly lower in postpubertal males and females in comparison with prepubertal animals after the location of an escape platform was moved. a > b; P < 0.03. From Willing et al. (2016). Copyright © 2016 by American Psychological Association. Reproduced with permission.

Role of the environment

Although no one labeled it as such, most of the work examining the effect of enriched environments on the brain and behavior occurs using rats in the juvenile to adolescent age range, when the largest effects can be seen (for review, see Juraska and Wise 2015). Although most studies have only used males, we have compared the effects of enrichment on dendritic changes in the visual cortex, the dentate gyrus, and CA3 of the hippocampus in male and female rats. Both sexes tend to have larger dendritic trees following 1 mo of enrichment (EC; objects changed daily in social groups of 12) compared with individually caged (IC) animals in the same room; however, the largest dendritic response in the visual cortex was in males, and in the granule cells of the dentate gyrus, it was in females. These environments also changed the direction of sex differences in the dendritic tree with males > females in the size of dendritic fields in the visual cortex following EC, while females raised in EC had more dendritic material in the dentate granule cells than males. Sex differences were not detected in these areas in rats raised IC (Juraska 1984; Juraska et al. 1985). The hippocampal CA3 pyramidal neurons receive direct input from the dentate granule neurons onto the proximal portion of large apical dendritic tree, where sex differences (female > male) mirror those seen in the dentate granule neurons. It also can be noted that males in EC have a decrease in dendritic material compared with males IC, presumably as part of the restructuring of neural circuits where more is not always useful. Interestingly, the sex difference in the proximal tree is reversed in the distal dendrites of these neurons (Fig. 5), and again no significant sex differences were found in the rats raised IC (Juraska et al. 1989). Another example of how intricate sex differences can be comes from the splenium of the rat corpus callosum, where following EC rearing, female rats had more myelinated axons than males, but males had larger myelinated axons. Neither of these differences occurred in rats raised IC (Juraska and Kopcik 1988). Overall, the work from my laboratory indicates that a more stimulating environment induces structural sex differences that are not apparent when rats are relatively deprived. Also, there is no broad generalization that can be made about the direction of the differences.

Figure 5.

Figure 5.

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The number of intersections between apical dendrites from pyramidal neurons in hippocampal CA3 and parallel lines at 20-µm intervals grouped from 0% to 40% and from 60% to 100% of the distance from the soma to the top of CA3. The mossy fibers from dentate granule neurons synapse on the dendrites between 0% and 40%, and this area reflects the sex and environmental differences found in the dentate neurons. (**) P < 0.01. Reprinted with permission from Juraska et al. (1989).

Given how profoundly a stimulating environment can generate a diverse array of cellular sex differences, the behavioral consequences are of interest. We have investigated this by running rats on a 17-arm radial maze that was fully baited. We found that the environment had a substantial effect on maze performance, with almost no overlap in the performance of rats raised in EC versus IC, with EC rats having fewer errors than IC rats (Fig. 6). This was true for both sexes, and no sex differences were found in either environment. This was surprising given that female rats generally do not perform as well as male rats in mazes (Beatty 1979; Jonasson 2005); therefore, we ran the experiment two separate times and replicated the result (Juraska et al. 1984). In a subsequent study, we again raised rats in EC or IC but increased the difficulty of the task by using both baited (working memory) and unbaited (reference memory) arms in the 17 arms. The EC-raised rats again showed better (fewer errors) performance than those that were IC, but now males performed better on both baited (Fig. 7) and unbaited arms than females (Seymoure and Juraska 1996), indicating that degree of difficulty influences the presence of sex differences. Neither of these studies mirrored the results of the neuroanatomical measures, but any task relies on many neural areas, each of which may contribute different patterns of sex differences and influence strategies (e.g., Yagi et al. 2017).

Figure 6.

Figure 6.

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The errors for 2-d blocks of training on the completely baited 17-arm radial maze that were averaged for each environment and sex. There were significant differences between environments (P < 0.001) and days (P < 0.001) but no sex differences. Reprinted with permission from Juraska et al. (1984) (© 1984 Wiley Periodicals, Inc.).

Figure 7.

Figure 7.

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The errors for 2-d blocks on the on baited (working memory) arms of the baited/unbaited 17-arm radial maze averaged for each environment and sex. There was a sex difference (P < 0.01) and an effect of the environment (P < 0.004). Reprinted by permission from Springer Nature Customer Service Center GmbH, Springer Nature: Seymoure and Juraska (1996).

Thus, adolescence is a time of restructuring of the cortex and hippocampus, much of which is prompted by puberty. However, the environment also plays a role in dendritic development and in the formation of sex differences at this level in the cortex and hippocampus.

Sex differences in adulthood: structure and behavior

The hormonal and environmental influences during adolescence described above resulted in sex differences in adulthood. We have found that male rats have more neurons and more synapses in their visual cortex than do females (Reid and Juraska 1992, 1995). Interestingly, there are no sex differences in the number of synapses per neuron, indicating that if simple density of synapses were to be examined, no differences would be found in rats that were reared socially (with cagemates) rather than in EC or IC.

Sex differences in visual capabilities parallel sex differences in neuroanatomical structure. By running rats for weeks on a visual discrimination of spatial gratings on a Y-maze and jumping stand, we were able to establish grating acuities that matched those found with electrophysiological measures (Boyes and Dyer 1983; Silveira et al. 1987), but there were no sex differences (Seymoure and Juraska 1997). Grating acuity is limited by the spacing of retinal photoreceptors (Martin 1986), and there do not appear to be sex differences in the rat retina (Chaychi et al. 2015). However, vernier acuity is the ability to detect a small misalignment within a grating (Fig. 8A) and is thought to be dependent on the visual cortex (Berkley 1989; Swindale and Cynader 1989). In the first demonstration of vernier acuity in rats, we found that male rats were better at detecting smaller vernier offsets than females (Fig. 8B; Seymoure and Juraska 1997), potentially mirroring the sex differences in the visual cortex.

Figure 8.

Figure 8.

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(A) Representative grating stimuli for testing vernier acuity. At the left is the control stimulus, and at the right is the offset stimulus. The offset is 63%, 34.1 min of arc at a distance of 40 cm, and both sexes could detect this offset versus the control stimulus. (B) The number of subjects above chance (34 or more out of 50 trials) in the vernier acuity task. Significance was determined with a χ2 test. From Seymoure and Juraska (1997). Copyright © 1997 by American Psychological Association. Reproduced with permission.

We also have found that males have more neurons in the adult mPFC than females (Markham et al. 2007; Kougias et al. 2018) as well as a larger dendritic tree in layer five pyramidal neurons (Markham and Juraska 2002). As mentioned previously, males (in both the control and perinatal phthalate-exposed groups) perform better than females on an extradimensional shift task, which is concordant with structural differences (Kougias et al. 2018).

Sex differences in performance can be influenced by manipulations in adults. The simple use of nonspatial pretraining trials has been shown to abolish sex differences in performance on the water maze (Perrot-Sinal et al. 1996), and indeed, we have replicated this lack of sex differences even while finding that females in estrus (low estrogen) performed better than females in proestrus (high estrogen) (Warren and Juraska 1997). Water temperature also had an effect, with better performance reversed (proestrus > estrus) when warmer water is used (Rubinow et al. 2004), although males were not tested. It should be added that the effects of stress on learning tasks usually differ between the sexes in complicated ways; this has been thoughtfully reviewed in Shors (2004).

Sex differences in aging: structure and behavior

In studying sex differences in aging rats, it is important to realize that female rats continue to secrete estrogen and progesterone in a moderate, steady fashion after they stop cycling in middle age (∼12 mo). This occurs because, unlike humans, who run out of eggs at menopause, in middle age female rats, it is the hypothalamus that ages and does not support the feedback necessary to maintain a cycle (Huang et al. 1978; Wise and Ratner 1980). After the cycle stops (estropause) in middle age (∼12 mo), females secrete moderate levels of estrogen and low levels of progesterone; this phase is termed persistent estrus. As females get older, many have increased progesterone secretion, while estrogen levels decrease slightly or remain the same, changing the ratio of estrogen to progesterone; this phase is known as persistent diestrus or pseudopregnancy (Huang et al. 1978; Miller and Riegle 1980). The phase of estropause can influence performance on the water maze such that aged females in persistent estrus performed better than both aged males and aged females in pseudopregnancy at 22 mo (Fig. 9; Warren and Juraska 2000). When females lose estrogen at middle age through ovariectomy, there are no sex differences in performance in the water maze in old (19 mo) age (Kougias et al. 2017), indicating the beneficial effects of estrogen exposure during aging.

Figure 9.

Figure 9.

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Path length to find the submerged platform in the water maze. Aged males and aged females in PE (higher estrogen) and PP (higher progesterone) are shown. (*) P < 0.05. Reprinted with permission from Warren and Juraska (2000).

In the hippocampus, no one has investigated potential sex differences in neuron loss during aging, but male rats do not have any detectable loss (Rapp and Gallagher 1996; Rasmussen et al. 1996). In addition, loss of dendrites is small (for review, see Juraska and Lowry 2012), but a decrease has been detected in the apical dendritic tree of hippocampal CA1 in aged males, but not females, that erases the sex difference (male > female) that occurred in young adults (Markham et al. 2005). No sex differences were found in the density of dendritic spines on these branches in either young or aged adults, but given that males have losses in the size of the tree, the total number of spines does decrease in males but not in females.

The mPFC, like the human prefrontal cortex, has greater losses in aging than the hippocampus, and this affects sex differences. Young adult males have more neurons in layer 5/6 of the mPFC than females, but this difference is absent in the aged (19–22 mo) (Yates et al. 2008). Similarly, there are sex differences in the size of the dendritic tree and spine density in layer 5/6 pyramidal neurons of young adult rats (males > females), and these differences disappear in the aged (Markham and Juraska 2002). We found that young adult males performed better than females on a delayed alternation task, which involves the mPFC, and this sex difference reversed in 17-mo-old rats because males had a decrease in accurate performance with age (Fig. 10). The same pattern of differences occurred in the density of tyrosine hydroxylase throughout the layers of the mPFC, so that males had more density as adults while females had a higher density during aging (Chisholm et al. 2013). Again, it should be noted that the aging females in all of these studies were secreting moderate to low levels of estrogen and progesterone. In contrast, when middle-aged females underwent ovariectomy, there were no sex differences in the dendritic tree and spine density in mPFC layer 5/6 neurons (Kougias et al. 2016).

Figure 10.

Figure 10.

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Average number of correct alternations across all delays. Age (P = 001) and an interaction between age and sex (P = 0.001) were significant. Adult males made more correct choices than adult females across all delays, while aged females made more correct choices than aged males across all delays. (**) P < 0.02, (*) P < 0.05. Reprinted with permission from Chisholm and Juraska (2013).

Thus, estrogen appears to decrease the neural and behavioral effects of aging in comparison with males. This neuroprotective role for estrogen in aging can also be seen when hormones are replaced after ovariectomy in middle age (for review, see Chisholm and Juraska 2013).

Summary

Sex differences in cognitive behavior and the underlying neural structures occur through the life span of rats but are not stable across time. A major factor in the instability is due to the changing role of estrogen with age, from increasing sex differences at puberty by promoting pruning, especially in the cortex, to helping to preserve structure and function during aging. Another part of the unpredictability is due to environmental factors early in life and even the parameters of how a behavioral task is run.

Most researchers will find sex differences in their data now that the National Institutes of Health requires that both sexes be included in studies. Most researchers will not investigate the origin of the differences, but they should realize that hormones play many roles beyond their immediate circulating effects. If we are to understand how the brain produces behavior, sex and hormones have to be taken into account.

Acknowledgments

I thank the federal agencies that funded this research over the decades: the National Institute of Mental Health, the National Institute on Aging, and the National Institute of Environmental Health Sciences, and especially the National Science Foundation, which funded sex difference research outside of the hypothalamus before the National Institutes of Health decided it needed to.

Footnotes

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