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Sex and Menstrual Phase Influences on Sleep and Memory

Sex and Menstrual Phase Influences on Sleep and Memory Purposes of Review This review highlights the effect of sex differences in sleep mediated memory consolidation and cognitive performance. In addition, the role of menstrual cycle and the fluctuating level of sexual hormones (mainly oestrogen and progesterone) are stressed. Recent Findings The literature indicates that sex hormones mediate and orchestrate the differences observed in performance of females in comparison with males in a variety of tasks and can also be related to how sleep benefits cognition. Although the exact mechanism of such influence is not clear, it most likely involves differential activation of brain areas, sensitivity to neuromodulators (mainly oestrogen), circadian regulation of sleep and temperature, as well as modification of strategies to solve tasks across the menstrual cycle. Summary With the evidence presented here, we hope to encourage researchers to develop appropriate paradigms to study the complex relationship between menstrual cycle, sleep (its regulation, architecture and electrophysiological hallmarks) and per- formance in memory and other cognitive tasks. . . . . . . . Keywords Menstrual cycle Humans Rodents Sex differences Cognition Memory Sleep Sleep-regulation Introduction with studies that include sleep, learning and memory. Within each section, we describe sex driven differences as well as Sex is a variable known to influence diverse aspects of brain menstrual phase differences, focusing in common results and behaviour, but surprisingly, sex differences and their con- across human and rodent studies. While rodent studies present sequences are often overlooked and are considered negligible with the opportunity for controlled designs (i.e. administration by many researchers. Instead, rodent and human studies re- of hormones and gonadectomization) and limiting the influ- gard male and female subjects as simply equal and opt to ence of confounders such as self-reported sleep and cultural include only males; thus, females end up being underrepre- bias, they rely on behavioural measures as proxy of the sub- sented in neuroscience research [1]. In this review, in addition jacent cognitive skill, requiring extra efforts to clarify a par- to general sex differences, we also discuss how a specific ticular strategy taken by the individual to solve an experimen- aspect of sex differences (the menstrual cycle) may exert in- tal task. Human studies are often weak in control and can only fluences in sleep and learning in the context of sleep’scontri- capture snapshots of the desired variable studied, which can bution to cognition. We start with the general effects on sleep, be an important limitation in a phenomenon of repetitive na- continue with effects on cognition and memory and finish ture such as menstrual cycle. Both types of studies offer a window into the fluctuating influence of menstrual cycle and sex hormones in the functioning of female individuals. This article is part of the Topical Collection on Sleep and Learning * Alejandra Alonso a.alonsogarrido@donders.ru.nl Influence of Sex on Sleep Department of Neuroinformatics, Faculty of Science, Donders Sex differences can be anatomical or functional [2] and ex- Institute for Brain, Cognition and Behaviour, Radboud University, P.O. Box 9010, 6500 GL Nijmegen, The Netherlands press themselves both at volumetric and connective levels [3]. Those differences emerge early on during development and Department of Psychology, Universidad de los Andes, Cra. 1 N° 18A–12, Bogota, Colombia are later reinforced by exposure to sex steroids [4�� ]. 2 Curr Sleep Medicine Rep (2021) 7:1–14 Circulating gonadal hormones exert their effects on not only promote REM during the light phase and reduces NREM delta secondary sexual features but also most brain regions express power (1–4 Hz) during the dark phase [16, 19]. Gonadectomy oestrogen and progesterone receptors. These brain regions on mice of both sexes eliminates most of the differences seen include sleep regulating areas such as the ventrolateral in recovery sleep after sleep deprivation [13]. preoptic [2, 5] median preoptic and suprachiasmatic nuclei, To further study the effect of sex chromosomes in sleep, the lateral hypothalamus [3], as well as areas involved in cogni- core four-genotype mouse model [20]allowstohave females tion and memory such as the prefrontal cortex [6] and the and males with either XX or XY chromosomes. This is a hippocampal formation [7, 8]. transgenic line that manipulates the presence or absence of Sleep presents itself in a complex form, featuring behav- the Sry gene, which determines testes development and is ioural (for instance, diminished response to stimuli), as well as normally found on the Y chromosome. By knocking Sry out physiological changes compared with wakefulness (such as of the Y chromosome, they can obtain females XY, and by brain activity that displays distinct patterns of neuronal firing). knocking Sry into the X chromosome, they can obtain males In most animals, it is possible to differentiate between two XX. Studies in this line showed that genetic sex does not main sleep stages: non-rapid eye movement sleep (NREM) influence sex differences in spontaneous sleep, but rather and rapid eye movement sleep (REM) [9]. NREM is distin- has an impact in recovery sleep, where XY females had more guishable by its higher amplitude, slower waves relative to total recovery sleep and more NREM than XX females at the wake, while REM displays a more similar brain activity pat- midpoint of the dark phase, suggesting that increased sleep tern to wakefulness, with low amplitude and high frequency propensity is linked to the Y chromosome. In gonadectomized waves [10](Fig. 1a). Muscle atonia and the characteristic eye animals, after sleep deprivation, the dissipation of delta power movements (similar to saccades) that give name to the state was quicker in XX males than XX females [12], indicating are also a hallmark of REM. that in the absence of female gonadal hormones, the advantage that females had in recovery sleep compared with males is Rodents lost. When studying sleep in rodents, it is important to note that, Humans contrary to humans, they are most active during the dark phase, and their sleep pattern is polyphasic, with several bouts Overall, female humans display more consolidated sleep (less of sleep during both light and dark phases of the day (see Fig. awakenings), shorter sleep latencies and lower percentage of 1b). light sleep, than aged-matched males [3, 21], and this is con- Studies on spontaneous sleep show that female mice have sistent for different age groups and experimental assessments less total sleep and daily NREM compared with males of sleep (laboratory vs home sleep-recoding conditions). [11–13] and, during the dark phase, males exhibit more Paradoxically, women report consistently worse subjective wake-sleep shifts, while females have longer bouts of wake- sleep quality than men. Females tend to describe their sleep fulness [12]. REM is also decreased in female rats [13]and quality as poor due to nighttime disruptions, insufficient quan- mice [11]. Gonadectomy in mice of both sexes eliminates the tity and long sleep latencies. Women also claim suffering from differences seen in total spontaneous sleep and NREM, as insomnia in a greater proportion than men [22, 23], and this well as in delta power and sleep fragmentation, which implies disruption grows stronger as women age (with menopause that the differences in current hormones levels are responsible onset) [24]. for these variations in sleep and not general developmental Concerning circadian regulation of sleep, women seem to differences. Ovariectomized rats show decreased REM and have shorter and earlier rhythms of temperature change and total sleep time during the light phase, compared with castrat- melatonin secretion (induces drowsiness and sleep) under a ed males [14]. When treated with stable levels of 17β- normal schedule [3]. It has also been documented that women oestradiol or oestradiol and progesterone, they show increases go to bed and wake up earlier than men [25] Since often, wom- in wake and decreases in REM and NREM during the dark en extend the time before going to sleep to after the melatonin phase [15–17]. peak, this could be related to their complain of longer sleep Studies on recovery sleep after sleep deprivation in mice onset latencies [23] due to the missing of the optimal time- show for both sexes decreased NREM the first 2 h of recovery window for sleep onset. However, under a 28-h desynchrony sleep, followed by an increase during the first half of the dark paradigm (9.5 h sleep and 18.5 h wake), women show lower phase, but this rebound is greater in females [13]. Female rats accuracy and exert more effort in cognitive tests after also showed an increased NREM rebound during recovery prolonged wakefulness compared with men [26]. sleep as well as increased delta power compared with males In terms of the features of brain oscillatory events during [18� ]. Studies on gonadectomized rats with hormone implants sleep (i.e. power of electroencephalography signal and its fre- show that during recovery sleep oestradiol and progesterone quency), Carrier and colleagues [27] showed, in a sample of Curr Sleep Medicine Rep (2021) 7:1–14 3 ab Wake Wake REM REM NREM N1 Light phase N2 Wake N3 REM NREM A night’s sleep Dark phase cd Estrous cycle Menstrual cycle Progesterone Progesterone Estradiol Estradiol Menses 1 M Diestrous Proestrous Estrous Metestrous D 6 days 12 Follicular phase Luteal phase 8 days Fig. 1 Diagrams of the menstrual cycle and sleep patterns in humans and and wake throughout the day. During their active phase, they also sleep, rodents. a Sleep pattern in humans. N1 is the transition state into sleep, with bouts of short sleep-wake transitions followed by a wake period, characterized by drowsiness and a low arousal threshold. N2 is a deeper back to the sleep bouts. c Oestrous cycle in rodents, divided in diestrous, sleep than N1, during which breathing and heartbeat decrease. It is also in proestrous, oestrous and met oestrous for an average of 5 days. During this state when sleep spindles can be observed. N3 also known as slow proestrous, a peak of estradiol followed by a peak of progesterone gives wave sleep is characterized by a predominance of delta oscillations, with place to ovulation. Rodents do not menstruate; instead, they experience a the EEG signal showing slow frequencies and high amplitude resorption of the endometrium, marked as magenta lines. d Menstrual waveforms, believed to be a regenerative period during sleep. REM cycle in humans is divided into follicular phase and luteal phase, with sleep or paradoxical sleep is characterized by an EEG state of high an average length an average of 28 days. On the last days of the follicular frequency and low amplitude oscillations, similar to wake, but with phase, estradiol increases, followed by a spike of luteinizing hormone complete muscle atonia. The line depicts transitions between states which drives ovulation. The corpus luteum remaining secretes throughout the night, with REM episodes becoming longer as the night progesterone, and when both progesterone and estradiol are low, the progresses. b Sleep patterns in rodents. These animals sleep the most uterine lining detaches along with the unfertilized egg, with the menses during the light cycle, where they have numerous short bouts of sleep marked as a magenta box men and women between 20 and 60 years, that women display display greater SWA rebound after sleep deprivation, which higher power in diverse physiological frequencies considered has been interpreted as women accumulating a greater sleep during sleep (delta 0.1–4Hz, theta 4–7 Hz and alpha 8–12 Hz debt than men and making them more sensitive to sleep loss and spindles 14–16 Hz). Spindles are a prominent feature of due to work-shifts and more propense to accidents [4�� ]. NREM sleep and have been associated, with intelligence and learning capabilities [28, 29]. A difference in spindle power Interim Summary between the sexes has been consistently described [30]and may be related to the variations in spindle topography [31]. In sum, across both rodents and humans, sleep differs between For instance, a study by Huupponen and colleagues [32] the sexes for variables such as sleep architecture and its circa- found that women had a higher percentage of spindles in the dian regulation, as well as features of electrophysiological left frontal electrode (Fp1-A2) and men displayed more spin- events characteristic of sleep (for instance, spindles and slow dles in the occipital electrodes (O2-A1). However, it is not wave activity differ in their power and frequency). However, completely clear whether this is due to lower skull thickness in terms of observed sleep quality, the direction of the differ- in women, since skull thickness could influence surface elec- ence seems to be opposite among rodent findings and human troencephalography power and thus spindle detection [33�� ]. studies, since the latter point towards better sleep- quality in Regarding slow wave activity (SWA), a low-frequency (2- females not seen in female rodent models. 4 Hz) activity observed in NREM and a proxy for sleep pres- sure, men and women do not show differences in power, but the proportion of SWA was more strongly regulated by circa- Influences of Menstrual Cycle on Sleep dian rhythms in women than in men. As for age effects on sleep, mid-age women display greater percentage of SWA After puberty, females experience on a regular basis changes than same-age men [27] and SWA/delta decline is less severe in the reproductive system that allow for pregnancy to occur, in women than in men [24, 25]. In the same direction, women known as the menstrual cycle. It allows oocytes to mature and Relative hormone concentration Resorption of endometrium Ovulation Relative hormone concentration Ovulation 4 Curr Sleep Medicine Rep (2021) 7:1–14 prepares the uterus by thickening the uterine lining. Different and oestrogen rise; as the non-fertilized ovule degenerates, hormones produced by the hypothalamus and the gonads or- the production of hormones drops again [36]. Sexual steroid chestrate the different stages of the menstrual cycle; however, hormones levels and the feedback for their cyclical regulation these hormones affect not only the reproductive system but depend on the central nervous system. The nature of the re- also the nervous system. In this section, we will highlight how lease of such substances is recurrent and pulsates across the the menstrual cycle influences sleep on both humans and cycle, and therefore, their effects are transient in nature [37] rodents. (Fig. 1d). Sex differences in reported sleep quality begin in the ado- Rodents lescence, with the onset of sexual maturation (menarche in women) [23]. As previously mentioned, subjective sleep qual- In rodents, the oestrous cycle lasts around 5 days and is divid- ity is lower in women but appears as specially affected before ed in proestrous, oestrous, metestrous and diestrous. the menses [38] and women (mainly those affected by pre- Proestrous occurs the day before ovulation, with the highest menstrual disruptive symptom [36]) report insufficient and concentration of progesterone and oestradiol, the highest peak fragmented sleep [30]. Yet insomnia reports from women ex- is at the end of the light phase for oestradiol, and at the start of tend across all phases of the menstrual cycle [23], but insomnia the dark phase for progesterone. Oestrous is ovulation day, worsens during the premenstrual phase (mid-luteal phase) and with oestradiol and progesterone starting to decay; during is linked to women’s anxiety and perception of life-disruption metestrous and diestrous, oestradiol starts to increase gradual- due to the menses [3, 23]. Paradoxically, oral contraceptives do ly, with a small increase in progesterone. In most mammals, not seem to influence subjective sleep quality [6]. after ovulation, there is a luteal phase; however, in rodents, Nonetheless, the International Classification of Sleep only if the female has been involved in sexual behaviours does Disorders (ICSD-10) includes a category of menstrual sleep the corpus luteum secretes progesterone [34] (see Fig. 1c). related disturbances: menstrual-related hypersomnia [2], Mice show little change in sleep distribution during the which is described as consistent episodes of hypersomnia that oestrous cycle, with variations between different mouse begin 1 week before menses. In line with this, subjective day- strains, but overall limited differences in oestrous cycle. For time sleepiness was rated higher in the luteal phase by a group instance, in the C57 strain, there is decreased REM during the of women who were freely allowed to take 10 min naps in a night of proestrous compared with diestrous [35], followed by 24-h day period. Slow wave sleep (a key component of an increase the next day [18� ]; this phenomenon is also seen in NREM) was also more frequent during luteal phase compared Sprague-Dawley rats [14]. On proestrous night, rats show an with the follicular phase. Both hypersomnia and insomnia increase in wake and decrease in NREM compared with seem to be linked to abnormal temperature variation due to oestrous [26]. As for sleep architecture, proestrous females higher levels of progesterone and oestrogens [6]. had a higher number of short duration wake bouts compared Body temperature is also highly dependent of the hormone with oestrous, metestrous, and diestrous [18� ]. These differ- level and menstrual phase. Men and women are most similar ences are dependent on light/dark cycles. During the light in the circadian regulation of the body temperature in the phase, REM sleep is not affected by the oestrous cycle, but follicular phase of the latter [38]. Body temperature in women in dark phase, REM is inhibited during proestrous and seems to be at its lowest during the periovulatory days, due to oestrous [14]; this has also been shown in ovariectomized rats the high level of oestradiol. In the luteal phase, body temper- with oestradiol replacement (which tries to mimic proestrous ature increases due to high levels of progesterone. During the night) having decreased REM and NREM only during the night, temperature falls, but during the luteal phase, night tem- dark phase [19]. perature shows a reduced amplitude decay, which has been attributed to the progesterone counteracting the hypothermic Humans action of melatonin [6]. Wright and colleagues [39]studied the relationship between phase of the menstrual cycle, use of In women, menstrual cycle can vary from 24 to 35 days, with oral contraceptives and circadian regulation on alertness and an average of 28 days and is divided in (i) a follicular phase, body temperature in a constant routine paradigm. They did not during which the ovarian follicles develop and mature, and find an effect of oral contraceptives or phase of the menstrual blood shedding occurs, (ii) an ovulation phase in which the cycle in circadian phase, however during the luteal phase mature egg is released and leaves the fallopian tube and (iii) a women showed higher levels of alertness (measure with the luteal phase characterized by the formation of the luteal corpus Psychomotor Vigilance Test) and this is related to lower day- (uterine lining) [33�� ]. On the first day of menses, the hor- time temperature. Melatonin levels were similar in luteal mones regulating the cycle are low (progesterone, oestrogen phase and follicular phase, but higher along night hours for luteinizing hormone, follicle-stimulating hormone). In con- women using oral contraceptives, who also displayed higher temperatures. trast, during the luteal phase, follicle stimulating hormone Curr Sleep Medicine Rep (2021) 7:1–14 5 Sleep continuity and sleep efficiency measured through during the luteal phase and the frequent sleep disturbances polysomnographic recordings of healthy women remain sta- displayed during menopause (due to the sudden drop of pro- ble across the different phases of the menstrual cycle [30]. gesterone) [23]. Individual percentages of sleep stages are also comparable Sleep’s role in cognition and specially the consequences of across phases. Only a shorter sleep latency and decrease per- its deprivation have been extensively studied in literature. centage of REM sleep during the luteal phase are documented, Sleep is known to influence cognitive abilities [10, 45], in- but this effect appears only on the first sleep cycle [36]. These cluding working memory, planning and, hence, it is expected changes seem to be linked to the mentioned raise in body that sleep differences in both sex and menstrual cycle will also temperature that takes place during this phase [40]. As for affect learning and memory. the women using hormonal contraceptives, they have been associated with lower percentage of slow-wave sleep (SWS), shorter REM sleep onset latency and increased REM sleep Effects of Sex on Cognition efficiency in the active phase of the contraceptive method and this compared with women [3]. SWA and SWS do not As mentioned before, sex differences seem to permeate the appear to be sensitive to the influence of menstrual cycle; organization of brain [8, 46] and even the mechanisms behind however, a transient increase during the first sleep-cycle was the observed cognitive performance in certain tasks, such as evident in a study by Driver and colleagues, and it was attrib- synaptic plasticity (in the long- and short-term) and activation uted to temperature increase during the luteal phase [40]. of other molecular pathways (neurotransmitter’srelease, gene Spindle activity is reported as higher in women during their expression and transcriptional factors) [47]. It is difficult to luteal phase [41], concretely their duration, number and spec- distinguish between the cause of such differences, since sex tral frequency increases during mid-luteal phase, especially hormones, sex chromosomes and environmental factors inter- after the first cycle of sleep [40]. The upper spindle frequency act to enable cognition and behaviour. In this section, the most (14 to 16 Hz) appears as particularly sensitive to menstrual relevant findings regarding the differential performance of fluctuation. Ishizuka and colleagues [42] report spindle fre- sex, in both humans and rodents in cognitive performance, quency reaching a high peak 3 days before menses and a are described. valley 18 days before the period. Plante and Goldstein [43] propose that this luteal enhancement of spindles can be attrib- Rodents uted to higher levels of progesterone, as their sample of wom- en taking the progestin drug Medroxyprogesterone acetate, Studies of gonadal hormones and sex differences in learning displayed increased spindle density, power and amplitude in have shown mixed results, probably because sex studies do the spindle band (11–16 Hz). In this study, menstrual phase not usually discern between the different stages of the oestrous was not controlled. This effect was explained as progesterone cycle in females. Differences in hormone levels can alter the being responsible for an increased binding in the reticular strategies used by rodents to perform different tasks. These thalamic nucleus to GABA receptors, which may enhance differences in cognitive strategy seem to emerge after puberty spindles role in brain inhibition [4, 36]. in rats [48], one potential reason why the role of sexual hor- mones seems to be central. In general, as with humans, male Interim Summary rodents are attributed to have better spatial learning, which is expressed in better spatial working and reference memory [49, Regarding effects of menstrual cycle in sleep, findings are 50]. In the skilled reaching task (Fig. 2a), in which rats have to weaker than expected in both humans and rodents. In rodents, reach with their paws through a small opening for a food changes seem to be more related to sex than to hormonal pellet, females had better performance during acquisition of variation with females spending more time in wake and less the task compared with males. In a discriminative fear- in NREM during the light phase. One exception is the ob- conditioned to context task (Fig. 2b), in which the rat has to served decrease of REM on proestrous night and rebound of associate a context with a foot shock, Long Evan females REM on the following oestrous day in rodents. In humans, showed longer freezing time than males, showing an increased effects of menstrual cycle in sleep are intertwined with body emotional memory to a particular context [53]. temperature changes across menstrual phases. The intersec- There are many factors to consider, apart from sex, when tion of human and animal studies indicates that progesterone trying to compare these different findings, such as age, strain, reduces arousal, while oestrogen increases the availability of and variations in the tasks themselves [54], as well as the norepinephrine, decreasing the time in REM sleep [6]. These housing conditions (enriched environments, physical activity, findings are consistent with the documented anxiolytic/ handling). At the same time, when studying the menstrual sedative effect of oestrogen and progesterone in animal phase influences, studies introduce a large variation in timing, models [6, 44] and the reported decrease in sleep quality route, length and dosage of hormone administration. Rhyme “Road” Name Animals 6 Curr Sleep Medicine Rep (2021) 7:1–14 Fear conditioning to context Skilled reaching task c Image rotation Which object corresponds to the original figure? a b Motor skills Emotional memory Original T maze d Morris Water Maze Natural alternation f Response delayed matching to sample task Working memory Wet navigation Radial arm strategy maze Allocentric navigation Y maze Delay How is it solving the task? Object placement Object recognition g Attention tasks/Prime Fragment Object Fluency tasks h j Novelty of location Explore novelty Rhyme Raise your hand if the word Identification Road/Toad/Code has been said before prime Semantic Words with c (cake/curry/cold) Flea Delay Delay Category Fruits (plum/pear/orange) Sample Test Sample Test Horseshoe Toad Working spatial memory Category exemplar Fragmented object test Object to position assignment generation Place the objects where they belong Plum Animals (flea/toad) Positions-only assignment Place the objects where they belong Experimental trial Combined condition Place the objects where they belong Fig. 2 Examples of tasks used for evaluating learning in humans and recently. Natural alternation between arms is counted. f Morris water rodents. a Skilled reaching task; the animal has to learn to reach maze; animal is placed in circular pool with opaque water, surrounded through a small opening, grasp a food reward and retrieve it. Tests fine by extra maze cues (black square and triangle), where they have to swim motor skills. b Fear-conditioning to context; animal is placed either in the to find a submerged platform (red line). The dashed line represents the light box, or in the contiguous dark box, each paired with a specific aroma swimming pattern of the rodent to reach the platform, from which as well. Both boxes are connected but the passage is blocked once the distance and latency are measured. g Object placement; animal is animal moves to the contiguous context, where a foot shock is given. presented in a box with two identical objects during a sample trial, with After a day delay, a probe is conducted, where the animal is exposed to extra maze cues, and exploration time of the objects is measured. During the shock context, and the freezing time is measured, or the animal is the test trial, one of the objects is moved to a different position. h Object placed in the non-shock context and the latency to enter the shock context recognition. Animal is presented in a box with two identical objects is measured. c Example of item in an Image rotation test. A classically during a sample trial, and exploration time of the objects is measured. used task to measure spatial cognition. d Delayed matching to sample During the probe, one of the objects changes identity but not position. i task. During several trials the rewards stays in the same arm, and the Working spatial memory test as described in Postman et al. [51]. Contains animal has to turn towards the east of the room, or turn right to get it. a trial stimulus showing ten objects that disappear and a test, in which There are extra maze cues. During the probe, the maze is turned 180°, or objects are to be reordered as per three conditions: object to position in this case, if using a plus maze, the lower arm is cut off and the animal assignment (original position marked by a dot), positions only (organize now starts from the north. If the animal, during the trials used an the objects in space) and the combined condition (organize the object egocentric or response strategy, it would turn right to reach the goal. If, without spatial cue). j Implicit memory tests, such as the fragmented on the other hand, the animal had been using the cues to navigate towards object identification (middle) uses perceptual priming and category the reward, it would have been using allocentric navigation. e Natural exemplar generation test (right) uses semantic categories, reported in alternation. Either on the Y maze (dashed lines) or the radial arm maze Maki and colleagues [52] (black line), animals need to remember in which arms had they been Humans because they remain stable even when this factor is controlled for [55]. On a different note, women perform on average Numerous studies [46, 47, 51] point towards men and women worse than men in an object position memory task, even when consistently performing differently in memory tasks accord- verbal interference (repetition of meaningless syllable) was ing to the prevalence of verbal vs. spatial processing of infor- used [51]. However, the crucial element appears to be whether mation. For instance, women on average perform better in information can be verbally described, which gives an advan- word recall and recognition, story recall, name recognition tage to women (in these studies, menstrual cycle phase is and object (including faces) recognition in complex settings. typically overlooked) [55]. Also, the need to perform mental These results do not seem to be explained by verbal fluency, rotation of objects (see Fig. 2c) also seems to be critical, since Test Training Curr Sleep Medicine Rep (2021) 7:1–14 7 women from puberty on seem to display diminished perfor- Influence of Menstrual Phase on Cognition mance compared with age-matched males [56]. In contrast to navigational and spatial reasoning tasks, In this section, we will summarize the influence of the men- in verbal activities (fluency, recall of wordlists and strual phase on memory first in human subjects and then in categorial naming) women on average appear to surpass rodents. men’s performance [46, 47, 51, 55]. However, the origin of such differences is controversial, since performance divergence appear early in childhood (before sexual mat- Rodents uration) and persist after menopause and seems to be more related to divergent brain activation (more Depending on the type of information needed to solve a par- lateralized in women) than to the effect of sex hormones ticular task, the presence of gonadal hormones will favour or [46]. This verbal advantage has been connected to more deter cognition. In tasks involving working memory, such as precise episodic memory in women [55–57]. Thus, epi- T maze delayed matching to sample task (Fig. 2d), which can sodic memory and particularly memory, involving emo- be solved either by a place strategy (allocentric navigation/ tional arousal, seem to be favoured in women, and this always turning towards a location in the room) or a response advantage has been attributed to the dimorphic activation strategy (egocentric navigation/always turning to the right), of the left amygdala in women (presumably concentrating disambiguation of strategy use can be determined by rotating in context details) compared with right amygdala activa- the maze 180°, or as shown in the figure, with a plus maze and tion in men (focusing on gist encoding) [46]. starting from a different position within the maze. Females Besides physiological/structural differences between the during proestrous are more likely to exhibit a place strategy, sexes to explain the observed performance, men and women and during oestrous response strategies [60], both in appeti- can differ in the strategy used to resolve experimental tasks tive (food reward) and aversive wet navigation tasks (sub- (just as seen in rodents). For instance, in navigational memory, merged platform) [61]. Similarly, in ovariectomized rats treat- it has been reported that women rely more on egocentric cues ment with oestradiol while performing a plus maze, in which while men incline towards allocentric references. Solving place and response strategies can be evaluated, oestradiol strategies in turn will affect which brain structures are in- favoured place strategies and decreased performance when volved, and in turn, different brain areas can be more or less response strategies were required [62]. impacted by sex hormones [55]. Concretely, as per animal In the Y maze [60] or radial arm maze (Fig. 2e), where evidence [58� ], oestrogen level has been pointed out as factor working memory is measured by alternation, performance modifying cognition by enhancing plasticity in key areas such during oestrous was decreased compared with other stages as the hippocampus and prefrontal cortex [59], in female but of the cycle. Testing alternation in the T maze shows that mice not in males [8]. during proestrous had more alternations than mice in diestrous [63]. In ovariectomized rats, performance during early acqui- sition in the radial arm maze was decreased compared with Interim Summary sham operated females [64], and treatment with oestradiol improved performance [65]. Similarly, in a water radial arm In both humans and rodents, a higher performance is maze in which platforms were removed (which increases the credited consistently to male individuals in tasks related working memory load as the trials advance), ovariectomized to spatial navigation and a higher performance to females rats treated with oestradiol made fewer mistakes during the in tasks related to domains other than spatial. The factors latest trials [66]. In contrast, for wet navigation tasks such as contributing to such observed advantages are not clear the classical Morris water maze (Fig. 2f)[67], in which per- and range from anatomical, and functional differences in formance is measured by path length and latency to find a the brain (mainly due to oestrogen level), to confounders submerged platform, rats at proestrous show decreased perfor- such as stress and experimental manipulations. For in- mance during acquisition [68] and later trials [69]. In mice, stance, experimentally instilled stress before a navigation- however, it seems that it is during oestrous that they have al spatial task affect women but not men, independent of worse performance [70]. Ovariectomized rats, treated with cycle phase [60]. In women, the presence of language and oestradiol and oestradiol plus progesterone, decreased their semantic processing gives another dimension to the dif- performance [71]. In a variation of this navigational task, in ferences in cognitive performance between sexes. As the which there is a cue hanging above the platform (a beaconing range for variation for sex-dependent performance is strategy) for each trial the platform location and the cue would wide, in the next section, we will focus on cognitive tasks move to a new position together, rats during proestrous exhib- that show differences in females across the menstrual ited better performance during acquisition than female rats in oestrous or diestrous [69]. Ovariectomized rats, treated with phase. 8 Curr Sleep Medicine Rep (2021) 7:1–14 progesterone and oestradiol plus progesterone, decreased cue- the perceptual modality exerted carryover effects when first guided task performance [71]. encountered during the follicular phase relative to the retest In object placement (Fig. 2g) and object recognition (Fig. during luteal phase. These results were highly correlated with 2h) tasks, in which performance is evaluated as exploring time estradiol level in the participants. of novel versus familiar locations or objects respectively, both In terms of recollection of emotional memory (stimuli rats [72] and mice performing object recognition during causing positive or negative arousal), Bayer and colleagues proestrous and oestrous show better discrimination of the nov- [44] found that women during their follicular phase displayed el object than in diestrous or metestrous [63, 73], and discrim- increased detail and contextual recall (48 h after encoding) of ination during proestrous is better than oestrous [63]. Rats negative images compared with luteal phase and to positive performing the object placement task showed discrimination and neutral images, which were not affected by menstrual for the novel placement only during oestrous [72]. phase. These differences were also correlated to decreased Ovariectomized rats treated with oestradiol immediately after hippocampal (and in a portion of the accumbens) activation the sample trial showed at test trial better discrimination of the during the luteal phase in comparison with the follicular displaced or novel object. This response was dose-dependent phase. There is also a reported differential lateralization of (object placement task needed higher concentration than ob- the amygdala during encoding of negatively arousing images, ject recognition task, which fits into proestrous improving with women showing greater activation in the left amygdala place and oestrous improving response strategies). and men showing the opposite pattern [77], but this asymme- Ovariectomized rats without hormone treatment showed try has also been reported for encoding happy faces and seems worse performance in the object placement task than in the to be related to activation of other brain areas [78]. object recognition task, and treatment with oestradiol given Convergently, the amygdala appeared to be activated with 30 min before (or right after sample trial) improved discrimi- preference for encoding emotional memory in women during nation in both tasks [74]. For further details in ovarian hor- the luteal phase. Interestingly, Bayer’sneuroimaging results mones regulating object recognition and object placement seem to support the idea of a shift in strategy for dealing with tasks, see [75]. cognitive tasks during the different phases of the menstrual cycle, with a focus on arousing emotional aspects during fol- Humans licular phase (linked to anterior hippocampal activation and accumbens) and a more semantic approach in the luteal phase It has been claimed that women’s advantage in tasks in which (with preferential activation of posterior hippocampus). they outperform men (verbal) intensifies during the luteal phase of the cycle when female hormones are of their highest Interim Summary levels. Contrarily, during women’s menses, with low levels of female hormones, their performance drops in those tasks [41]. Hormonal level changes during the menstrual cycle seem to Men and women are more similar in spatial centred tasks have an effect on the performance of both female humans and during women’s menses [76]. Classically, spatial memory rodents. Those changes can be related to differential activation and spatial cognition tasks have been used to study the change of brain areas implicated in cognition and emotion (for in- in performance for women during the different phases of their stance amygdala and hippocampus), as well as use of cogni- cycle. In their study, Postma and colleagues [51]showed that tive strategies to resolve tasks during different phases of the women displayed difference in performance only in the abso- cycle. Overall oestrogen seems to facilitate memory encoding lute (fine grain) positioning of objects (see an example in Fig. and recall during experimental tasks, and its effects seem to be 2i) with respect to men and this difference was obvious when related to its action in neuronal spine density, neurogenesis, women were in their menses. The intake of oral contraceptives connectivity and ultimately plasticity in key brain areas as the did not exert significant effects on position accuracy for this hippocampi (for a detailed review on this topic, see the work sample. Effects in women were not related to levels of testos- of Hyer and colleagues [58� ] and Romeo et al. [8]). A sum- terone during the menstrual phase, but more likely to the level mary of these effects can be seen in Fig. 3. The effects of of oestrogen. progesterone are less clear, and research is needed to see if A study by Maki and colleagues [52]showed thatperfor- has complementary or opposite effects to oestrogen [8, 44]. manceinanimplicitmemorytask(based on Category Exemplar Generation: an example primes future word pro- duction) was better for women in the luteal phase compared Sex Differences in Sleep, Learning with the follicular phase. On the other hand, Fragmented and Memory Object Identification (a perceptual implicit test) showed great- er priming effect in the follicular phase compared with In this section, we will highlight the findings in studies that midluteal phase (see Fig. 2j). Moreover, priming effect in take into account both sleep and cognitive performance in Curr Sleep Medicine Rep (2021) 7:1–14 9 Spindle frequency valley = Alertness Similar body temperature in men and women Body temperature Body temperature (Progesterone action) Priming effect from perceptual stimuli Performance in implicit memory Sleep latency task with verbal priming Recall of details and REM % during first contextual facts in Hormone Amygdalar activation in memory sleep cycle emotional memory tasks levels task compared to FP Spindle density Performance in recall of word- Hippocampal activation during associated pairs (estradiol) and encoding of emotional memories finger tapping task (progesterone) Semantic approach Spindle frequency No specific findings to information encoding Emotional approach to Sleep insomia complaints encoding information Fine-grain spatial task differences Response strategy REM Place strategy Wake Working memory Working memory NREM (Y maze) (Y maze) REM Morris Water Morris Water Hormone Maze Maze levels acquisition acquisition Fig. 3 Graphic summary of main findings in sleep and cognitive menstrual phases in cognition and sleep. Only the results for proestrous performance during the menstrual/oestrous cycle in women and rodents. (on the left) and oestrous (on the right) are shown. The sun represents the a Main findings in humans for differences during menstrual phases in day or light phase and the moon the night or dark phase cognition and sleep. b Main findings in rodents for differences during relationship to sex and menstrual cycle changes in human and foot-shock. On a test 24 h later, the latency for the animal rodent models. It is important to underscore the need for stud- to enter the foot-shock context is measured. Under control ies in this topic to better understand how these differences conditions, males had longer latencies than females before affect cognitive processes. entering the shock section, but under sleep deprivation, it was females that showed a longer latency compared with Rodents males, showing that females express a stronger fear mem- ory than males under sleep deprivation conditions. In the object recognition task, there were no sex differences after REM sleep deprivation affected the performance in the sleep deprivation [81�� ], but there was a main effect, in Morris water maze of females more than of males [79], which the discrimination index dropped for both sexes. and ovariectomized rats had worse performance compared They also showed that after sleep deprivation, at hippo- with intact females [80]. In the same page, in a fear con- campal and cortical level, there was an elevated concen- ditioning to context task (Fig. 2b), NREM and REM sleep tration of kynurenic acid (a metabolite of tryptophan deg- deprivation, before and after acquisition of the task, af- radation) known to affect cognition, on males but not fected males more than females [81�� ]. Rats were exposed females. This effect was lost when males were to two contexts, one of which would be associated with a 10 Curr Sleep Medicine Rep (2021) 7:1–14 gonadectomized. When corticosterone levels were mea- different in skill performance or sleep parameters than control sured, these were higher in females than males following males. The phase of the menstrual cycle was not controlled in sleep deprivation [81�� ]. this study; however, the authors speculate that oestrogens may exert protective effects on the sleep of female ex users. Humans Interim Summary Sex differences related to sleep-dependent performance in cognitive tasks are reflected in a small number of experimental By observing the differential effect of sleep deprivation on results in humans, but there is not an integrated picture of the memory tasks performance in males and females, the sex di- relationship. These findings are described next. morphism consequences in sleep-dependent learning can be McDevitt and colleagues [82] reported that differences in tackled. From these studies, it seems that under many circum- memory consolidation after a day nap are observed for per- stances, females perform better compared with males after ceptual learning in a task to discriminate targets’ motion di- sleep deprivation. As animal studies revealed, this could be rection. In this task, women showed a more generalized im- related to elevated corticosteroid levels, a neuromodulator re- provement, extending to target-direction and visual field loca- lated to enhanced encoding under acute paradigms of stress. tions not trained before sleep; while men only improved their Also, in purely sleep-dependent tasks (visual memory and performance for the trained motion direction. In women these emotional memory) females seem to benefit more from sleep findings were independent of whether the nap contained or not than males, these findings will be revisited in the next section. REM sleep. According to the authors, a candidate mechanism behind those differences could be the differential level of ACh hippocampal release in males and females (a fact observed in Menstrual Phase Influence on Sleep and Its rodents but not confirmed in humans), since women in their Relationship with Memory luteal phase display an increase in this neurotransmitter that would facilitate memory performance. As highlighted in the previous section, sleep-dependent learn- Koriyama and colleagues [83] found that in relation to the ing displays differential features in female and males; in the circadian time for encoding aversive stimuli (violent scenes present section, the causes attributable to variation in females from a picture), women displayed greater accuracy in the rec- due to the menstrual cycle and the implicated hormones are ognition of the scenes after they have passed their habitual described. sleep onset periods, even when men performed better in their pre-sleep onset periods. Also, women recognized aversive Rodents scenes less accurately than neutral scenes if tested in their pre sleep-onset-periods, so women display a circadian (per- Very few studies take into account both sleep and learning haps sleep-pressure-related) sensitivity to memory of aversive when looking at differences between sexes and even less stimuli, while men display a stable pattern across time. when looking at differences within the menstrual cycle. As mentioned in a previous section, sleep deprivation ap- Cordeira et al. found that sleep deprivation negatively affected pears to have differential results in men and women. performance in Object recognition in mice during proestrous Interestingly, Binks, Waters and Hurry [84] found that sex and oestrous [73�� ]. had an effect on the IQ test measure of their sample. Sleep- deprived (36 h) females scored slightly higher than sleep- Humans deprived males on the WAIS-R test, no pre-sleep deprivation scores were obtained from participants. Unfortunately, the au- Sleep-dependent memory consolidation is one of the fields thors do not discuss the implications of such finding, but it where the influence of sleep on cognition has offered abun- seems to contradict the claim that sleep deprivation affects dant evidence [87]; it is surprising that relatively few studies women more severely in their cognitive performance [4�� ], have explored the possible dimorphisms in this area. Below, as well as social jet lag impacts their academic performance the few studies that exist are highlighted. more harshly [85]. Sleep-dependent memory consolidation exhibits differ- A study into the differences for male and female ex users of ences in women across the menstrual cycle. Genzel and col- cocaine (in recovery/abstinence) [86] allowed to see that leagues [41] demonstrated that women performed at the same women are not sensitive to sleep disturbances caused by ab- level as men, during their mid-luteal phase in an associated- stinence (low sleep efficiency) as were men. Also importantly, word-pairs and finger-tapping tasks. Overall women in their women performed in a version of the motor sequence task, luteal phase in general, independently of the wake-sleep con- 24 h after learning it, as well as control participants and sig- dition assigned to them, outperformed women in their follic- nificantly better that male ex users. Female controls were not ular phase. The Nap-dependent performance increase, in both Curr Sleep Medicine Rep (2021) 7:1–14 11 the motor and declarative tasks, was more noticeable in the irregular hormonal levels (i.e. menopause) are key to disen- luteal phase of participants compared with the follicular one. tangle the relationship between sexual hormones and system Furthermore, this nap-related-enhancement was correlated consolidation of information in the brain. with increased spindle activity in both men and women, but specifically with progesterone level for the motor task and oestradiol level for the verbal one. In a different type of sleep-related memory enhancement Conclusions study, women did not display the effects of odour-sequence memory cueing (a well-established paradigm in the study of The studies presented in this review underscore the fact that sleep effects on memory consolidation) during different sex hormones, and subsequently, the menstrual cycle in fe- phases of their menstrual cycle [88]. Overall, women were males, influence sleep and cognition in a variety of ways not unaffected by the experimental manipulation, in comparison fully comprehended. Among those areas, we find an intersec- with men, for whom exposure to encoded odours during sleep tion of brain anatomical differences, activation changes in resulted in performance enhancement. The fact that specific those areas, cognitive strategies to deal with a task and brain menstrual cycle effects on the observed outcomes for the fe- plastic changes. Overall, the results of the studies reviewed male participants cannot be further explored, due to lack of here point towards not only an effect of sex and hormones experimental control of this variable, underscores the need to on sleep and cognition separately but also at a differential consider menstrual phase and the influx of external sex hor- effect on the interaction of sleep and cognition. Those effects mones (due to oral contraceptives) when it comes to describe are expressed for instance as a change of strategy in spatial the effects of sleep on memory consolidation. Since the effects navigation task in both female humans and rodents (from of sleep can oscillate according to the momentary level of allocentric to egocentric), in the fluctuating role of amygdala progesterone and oestrogen, the high oestrogen time window and hippocampi in encoding and consolidating stimuli in the for performance enhancement due to sleep (and spindle) in- different menstrual phases, as well as in the changes in sleep crease could perhaps explain the differences across samples architecture and body temperature control according to hor- obtained in research. monal level (oestrogen and progesterone). The main purpose Oral contraceptives have been shown to influence cogni- of this review was to highlight the importance and the need to tive task performance and memory results. For instance, consider sex and its significances into any research endeavour. Genzel and colleagues [89] showed in a sample of females Instead of seeing sex as a confound or a variable to control for, that memory performance for both verbal (word-pairs) as well it can be approached as an opportunity to study the role of as motor (finger tapping) tasks was beneficially influenced by hormones in cognition, sleep and their interplay. Since in fe- a delay in recall (whether it was filled with wake or nap time) males influence of sex hormones is more pronounced due to and was comparable across active or rest weeks of oral con- the cyclical variation on their level, this offers a natural milieu traceptives intake. This finding has been observed across nu- for the study of the impact of those substances in cognition, merous populations (for a review, see Stickgold [90]and memory and behaviour and the influence that sleep—as a Diekelmann, Wilhelm and Born [87]) but has been rarely complex mechanism—exerts on them. studied in women using oral contraceptives. Furthermore, Innovative methods to study the relationship between sleep women taking contraceptives are rarely divided between the and cognitive performance across the phases of the menstrual active and rest phase and by type of method used. The main- cycle need to be applied, since the literature reveals that cor- tenance of the offline consolidation effect across contraceptive relational and subjective measures do not seem to capture the weeks can be attributed to higher levels of oestrogens (spe- complexity in the changes that the female brain undergoes due cially compared with the one of women not taking oral con- to the developmental and cyclical exposure to sex hormones. traceptives) but not to an additional influence of sleep on These sex-dependent and hormonal fluctuation variations in memory consolidation. learning and cognitive performance can be studied as mediat- ed by other processes, from which sleep seems to be a topic Interim Summary especially prolific and promising. Incorporation of female samples, accompanied by standardization of normative There is a lack of studies regarding the role of menstrual cycle criteria for their parameters, into sleep research is urgently in the relationship between sleep and its effects on learning, needed. and concretely on memory consolidation. From the human Among some of the topics to be tackled is the exact role of studies, it seems plausible that different hormones affect sex steroids in sleep regulation and its complex relationship sleep-consolidation based on the type of information being with temperature oscillations in the mammal body. Animal dealt with (motor or verbal, for instance). For this purpose, studies are key to disentangle the relationship between phys- iological factors in sleep regulation and sleep behaviours and studies in women using oral contraceptives or suffering from 12 Curr Sleep Medicine Rep (2021) 7:1–14 4.�� Hajali V, Andersen ML, Negah SS, Sheibani V. 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Available from: https://doi.org/10.1016/j.bbr.2014.08.001,2015. 76. Barel E, Maayan Krispil, Inbar Yaari. Cognitive performance Publisher’sNote Springer Nature remains neutral with regard to jurisdic- across the menstrual cycle. J Psychol Cogn. Allied Academies; tional claims in published maps and institutional affiliations. 2019;4. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Current Sleep Medicine Reports Springer Journals

Sex and Menstrual Phase Influences on Sleep and Memory

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Abstract

Purposes of Review This review highlights the effect of sex differences in sleep mediated memory consolidation and cognitive performance. In addition, the role of menstrual cycle and the fluctuating level of sexual hormones (mainly oestrogen and progesterone) are stressed. Recent Findings The literature indicates that sex hormones mediate and orchestrate the differences observed in performance of females in comparison with males in a variety of tasks and can also be related to how sleep benefits cognition. Although the exact mechanism of such influence is not clear, it most likely involves differential activation of brain areas, sensitivity to neuromodulators (mainly oestrogen), circadian regulation of sleep and temperature, as well as modification of strategies to solve tasks across the menstrual cycle. Summary With the evidence presented here, we hope to encourage researchers to develop appropriate paradigms to study the complex relationship between menstrual cycle, sleep (its regulation, architecture and electrophysiological hallmarks) and per- formance in memory and other cognitive tasks. . . . . . . . Keywords Menstrual cycle Humans Rodents Sex differences Cognition Memory Sleep Sleep-regulation Introduction with studies that include sleep, learning and memory. Within each section, we describe sex driven differences as well as Sex is a variable known to influence diverse aspects of brain menstrual phase differences, focusing in common results and behaviour, but surprisingly, sex differences and their con- across human and rodent studies. While rodent studies present sequences are often overlooked and are considered negligible with the opportunity for controlled designs (i.e. administration by many researchers. Instead, rodent and human studies re- of hormones and gonadectomization) and limiting the influ- gard male and female subjects as simply equal and opt to ence of confounders such as self-reported sleep and cultural include only males; thus, females end up being underrepre- bias, they rely on behavioural measures as proxy of the sub- sented in neuroscience research [1]. In this review, in addition jacent cognitive skill, requiring extra efforts to clarify a par- to general sex differences, we also discuss how a specific ticular strategy taken by the individual to solve an experimen- aspect of sex differences (the menstrual cycle) may exert in- tal task. Human studies are often weak in control and can only fluences in sleep and learning in the context of sleep’scontri- capture snapshots of the desired variable studied, which can bution to cognition. We start with the general effects on sleep, be an important limitation in a phenomenon of repetitive na- continue with effects on cognition and memory and finish ture such as menstrual cycle. Both types of studies offer a window into the fluctuating influence of menstrual cycle and sex hormones in the functioning of female individuals. This article is part of the Topical Collection on Sleep and Learning * Alejandra Alonso a.alonsogarrido@donders.ru.nl Influence of Sex on Sleep Department of Neuroinformatics, Faculty of Science, Donders Sex differences can be anatomical or functional [2] and ex- Institute for Brain, Cognition and Behaviour, Radboud University, P.O. Box 9010, 6500 GL Nijmegen, The Netherlands press themselves both at volumetric and connective levels [3]. Those differences emerge early on during development and Department of Psychology, Universidad de los Andes, Cra. 1 N° 18A–12, Bogota, Colombia are later reinforced by exposure to sex steroids [4�� ]. 2 Curr Sleep Medicine Rep (2021) 7:1–14 Circulating gonadal hormones exert their effects on not only promote REM during the light phase and reduces NREM delta secondary sexual features but also most brain regions express power (1–4 Hz) during the dark phase [16, 19]. Gonadectomy oestrogen and progesterone receptors. These brain regions on mice of both sexes eliminates most of the differences seen include sleep regulating areas such as the ventrolateral in recovery sleep after sleep deprivation [13]. preoptic [2, 5] median preoptic and suprachiasmatic nuclei, To further study the effect of sex chromosomes in sleep, the lateral hypothalamus [3], as well as areas involved in cogni- core four-genotype mouse model [20]allowstohave females tion and memory such as the prefrontal cortex [6] and the and males with either XX or XY chromosomes. This is a hippocampal formation [7, 8]. transgenic line that manipulates the presence or absence of Sleep presents itself in a complex form, featuring behav- the Sry gene, which determines testes development and is ioural (for instance, diminished response to stimuli), as well as normally found on the Y chromosome. By knocking Sry out physiological changes compared with wakefulness (such as of the Y chromosome, they can obtain females XY, and by brain activity that displays distinct patterns of neuronal firing). knocking Sry into the X chromosome, they can obtain males In most animals, it is possible to differentiate between two XX. Studies in this line showed that genetic sex does not main sleep stages: non-rapid eye movement sleep (NREM) influence sex differences in spontaneous sleep, but rather and rapid eye movement sleep (REM) [9]. NREM is distin- has an impact in recovery sleep, where XY females had more guishable by its higher amplitude, slower waves relative to total recovery sleep and more NREM than XX females at the wake, while REM displays a more similar brain activity pat- midpoint of the dark phase, suggesting that increased sleep tern to wakefulness, with low amplitude and high frequency propensity is linked to the Y chromosome. In gonadectomized waves [10](Fig. 1a). Muscle atonia and the characteristic eye animals, after sleep deprivation, the dissipation of delta power movements (similar to saccades) that give name to the state was quicker in XX males than XX females [12], indicating are also a hallmark of REM. that in the absence of female gonadal hormones, the advantage that females had in recovery sleep compared with males is Rodents lost. When studying sleep in rodents, it is important to note that, Humans contrary to humans, they are most active during the dark phase, and their sleep pattern is polyphasic, with several bouts Overall, female humans display more consolidated sleep (less of sleep during both light and dark phases of the day (see Fig. awakenings), shorter sleep latencies and lower percentage of 1b). light sleep, than aged-matched males [3, 21], and this is con- Studies on spontaneous sleep show that female mice have sistent for different age groups and experimental assessments less total sleep and daily NREM compared with males of sleep (laboratory vs home sleep-recoding conditions). [11–13] and, during the dark phase, males exhibit more Paradoxically, women report consistently worse subjective wake-sleep shifts, while females have longer bouts of wake- sleep quality than men. Females tend to describe their sleep fulness [12]. REM is also decreased in female rats [13]and quality as poor due to nighttime disruptions, insufficient quan- mice [11]. Gonadectomy in mice of both sexes eliminates the tity and long sleep latencies. Women also claim suffering from differences seen in total spontaneous sleep and NREM, as insomnia in a greater proportion than men [22, 23], and this well as in delta power and sleep fragmentation, which implies disruption grows stronger as women age (with menopause that the differences in current hormones levels are responsible onset) [24]. for these variations in sleep and not general developmental Concerning circadian regulation of sleep, women seem to differences. Ovariectomized rats show decreased REM and have shorter and earlier rhythms of temperature change and total sleep time during the light phase, compared with castrat- melatonin secretion (induces drowsiness and sleep) under a ed males [14]. When treated with stable levels of 17β- normal schedule [3]. It has also been documented that women oestradiol or oestradiol and progesterone, they show increases go to bed and wake up earlier than men [25] Since often, wom- in wake and decreases in REM and NREM during the dark en extend the time before going to sleep to after the melatonin phase [15–17]. peak, this could be related to their complain of longer sleep Studies on recovery sleep after sleep deprivation in mice onset latencies [23] due to the missing of the optimal time- show for both sexes decreased NREM the first 2 h of recovery window for sleep onset. However, under a 28-h desynchrony sleep, followed by an increase during the first half of the dark paradigm (9.5 h sleep and 18.5 h wake), women show lower phase, but this rebound is greater in females [13]. Female rats accuracy and exert more effort in cognitive tests after also showed an increased NREM rebound during recovery prolonged wakefulness compared with men [26]. sleep as well as increased delta power compared with males In terms of the features of brain oscillatory events during [18� ]. Studies on gonadectomized rats with hormone implants sleep (i.e. power of electroencephalography signal and its fre- show that during recovery sleep oestradiol and progesterone quency), Carrier and colleagues [27] showed, in a sample of Curr Sleep Medicine Rep (2021) 7:1–14 3 ab Wake Wake REM REM NREM N1 Light phase N2 Wake N3 REM NREM A night’s sleep Dark phase cd Estrous cycle Menstrual cycle Progesterone Progesterone Estradiol Estradiol Menses 1 M Diestrous Proestrous Estrous Metestrous D 6 days 12 Follicular phase Luteal phase 8 days Fig. 1 Diagrams of the menstrual cycle and sleep patterns in humans and and wake throughout the day. During their active phase, they also sleep, rodents. a Sleep pattern in humans. N1 is the transition state into sleep, with bouts of short sleep-wake transitions followed by a wake period, characterized by drowsiness and a low arousal threshold. N2 is a deeper back to the sleep bouts. c Oestrous cycle in rodents, divided in diestrous, sleep than N1, during which breathing and heartbeat decrease. It is also in proestrous, oestrous and met oestrous for an average of 5 days. During this state when sleep spindles can be observed. N3 also known as slow proestrous, a peak of estradiol followed by a peak of progesterone gives wave sleep is characterized by a predominance of delta oscillations, with place to ovulation. Rodents do not menstruate; instead, they experience a the EEG signal showing slow frequencies and high amplitude resorption of the endometrium, marked as magenta lines. d Menstrual waveforms, believed to be a regenerative period during sleep. REM cycle in humans is divided into follicular phase and luteal phase, with sleep or paradoxical sleep is characterized by an EEG state of high an average length an average of 28 days. On the last days of the follicular frequency and low amplitude oscillations, similar to wake, but with phase, estradiol increases, followed by a spike of luteinizing hormone complete muscle atonia. The line depicts transitions between states which drives ovulation. The corpus luteum remaining secretes throughout the night, with REM episodes becoming longer as the night progesterone, and when both progesterone and estradiol are low, the progresses. b Sleep patterns in rodents. These animals sleep the most uterine lining detaches along with the unfertilized egg, with the menses during the light cycle, where they have numerous short bouts of sleep marked as a magenta box men and women between 20 and 60 years, that women display display greater SWA rebound after sleep deprivation, which higher power in diverse physiological frequencies considered has been interpreted as women accumulating a greater sleep during sleep (delta 0.1–4Hz, theta 4–7 Hz and alpha 8–12 Hz debt than men and making them more sensitive to sleep loss and spindles 14–16 Hz). Spindles are a prominent feature of due to work-shifts and more propense to accidents [4�� ]. NREM sleep and have been associated, with intelligence and learning capabilities [28, 29]. A difference in spindle power Interim Summary between the sexes has been consistently described [30]and may be related to the variations in spindle topography [31]. In sum, across both rodents and humans, sleep differs between For instance, a study by Huupponen and colleagues [32] the sexes for variables such as sleep architecture and its circa- found that women had a higher percentage of spindles in the dian regulation, as well as features of electrophysiological left frontal electrode (Fp1-A2) and men displayed more spin- events characteristic of sleep (for instance, spindles and slow dles in the occipital electrodes (O2-A1). However, it is not wave activity differ in their power and frequency). However, completely clear whether this is due to lower skull thickness in terms of observed sleep quality, the direction of the differ- in women, since skull thickness could influence surface elec- ence seems to be opposite among rodent findings and human troencephalography power and thus spindle detection [33�� ]. studies, since the latter point towards better sleep- quality in Regarding slow wave activity (SWA), a low-frequency (2- females not seen in female rodent models. 4 Hz) activity observed in NREM and a proxy for sleep pres- sure, men and women do not show differences in power, but the proportion of SWA was more strongly regulated by circa- Influences of Menstrual Cycle on Sleep dian rhythms in women than in men. As for age effects on sleep, mid-age women display greater percentage of SWA After puberty, females experience on a regular basis changes than same-age men [27] and SWA/delta decline is less severe in the reproductive system that allow for pregnancy to occur, in women than in men [24, 25]. In the same direction, women known as the menstrual cycle. It allows oocytes to mature and Relative hormone concentration Resorption of endometrium Ovulation Relative hormone concentration Ovulation 4 Curr Sleep Medicine Rep (2021) 7:1–14 prepares the uterus by thickening the uterine lining. Different and oestrogen rise; as the non-fertilized ovule degenerates, hormones produced by the hypothalamus and the gonads or- the production of hormones drops again [36]. Sexual steroid chestrate the different stages of the menstrual cycle; however, hormones levels and the feedback for their cyclical regulation these hormones affect not only the reproductive system but depend on the central nervous system. The nature of the re- also the nervous system. In this section, we will highlight how lease of such substances is recurrent and pulsates across the the menstrual cycle influences sleep on both humans and cycle, and therefore, their effects are transient in nature [37] rodents. (Fig. 1d). Sex differences in reported sleep quality begin in the ado- Rodents lescence, with the onset of sexual maturation (menarche in women) [23]. As previously mentioned, subjective sleep qual- In rodents, the oestrous cycle lasts around 5 days and is divid- ity is lower in women but appears as specially affected before ed in proestrous, oestrous, metestrous and diestrous. the menses [38] and women (mainly those affected by pre- Proestrous occurs the day before ovulation, with the highest menstrual disruptive symptom [36]) report insufficient and concentration of progesterone and oestradiol, the highest peak fragmented sleep [30]. Yet insomnia reports from women ex- is at the end of the light phase for oestradiol, and at the start of tend across all phases of the menstrual cycle [23], but insomnia the dark phase for progesterone. Oestrous is ovulation day, worsens during the premenstrual phase (mid-luteal phase) and with oestradiol and progesterone starting to decay; during is linked to women’s anxiety and perception of life-disruption metestrous and diestrous, oestradiol starts to increase gradual- due to the menses [3, 23]. Paradoxically, oral contraceptives do ly, with a small increase in progesterone. In most mammals, not seem to influence subjective sleep quality [6]. after ovulation, there is a luteal phase; however, in rodents, Nonetheless, the International Classification of Sleep only if the female has been involved in sexual behaviours does Disorders (ICSD-10) includes a category of menstrual sleep the corpus luteum secretes progesterone [34] (see Fig. 1c). related disturbances: menstrual-related hypersomnia [2], Mice show little change in sleep distribution during the which is described as consistent episodes of hypersomnia that oestrous cycle, with variations between different mouse begin 1 week before menses. In line with this, subjective day- strains, but overall limited differences in oestrous cycle. For time sleepiness was rated higher in the luteal phase by a group instance, in the C57 strain, there is decreased REM during the of women who were freely allowed to take 10 min naps in a night of proestrous compared with diestrous [35], followed by 24-h day period. Slow wave sleep (a key component of an increase the next day [18� ]; this phenomenon is also seen in NREM) was also more frequent during luteal phase compared Sprague-Dawley rats [14]. On proestrous night, rats show an with the follicular phase. Both hypersomnia and insomnia increase in wake and decrease in NREM compared with seem to be linked to abnormal temperature variation due to oestrous [26]. As for sleep architecture, proestrous females higher levels of progesterone and oestrogens [6]. had a higher number of short duration wake bouts compared Body temperature is also highly dependent of the hormone with oestrous, metestrous, and diestrous [18� ]. These differ- level and menstrual phase. Men and women are most similar ences are dependent on light/dark cycles. During the light in the circadian regulation of the body temperature in the phase, REM sleep is not affected by the oestrous cycle, but follicular phase of the latter [38]. Body temperature in women in dark phase, REM is inhibited during proestrous and seems to be at its lowest during the periovulatory days, due to oestrous [14]; this has also been shown in ovariectomized rats the high level of oestradiol. In the luteal phase, body temper- with oestradiol replacement (which tries to mimic proestrous ature increases due to high levels of progesterone. During the night) having decreased REM and NREM only during the night, temperature falls, but during the luteal phase, night tem- dark phase [19]. perature shows a reduced amplitude decay, which has been attributed to the progesterone counteracting the hypothermic Humans action of melatonin [6]. Wright and colleagues [39]studied the relationship between phase of the menstrual cycle, use of In women, menstrual cycle can vary from 24 to 35 days, with oral contraceptives and circadian regulation on alertness and an average of 28 days and is divided in (i) a follicular phase, body temperature in a constant routine paradigm. They did not during which the ovarian follicles develop and mature, and find an effect of oral contraceptives or phase of the menstrual blood shedding occurs, (ii) an ovulation phase in which the cycle in circadian phase, however during the luteal phase mature egg is released and leaves the fallopian tube and (iii) a women showed higher levels of alertness (measure with the luteal phase characterized by the formation of the luteal corpus Psychomotor Vigilance Test) and this is related to lower day- (uterine lining) [33�� ]. On the first day of menses, the hor- time temperature. Melatonin levels were similar in luteal mones regulating the cycle are low (progesterone, oestrogen phase and follicular phase, but higher along night hours for luteinizing hormone, follicle-stimulating hormone). In con- women using oral contraceptives, who also displayed higher temperatures. trast, during the luteal phase, follicle stimulating hormone Curr Sleep Medicine Rep (2021) 7:1–14 5 Sleep continuity and sleep efficiency measured through during the luteal phase and the frequent sleep disturbances polysomnographic recordings of healthy women remain sta- displayed during menopause (due to the sudden drop of pro- ble across the different phases of the menstrual cycle [30]. gesterone) [23]. Individual percentages of sleep stages are also comparable Sleep’s role in cognition and specially the consequences of across phases. Only a shorter sleep latency and decrease per- its deprivation have been extensively studied in literature. centage of REM sleep during the luteal phase are documented, Sleep is known to influence cognitive abilities [10, 45], in- but this effect appears only on the first sleep cycle [36]. These cluding working memory, planning and, hence, it is expected changes seem to be linked to the mentioned raise in body that sleep differences in both sex and menstrual cycle will also temperature that takes place during this phase [40]. As for affect learning and memory. the women using hormonal contraceptives, they have been associated with lower percentage of slow-wave sleep (SWS), shorter REM sleep onset latency and increased REM sleep Effects of Sex on Cognition efficiency in the active phase of the contraceptive method and this compared with women [3]. SWA and SWS do not As mentioned before, sex differences seem to permeate the appear to be sensitive to the influence of menstrual cycle; organization of brain [8, 46] and even the mechanisms behind however, a transient increase during the first sleep-cycle was the observed cognitive performance in certain tasks, such as evident in a study by Driver and colleagues, and it was attrib- synaptic plasticity (in the long- and short-term) and activation uted to temperature increase during the luteal phase [40]. of other molecular pathways (neurotransmitter’srelease, gene Spindle activity is reported as higher in women during their expression and transcriptional factors) [47]. It is difficult to luteal phase [41], concretely their duration, number and spec- distinguish between the cause of such differences, since sex tral frequency increases during mid-luteal phase, especially hormones, sex chromosomes and environmental factors inter- after the first cycle of sleep [40]. The upper spindle frequency act to enable cognition and behaviour. In this section, the most (14 to 16 Hz) appears as particularly sensitive to menstrual relevant findings regarding the differential performance of fluctuation. Ishizuka and colleagues [42] report spindle fre- sex, in both humans and rodents in cognitive performance, quency reaching a high peak 3 days before menses and a are described. valley 18 days before the period. Plante and Goldstein [43] propose that this luteal enhancement of spindles can be attrib- Rodents uted to higher levels of progesterone, as their sample of wom- en taking the progestin drug Medroxyprogesterone acetate, Studies of gonadal hormones and sex differences in learning displayed increased spindle density, power and amplitude in have shown mixed results, probably because sex studies do the spindle band (11–16 Hz). In this study, menstrual phase not usually discern between the different stages of the oestrous was not controlled. This effect was explained as progesterone cycle in females. Differences in hormone levels can alter the being responsible for an increased binding in the reticular strategies used by rodents to perform different tasks. These thalamic nucleus to GABA receptors, which may enhance differences in cognitive strategy seem to emerge after puberty spindles role in brain inhibition [4, 36]. in rats [48], one potential reason why the role of sexual hor- mones seems to be central. In general, as with humans, male Interim Summary rodents are attributed to have better spatial learning, which is expressed in better spatial working and reference memory [49, Regarding effects of menstrual cycle in sleep, findings are 50]. In the skilled reaching task (Fig. 2a), in which rats have to weaker than expected in both humans and rodents. In rodents, reach with their paws through a small opening for a food changes seem to be more related to sex than to hormonal pellet, females had better performance during acquisition of variation with females spending more time in wake and less the task compared with males. In a discriminative fear- in NREM during the light phase. One exception is the ob- conditioned to context task (Fig. 2b), in which the rat has to served decrease of REM on proestrous night and rebound of associate a context with a foot shock, Long Evan females REM on the following oestrous day in rodents. In humans, showed longer freezing time than males, showing an increased effects of menstrual cycle in sleep are intertwined with body emotional memory to a particular context [53]. temperature changes across menstrual phases. The intersec- There are many factors to consider, apart from sex, when tion of human and animal studies indicates that progesterone trying to compare these different findings, such as age, strain, reduces arousal, while oestrogen increases the availability of and variations in the tasks themselves [54], as well as the norepinephrine, decreasing the time in REM sleep [6]. These housing conditions (enriched environments, physical activity, findings are consistent with the documented anxiolytic/ handling). At the same time, when studying the menstrual sedative effect of oestrogen and progesterone in animal phase influences, studies introduce a large variation in timing, models [6, 44] and the reported decrease in sleep quality route, length and dosage of hormone administration. Rhyme “Road” Name Animals 6 Curr Sleep Medicine Rep (2021) 7:1–14 Fear conditioning to context Skilled reaching task c Image rotation Which object corresponds to the original figure? a b Motor skills Emotional memory Original T maze d Morris Water Maze Natural alternation f Response delayed matching to sample task Working memory Wet navigation Radial arm strategy maze Allocentric navigation Y maze Delay How is it solving the task? Object placement Object recognition g Attention tasks/Prime Fragment Object Fluency tasks h j Novelty of location Explore novelty Rhyme Raise your hand if the word Identification Road/Toad/Code has been said before prime Semantic Words with c (cake/curry/cold) Flea Delay Delay Category Fruits (plum/pear/orange) Sample Test Sample Test Horseshoe Toad Working spatial memory Category exemplar Fragmented object test Object to position assignment generation Place the objects where they belong Plum Animals (flea/toad) Positions-only assignment Place the objects where they belong Experimental trial Combined condition Place the objects where they belong Fig. 2 Examples of tasks used for evaluating learning in humans and recently. Natural alternation between arms is counted. f Morris water rodents. a Skilled reaching task; the animal has to learn to reach maze; animal is placed in circular pool with opaque water, surrounded through a small opening, grasp a food reward and retrieve it. Tests fine by extra maze cues (black square and triangle), where they have to swim motor skills. b Fear-conditioning to context; animal is placed either in the to find a submerged platform (red line). The dashed line represents the light box, or in the contiguous dark box, each paired with a specific aroma swimming pattern of the rodent to reach the platform, from which as well. Both boxes are connected but the passage is blocked once the distance and latency are measured. g Object placement; animal is animal moves to the contiguous context, where a foot shock is given. presented in a box with two identical objects during a sample trial, with After a day delay, a probe is conducted, where the animal is exposed to extra maze cues, and exploration time of the objects is measured. During the shock context, and the freezing time is measured, or the animal is the test trial, one of the objects is moved to a different position. h Object placed in the non-shock context and the latency to enter the shock context recognition. Animal is presented in a box with two identical objects is measured. c Example of item in an Image rotation test. A classically during a sample trial, and exploration time of the objects is measured. used task to measure spatial cognition. d Delayed matching to sample During the probe, one of the objects changes identity but not position. i task. During several trials the rewards stays in the same arm, and the Working spatial memory test as described in Postman et al. [51]. Contains animal has to turn towards the east of the room, or turn right to get it. a trial stimulus showing ten objects that disappear and a test, in which There are extra maze cues. During the probe, the maze is turned 180°, or objects are to be reordered as per three conditions: object to position in this case, if using a plus maze, the lower arm is cut off and the animal assignment (original position marked by a dot), positions only (organize now starts from the north. If the animal, during the trials used an the objects in space) and the combined condition (organize the object egocentric or response strategy, it would turn right to reach the goal. If, without spatial cue). j Implicit memory tests, such as the fragmented on the other hand, the animal had been using the cues to navigate towards object identification (middle) uses perceptual priming and category the reward, it would have been using allocentric navigation. e Natural exemplar generation test (right) uses semantic categories, reported in alternation. Either on the Y maze (dashed lines) or the radial arm maze Maki and colleagues [52] (black line), animals need to remember in which arms had they been Humans because they remain stable even when this factor is controlled for [55]. On a different note, women perform on average Numerous studies [46, 47, 51] point towards men and women worse than men in an object position memory task, even when consistently performing differently in memory tasks accord- verbal interference (repetition of meaningless syllable) was ing to the prevalence of verbal vs. spatial processing of infor- used [51]. However, the crucial element appears to be whether mation. For instance, women on average perform better in information can be verbally described, which gives an advan- word recall and recognition, story recall, name recognition tage to women (in these studies, menstrual cycle phase is and object (including faces) recognition in complex settings. typically overlooked) [55]. Also, the need to perform mental These results do not seem to be explained by verbal fluency, rotation of objects (see Fig. 2c) also seems to be critical, since Test Training Curr Sleep Medicine Rep (2021) 7:1–14 7 women from puberty on seem to display diminished perfor- Influence of Menstrual Phase on Cognition mance compared with age-matched males [56]. In contrast to navigational and spatial reasoning tasks, In this section, we will summarize the influence of the men- in verbal activities (fluency, recall of wordlists and strual phase on memory first in human subjects and then in categorial naming) women on average appear to surpass rodents. men’s performance [46, 47, 51, 55]. However, the origin of such differences is controversial, since performance divergence appear early in childhood (before sexual mat- Rodents uration) and persist after menopause and seems to be more related to divergent brain activation (more Depending on the type of information needed to solve a par- lateralized in women) than to the effect of sex hormones ticular task, the presence of gonadal hormones will favour or [46]. This verbal advantage has been connected to more deter cognition. In tasks involving working memory, such as precise episodic memory in women [55–57]. Thus, epi- T maze delayed matching to sample task (Fig. 2d), which can sodic memory and particularly memory, involving emo- be solved either by a place strategy (allocentric navigation/ tional arousal, seem to be favoured in women, and this always turning towards a location in the room) or a response advantage has been attributed to the dimorphic activation strategy (egocentric navigation/always turning to the right), of the left amygdala in women (presumably concentrating disambiguation of strategy use can be determined by rotating in context details) compared with right amygdala activa- the maze 180°, or as shown in the figure, with a plus maze and tion in men (focusing on gist encoding) [46]. starting from a different position within the maze. Females Besides physiological/structural differences between the during proestrous are more likely to exhibit a place strategy, sexes to explain the observed performance, men and women and during oestrous response strategies [60], both in appeti- can differ in the strategy used to resolve experimental tasks tive (food reward) and aversive wet navigation tasks (sub- (just as seen in rodents). For instance, in navigational memory, merged platform) [61]. Similarly, in ovariectomized rats treat- it has been reported that women rely more on egocentric cues ment with oestradiol while performing a plus maze, in which while men incline towards allocentric references. Solving place and response strategies can be evaluated, oestradiol strategies in turn will affect which brain structures are in- favoured place strategies and decreased performance when volved, and in turn, different brain areas can be more or less response strategies were required [62]. impacted by sex hormones [55]. Concretely, as per animal In the Y maze [60] or radial arm maze (Fig. 2e), where evidence [58� ], oestrogen level has been pointed out as factor working memory is measured by alternation, performance modifying cognition by enhancing plasticity in key areas such during oestrous was decreased compared with other stages as the hippocampus and prefrontal cortex [59], in female but of the cycle. Testing alternation in the T maze shows that mice not in males [8]. during proestrous had more alternations than mice in diestrous [63]. In ovariectomized rats, performance during early acqui- sition in the radial arm maze was decreased compared with Interim Summary sham operated females [64], and treatment with oestradiol improved performance [65]. Similarly, in a water radial arm In both humans and rodents, a higher performance is maze in which platforms were removed (which increases the credited consistently to male individuals in tasks related working memory load as the trials advance), ovariectomized to spatial navigation and a higher performance to females rats treated with oestradiol made fewer mistakes during the in tasks related to domains other than spatial. The factors latest trials [66]. In contrast, for wet navigation tasks such as contributing to such observed advantages are not clear the classical Morris water maze (Fig. 2f)[67], in which per- and range from anatomical, and functional differences in formance is measured by path length and latency to find a the brain (mainly due to oestrogen level), to confounders submerged platform, rats at proestrous show decreased perfor- such as stress and experimental manipulations. For in- mance during acquisition [68] and later trials [69]. In mice, stance, experimentally instilled stress before a navigation- however, it seems that it is during oestrous that they have al spatial task affect women but not men, independent of worse performance [70]. Ovariectomized rats, treated with cycle phase [60]. In women, the presence of language and oestradiol and oestradiol plus progesterone, decreased their semantic processing gives another dimension to the dif- performance [71]. In a variation of this navigational task, in ferences in cognitive performance between sexes. As the which there is a cue hanging above the platform (a beaconing range for variation for sex-dependent performance is strategy) for each trial the platform location and the cue would wide, in the next section, we will focus on cognitive tasks move to a new position together, rats during proestrous exhib- that show differences in females across the menstrual ited better performance during acquisition than female rats in oestrous or diestrous [69]. Ovariectomized rats, treated with phase. 8 Curr Sleep Medicine Rep (2021) 7:1–14 progesterone and oestradiol plus progesterone, decreased cue- the perceptual modality exerted carryover effects when first guided task performance [71]. encountered during the follicular phase relative to the retest In object placement (Fig. 2g) and object recognition (Fig. during luteal phase. These results were highly correlated with 2h) tasks, in which performance is evaluated as exploring time estradiol level in the participants. of novel versus familiar locations or objects respectively, both In terms of recollection of emotional memory (stimuli rats [72] and mice performing object recognition during causing positive or negative arousal), Bayer and colleagues proestrous and oestrous show better discrimination of the nov- [44] found that women during their follicular phase displayed el object than in diestrous or metestrous [63, 73], and discrim- increased detail and contextual recall (48 h after encoding) of ination during proestrous is better than oestrous [63]. Rats negative images compared with luteal phase and to positive performing the object placement task showed discrimination and neutral images, which were not affected by menstrual for the novel placement only during oestrous [72]. phase. These differences were also correlated to decreased Ovariectomized rats treated with oestradiol immediately after hippocampal (and in a portion of the accumbens) activation the sample trial showed at test trial better discrimination of the during the luteal phase in comparison with the follicular displaced or novel object. This response was dose-dependent phase. There is also a reported differential lateralization of (object placement task needed higher concentration than ob- the amygdala during encoding of negatively arousing images, ject recognition task, which fits into proestrous improving with women showing greater activation in the left amygdala place and oestrous improving response strategies). and men showing the opposite pattern [77], but this asymme- Ovariectomized rats without hormone treatment showed try has also been reported for encoding happy faces and seems worse performance in the object placement task than in the to be related to activation of other brain areas [78]. object recognition task, and treatment with oestradiol given Convergently, the amygdala appeared to be activated with 30 min before (or right after sample trial) improved discrimi- preference for encoding emotional memory in women during nation in both tasks [74]. For further details in ovarian hor- the luteal phase. Interestingly, Bayer’sneuroimaging results mones regulating object recognition and object placement seem to support the idea of a shift in strategy for dealing with tasks, see [75]. cognitive tasks during the different phases of the menstrual cycle, with a focus on arousing emotional aspects during fol- Humans licular phase (linked to anterior hippocampal activation and accumbens) and a more semantic approach in the luteal phase It has been claimed that women’s advantage in tasks in which (with preferential activation of posterior hippocampus). they outperform men (verbal) intensifies during the luteal phase of the cycle when female hormones are of their highest Interim Summary levels. Contrarily, during women’s menses, with low levels of female hormones, their performance drops in those tasks [41]. Hormonal level changes during the menstrual cycle seem to Men and women are more similar in spatial centred tasks have an effect on the performance of both female humans and during women’s menses [76]. Classically, spatial memory rodents. Those changes can be related to differential activation and spatial cognition tasks have been used to study the change of brain areas implicated in cognition and emotion (for in- in performance for women during the different phases of their stance amygdala and hippocampus), as well as use of cogni- cycle. In their study, Postma and colleagues [51]showed that tive strategies to resolve tasks during different phases of the women displayed difference in performance only in the abso- cycle. Overall oestrogen seems to facilitate memory encoding lute (fine grain) positioning of objects (see an example in Fig. and recall during experimental tasks, and its effects seem to be 2i) with respect to men and this difference was obvious when related to its action in neuronal spine density, neurogenesis, women were in their menses. The intake of oral contraceptives connectivity and ultimately plasticity in key brain areas as the did not exert significant effects on position accuracy for this hippocampi (for a detailed review on this topic, see the work sample. Effects in women were not related to levels of testos- of Hyer and colleagues [58� ] and Romeo et al. [8]). A sum- terone during the menstrual phase, but more likely to the level mary of these effects can be seen in Fig. 3. The effects of of oestrogen. progesterone are less clear, and research is needed to see if A study by Maki and colleagues [52]showed thatperfor- has complementary or opposite effects to oestrogen [8, 44]. manceinanimplicitmemorytask(based on Category Exemplar Generation: an example primes future word pro- duction) was better for women in the luteal phase compared Sex Differences in Sleep, Learning with the follicular phase. On the other hand, Fragmented and Memory Object Identification (a perceptual implicit test) showed great- er priming effect in the follicular phase compared with In this section, we will highlight the findings in studies that midluteal phase (see Fig. 2j). Moreover, priming effect in take into account both sleep and cognitive performance in Curr Sleep Medicine Rep (2021) 7:1–14 9 Spindle frequency valley = Alertness Similar body temperature in men and women Body temperature Body temperature (Progesterone action) Priming effect from perceptual stimuli Performance in implicit memory Sleep latency task with verbal priming Recall of details and REM % during first contextual facts in Hormone Amygdalar activation in memory sleep cycle emotional memory tasks levels task compared to FP Spindle density Performance in recall of word- Hippocampal activation during associated pairs (estradiol) and encoding of emotional memories finger tapping task (progesterone) Semantic approach Spindle frequency No specific findings to information encoding Emotional approach to Sleep insomia complaints encoding information Fine-grain spatial task differences Response strategy REM Place strategy Wake Working memory Working memory NREM (Y maze) (Y maze) REM Morris Water Morris Water Hormone Maze Maze levels acquisition acquisition Fig. 3 Graphic summary of main findings in sleep and cognitive menstrual phases in cognition and sleep. Only the results for proestrous performance during the menstrual/oestrous cycle in women and rodents. (on the left) and oestrous (on the right) are shown. The sun represents the a Main findings in humans for differences during menstrual phases in day or light phase and the moon the night or dark phase cognition and sleep. b Main findings in rodents for differences during relationship to sex and menstrual cycle changes in human and foot-shock. On a test 24 h later, the latency for the animal rodent models. It is important to underscore the need for stud- to enter the foot-shock context is measured. Under control ies in this topic to better understand how these differences conditions, males had longer latencies than females before affect cognitive processes. entering the shock section, but under sleep deprivation, it was females that showed a longer latency compared with Rodents males, showing that females express a stronger fear mem- ory than males under sleep deprivation conditions. In the object recognition task, there were no sex differences after REM sleep deprivation affected the performance in the sleep deprivation [81�� ], but there was a main effect, in Morris water maze of females more than of males [79], which the discrimination index dropped for both sexes. and ovariectomized rats had worse performance compared They also showed that after sleep deprivation, at hippo- with intact females [80]. In the same page, in a fear con- campal and cortical level, there was an elevated concen- ditioning to context task (Fig. 2b), NREM and REM sleep tration of kynurenic acid (a metabolite of tryptophan deg- deprivation, before and after acquisition of the task, af- radation) known to affect cognition, on males but not fected males more than females [81�� ]. Rats were exposed females. This effect was lost when males were to two contexts, one of which would be associated with a 10 Curr Sleep Medicine Rep (2021) 7:1–14 gonadectomized. When corticosterone levels were mea- different in skill performance or sleep parameters than control sured, these were higher in females than males following males. The phase of the menstrual cycle was not controlled in sleep deprivation [81�� ]. this study; however, the authors speculate that oestrogens may exert protective effects on the sleep of female ex users. Humans Interim Summary Sex differences related to sleep-dependent performance in cognitive tasks are reflected in a small number of experimental By observing the differential effect of sleep deprivation on results in humans, but there is not an integrated picture of the memory tasks performance in males and females, the sex di- relationship. These findings are described next. morphism consequences in sleep-dependent learning can be McDevitt and colleagues [82] reported that differences in tackled. From these studies, it seems that under many circum- memory consolidation after a day nap are observed for per- stances, females perform better compared with males after ceptual learning in a task to discriminate targets’ motion di- sleep deprivation. As animal studies revealed, this could be rection. In this task, women showed a more generalized im- related to elevated corticosteroid levels, a neuromodulator re- provement, extending to target-direction and visual field loca- lated to enhanced encoding under acute paradigms of stress. tions not trained before sleep; while men only improved their Also, in purely sleep-dependent tasks (visual memory and performance for the trained motion direction. In women these emotional memory) females seem to benefit more from sleep findings were independent of whether the nap contained or not than males, these findings will be revisited in the next section. REM sleep. According to the authors, a candidate mechanism behind those differences could be the differential level of ACh hippocampal release in males and females (a fact observed in Menstrual Phase Influence on Sleep and Its rodents but not confirmed in humans), since women in their Relationship with Memory luteal phase display an increase in this neurotransmitter that would facilitate memory performance. As highlighted in the previous section, sleep-dependent learn- Koriyama and colleagues [83] found that in relation to the ing displays differential features in female and males; in the circadian time for encoding aversive stimuli (violent scenes present section, the causes attributable to variation in females from a picture), women displayed greater accuracy in the rec- due to the menstrual cycle and the implicated hormones are ognition of the scenes after they have passed their habitual described. sleep onset periods, even when men performed better in their pre-sleep onset periods. Also, women recognized aversive Rodents scenes less accurately than neutral scenes if tested in their pre sleep-onset-periods, so women display a circadian (per- Very few studies take into account both sleep and learning haps sleep-pressure-related) sensitivity to memory of aversive when looking at differences between sexes and even less stimuli, while men display a stable pattern across time. when looking at differences within the menstrual cycle. As mentioned in a previous section, sleep deprivation ap- Cordeira et al. found that sleep deprivation negatively affected pears to have differential results in men and women. performance in Object recognition in mice during proestrous Interestingly, Binks, Waters and Hurry [84] found that sex and oestrous [73�� ]. had an effect on the IQ test measure of their sample. Sleep- deprived (36 h) females scored slightly higher than sleep- Humans deprived males on the WAIS-R test, no pre-sleep deprivation scores were obtained from participants. Unfortunately, the au- Sleep-dependent memory consolidation is one of the fields thors do not discuss the implications of such finding, but it where the influence of sleep on cognition has offered abun- seems to contradict the claim that sleep deprivation affects dant evidence [87]; it is surprising that relatively few studies women more severely in their cognitive performance [4�� ], have explored the possible dimorphisms in this area. Below, as well as social jet lag impacts their academic performance the few studies that exist are highlighted. more harshly [85]. Sleep-dependent memory consolidation exhibits differ- A study into the differences for male and female ex users of ences in women across the menstrual cycle. Genzel and col- cocaine (in recovery/abstinence) [86] allowed to see that leagues [41] demonstrated that women performed at the same women are not sensitive to sleep disturbances caused by ab- level as men, during their mid-luteal phase in an associated- stinence (low sleep efficiency) as were men. Also importantly, word-pairs and finger-tapping tasks. Overall women in their women performed in a version of the motor sequence task, luteal phase in general, independently of the wake-sleep con- 24 h after learning it, as well as control participants and sig- dition assigned to them, outperformed women in their follic- nificantly better that male ex users. Female controls were not ular phase. The Nap-dependent performance increase, in both Curr Sleep Medicine Rep (2021) 7:1–14 11 the motor and declarative tasks, was more noticeable in the irregular hormonal levels (i.e. menopause) are key to disen- luteal phase of participants compared with the follicular one. tangle the relationship between sexual hormones and system Furthermore, this nap-related-enhancement was correlated consolidation of information in the brain. with increased spindle activity in both men and women, but specifically with progesterone level for the motor task and oestradiol level for the verbal one. In a different type of sleep-related memory enhancement Conclusions study, women did not display the effects of odour-sequence memory cueing (a well-established paradigm in the study of The studies presented in this review underscore the fact that sleep effects on memory consolidation) during different sex hormones, and subsequently, the menstrual cycle in fe- phases of their menstrual cycle [88]. Overall, women were males, influence sleep and cognition in a variety of ways not unaffected by the experimental manipulation, in comparison fully comprehended. Among those areas, we find an intersec- with men, for whom exposure to encoded odours during sleep tion of brain anatomical differences, activation changes in resulted in performance enhancement. The fact that specific those areas, cognitive strategies to deal with a task and brain menstrual cycle effects on the observed outcomes for the fe- plastic changes. Overall, the results of the studies reviewed male participants cannot be further explored, due to lack of here point towards not only an effect of sex and hormones experimental control of this variable, underscores the need to on sleep and cognition separately but also at a differential consider menstrual phase and the influx of external sex hor- effect on the interaction of sleep and cognition. Those effects mones (due to oral contraceptives) when it comes to describe are expressed for instance as a change of strategy in spatial the effects of sleep on memory consolidation. Since the effects navigation task in both female humans and rodents (from of sleep can oscillate according to the momentary level of allocentric to egocentric), in the fluctuating role of amygdala progesterone and oestrogen, the high oestrogen time window and hippocampi in encoding and consolidating stimuli in the for performance enhancement due to sleep (and spindle) in- different menstrual phases, as well as in the changes in sleep crease could perhaps explain the differences across samples architecture and body temperature control according to hor- obtained in research. monal level (oestrogen and progesterone). The main purpose Oral contraceptives have been shown to influence cogni- of this review was to highlight the importance and the need to tive task performance and memory results. For instance, consider sex and its significances into any research endeavour. Genzel and colleagues [89] showed in a sample of females Instead of seeing sex as a confound or a variable to control for, that memory performance for both verbal (word-pairs) as well it can be approached as an opportunity to study the role of as motor (finger tapping) tasks was beneficially influenced by hormones in cognition, sleep and their interplay. Since in fe- a delay in recall (whether it was filled with wake or nap time) males influence of sex hormones is more pronounced due to and was comparable across active or rest weeks of oral con- the cyclical variation on their level, this offers a natural milieu traceptives intake. This finding has been observed across nu- for the study of the impact of those substances in cognition, merous populations (for a review, see Stickgold [90]and memory and behaviour and the influence that sleep—as a Diekelmann, Wilhelm and Born [87]) but has been rarely complex mechanism—exerts on them. studied in women using oral contraceptives. Furthermore, Innovative methods to study the relationship between sleep women taking contraceptives are rarely divided between the and cognitive performance across the phases of the menstrual active and rest phase and by type of method used. The main- cycle need to be applied, since the literature reveals that cor- tenance of the offline consolidation effect across contraceptive relational and subjective measures do not seem to capture the weeks can be attributed to higher levels of oestrogens (spe- complexity in the changes that the female brain undergoes due cially compared with the one of women not taking oral con- to the developmental and cyclical exposure to sex hormones. traceptives) but not to an additional influence of sleep on These sex-dependent and hormonal fluctuation variations in memory consolidation. learning and cognitive performance can be studied as mediat- ed by other processes, from which sleep seems to be a topic Interim Summary especially prolific and promising. Incorporation of female samples, accompanied by standardization of normative There is a lack of studies regarding the role of menstrual cycle criteria for their parameters, into sleep research is urgently in the relationship between sleep and its effects on learning, needed. and concretely on memory consolidation. From the human Among some of the topics to be tackled is the exact role of studies, it seems plausible that different hormones affect sex steroids in sleep regulation and its complex relationship sleep-consolidation based on the type of information being with temperature oscillations in the mammal body. Animal dealt with (motor or verbal, for instance). For this purpose, studies are key to disentangle the relationship between phys- iological factors in sleep regulation and sleep behaviours and studies in women using oral contraceptives or suffering from 12 Curr Sleep Medicine Rep (2021) 7:1–14 4.�� Hajali V, Andersen ML, Negah SS, Sheibani V. Sex differences in especially to separate them from cultural or psychological sleep and sleep loss-induced cognitive deficits: The influence of traits. gonadal hormones. Horm Behav. 2019;108:50–61 This review fo- Based on the above, we consider that a multi-level ap- cuses on differential effects of sleep deprivation, sleep proach to the exploration of the variables involved in the re- homestasis and architecture, sex hormones in wake perfomance (in a wide range of cogntive tasks) both in rodents and humans. lationship between menstrual cycle, sleep and cognitive per- 5. Hadjimarkou MM, Benham R, Schwarz JM, Holder MK, Mong formance needs to be taken since physiological/molecular, JA. Estradiol suppresses rapid eye movement sleep and activation genetic, anatomical, behavioural as wells as circadian compo- of sleep-active neurons in the ventrolateral preoptic area. Eur J nents are simultaneously and interactively likely to produce Neurosci. 2008;27:1780–92. 6. Manber R. 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