An Interesting Study Reveals how the Hippocampus/Cortex Work Together: Sex Differences? Of Course

Estrogen and Progesterone Levels Determine Strategy Chosen for Navigation

Women use spatial navigation just before their periods, but rely more on cues from their surroundings during ovulation.

The present study shows that menstrual cycle phase influences the type of memory system that is likely to be engaged in by women when solving a task or effectively navigating a virtual environment. However, the finding of this study which deserves more focus is that Progesterone, as it varies over the monthly cycle, is found to be a key modulator of which strategy is utilized. in fact as the researchers state, their initial hypotheses, which did not take Progesterone levels sufficiently into account as being a key determinant, were proved wrong.

Different learning sys- tems were first documented by Tolman and colleagues (1946) who showed that rats utilize different strategies to find their way in a maze . Namely, several learning strategies can be used: one is response strategy, which is a strategy that relies on body turns at specific points in the environment forming stimulus- response associations, and the second is spatial strategy, which is allocentric, i.e. independent of the position of the observer and relies on forming stimulus–stimulus associations between land- marks in order to create a cognitive map of the environment.

These systems are dissociable, they can be competitive, and rely on dif- ferent brain regions to function optimally. The hippocampus is implicated in spatial memory whereas the dorsal striatum (which includes the caudate nucleus) is crucial for response memory

Women tested in the mid/late luteal phase, when P is high, use a spatial strategy significantly more than a response strategy. In contrast, during the early follicular (low E2 and P) and ovulatory (high E2) phases, response strategy was used more fre- quently

Thus, these results do NOT support our hypothesis that a high E2 state would be associated with spa tial strategy use and a low E2 state with higher proportion of response strategy use, BUT they suggest that multiple memory system bias in cycling women is mediated by changes in P such that response memory is promoted when P is low, and spatial memory is enhanced in the phase of the cycle that is characterized by high P levels.

The mid/late luteal phase, when P is high, is associated with a significant increase of spatial strategy. Conversely, a response strategy is used in the early follicular and ovulatory phase, when P is low. Thus, it would appear that multiple memory system bias is mediated by changes in P and, possibly, how P and E2 interact.

Consistent with other studies (Maki et al., 2002; Mordecai et al., 2008; ), here, women learned and remembered more words during the ovulatory phase, when E2 levels are high.

These findings support the growing body of research showing that cognitive func- tion is modulated by and change with fluctuating hormones across the menstrual cycle.

It has been consistently shown in rodents that estrogen impacts multiple memory system bias such that low estradiol (E2) is associated with increased use of a striatal-mediated response strategy whereas high E2 increases use of a hippocampal-dependent spatial memory.

It has been observed that E2 is associ- ated with changes in cognition in women; for example, E2 has been linked with improved verbal memory whereas it is associated with impaired performance on mental rotation tasks Hippocampal volume changes across the menstrual cycle in women, i.e., high endogenous E2 levels are asso- ciated with an increase in hippocampal grey matter

In addition, it has previously been found that estrogen receptors are present in the human hippocampus . Thus, E2 could be structurally altering the hippocampus and binding to estrogen receptors within this brain area to promote spatial memory.

Progesterone (P) has been shown to be associated with both enhanced and disrupting (Freeman et al., 1992) effects on verbal memory in women. It is important to note that the majority of studies that are focused on hormones and cognition in women, are carried out with a post- menopausal sample, taking hormone replacements.

These samples of women typically receive progestin with their hormone treat- ments that include E2, thus, very few studies have focused on the effects of P in isolation. P has been shown to increase hippocampal spine density when administered with E2, but these spine den- sities decrease more rapidly than when E2 is administered alone

P receptor function is dependent on induction of E2 receptors (Lydon et al., 1995), which suggests that many of the effects linked to P are also underscored by E2 action. Furthermore, E2 and P are often studied separately so the interac- tion between the two hormones, and how this can potentially affect cognitive function, is not well understood. E2 and P seem to work in concert to affect hippocampal function and, possibly, multiple memory system bias.

Participants were split into either an early follicular (i.e., when E2 levels are low), ovulatory (i.e., when E2 levels are high) or mid/late luteal (i.e., end of the cycle, when E2 levels decrease and progesterone levels rise) phase group, using self-reported date of the menstrual cycle. Serum hormone level measurements (E2, progesterone, testosterone) were used to confirm cycle phase assignment.

NOTE: Recall that Estradiol peaks towards the end of the follicular phase (ovulation) and then rises and plateaus across the luteal phase. The menstrual cycle is also marked by changes in P levels such that they are low throughout the follic- ular phase while they peak and plateau in the luteal phase, before dropping at the onset of menstruation (for review, see Ref.: Hussain et al., 2014; Mihm et al., 2011). E2 levels are higher in the ovulatory phase compared to the early follicular phase, which is marked by low E2 levels throughout menstruation

We used a virtual navigation task. Basically, it was like a video game where women had to find their way through a maze. The maze can be completed either by using the cues in one’s surroundings and making a mental (cognitive) map of the area, or by remembering where each maze arm is relative to another, for example noting that you have to skip two arms then take the next arm. Later we remove the surrounding cues and see how well or poorly someone completing the maze does. This allows us to test which memory system they preferentially use.

Participants were administered a verbal memory task as well as a virtual navigation task that can be solved by using either a response or spatial strategy. Women tested in the ovulatory phase, under high E2 conditions, performed better on a verbal memory task than women tested during the other phases of the cycle

We found that during the ovulatory phase when estrogen peaks, women tend to use response memory to solve the maze. Asked to navigate a virtual maze, most women who are ovulating (i.e., when E2 levels are high) will rely on response memory, using cues from their surroundings to memorize turns.

Response memory is like basic habitual motor memory, such as turning right then left to get to work. However, when women are in the mid/late luteal phase of the cycle, just prior to menstruation when progesterone peaks and estrogen also rises again, they are more likely to use spatial memory.

Women in the premenstrual phase of their cycle, however, relied on spatial memory, picturing an aerial map of the maze in their heads.

Interestingly, women tested in the mid/late luteal phase mid/late luteal (i.e., end of the cycle, when E2 levels decrease and progesterone levels rise) when progesterone is high, predominantly used a spatial strategy, whereas the opposite pattern was observed in the early follicular and ovulatory groups

Spatial memory is what you’d use if you encountered a roadblock on your way to work, and had to mentally pull up a map of the neighborhood to think of an alternate rout

An interesting set of observations here, but we suspect that they might be more strongly phrased in terms of the details and mechanisms of hippocampal/cortical partnering in regard to the two different situations. In other words it is our belief that it would indicate more to state that the landmarks..and so called “response” strategy were dependent on cued recall by the women and thus reliant on the arisal of verbal or other indices via a process akin to “episodic memory recall”. This would go hand in hand with the performance on the verbal recall test, as well.

What is more problematic to us is that the researchers do not have a suficiently articulated or sophisticated view of just how it is that the hippocampus works in tandem with other systems to aid in both navigation and in episodic memory.

The ‘response” strategy is not sufficiently appreciated as depending upon much more than some merely “procedural” movement control function. The “responses” in that strategy depend on a back and forth dialogue with ‘episodically” based neuronal ensembles in the hippocampal area that are accessible via verbal and cortical efforts….and to which priority is given by the user. On the contrary the spatial strategy is one where the user has faith in the mapping and the abstract spatial configurations implied by the geometry of the “map” being relied upon.

It is truly frequently disheartening to watch neuroscience researchers seemingly lost in a maze of their own when trying to speak coherently and usefully about how the hippocampus works. The segmentation of hippocampal function into some truly insipid aspect such as “verbal memory” that is apart and not ever articulated in terms of how it related to the other more well known functioning of the hippocampus in spatial navigation is truly an egregious omission…and the researchers deserve to be befuddled by their own data.

Clearly both these aspects of the hippocampus, verbal recall and navigation, MUST have something to do with each other. Yet they are treated as if they are too randomly placed items on a supermarket shelf to be selected by the researcher shopping for a research project. g

The verbal recall testing was enhanced during high Estradiol times of month…so you would think that the question of the potential inverse relation between performance on the two types of tests would be even briefly considered by the researchers. But alas they don’t get very far at all. In fact they flounder in their discussion through a variety of statisfical and other more superficial factors as causing their unexpected results, rather than focus on better DEFINING just how it might be that the hippocampus does its job..or jobs.

One of the points they do raise, to their credit, but only in passing is that It has been shown that hormonal changes across the cycle are also related with changes in lateraliza- tion during completion of a verbal task, such that lateralization is pronounced when E2 levels are low.

This should reasonably raise the notion that the hippocampus, too, has a left and right part, and that episodic memory as measured by verbal recall (as badly as that is defined) tends to depend on the left hippocampal areas and that the female hormone mix might indeed tend to lead to less “lateralization” within the hippocampus as well…and thus recruit both of its aspects in task performance? Sounds reasonable to us..but this is not discussed.

Additionally of the problem here is the surprise that Progesterone plays a vital function in modulating how Estradiol impacts upon the brain and the manner in which women choose to cope with events. The precedent studies were frequently based on work with rats and humans may be different from rodents in this regard. Here, both the lowest and highest E2 levels observed across the cycle were associated with response strategy use. The difference observed in how E2 impacts multiple memory system bias in rodents and in humans could be explained by the significant difference between the rat estrous cycle and the human menstrual cycle. In rats, E2 and P peak concurrently, such that a high E2 phase is also marked by high P.

Conversely, in women, the two hormones fluctuate dif- ferently and peak at different points in the cycle. It is possible that ovarian hormones interact differently in the human brain and, thus, affect cognitive functions, such as multiple memory system bias, in a unique way.

This interaction is critical in unraveling the mysteries of hormonal effect on preference of cognitive strategy and effectiveness of use, however, the absolutely incomopetent and bogus Women’s Health Initiative studies of the early 2000;s along with the almost fraudulent coverup by the medical cronies of those who incompegtently conducted those studies created massive confusion not only among clinicians but among researchers as the difference betwen use of ‘Progesterone” (the real thing) and various Toxic syntheic “progestagens” (formulated by big Pharma who sponsored the studies and has continued to promote the use of these toxic medications.

These “progestagens” do NOT act upon the brain and its neurosteroids and its neurotransmitters in the same way as bio identical Progesterone does..and in fact has some directly antithetical effects.

So as we read the literature search and discussions of current articles we find them totally confused, misinformed and practically incoherent in trying to reason out why they have such conflicting results on Estradiol and “progestagen” use’.. Thus, the WHI not only led to the damaging of the health of countless women but also succeeding in sabotaging the research data on the basis of which researchers such as the ones here have predicated their own research designs.

A Few comments from the Authors when Interviewed

RG: What is the significance of these results?

Brake: While we have known for years that estrogen affects the brain to cause memory bias in female rodents, this is the first study to see how hormones affect women’s memory.

RG: Does birth control interfere with these preferences for one memory strategy over another?

Brake: We did not test women on birth control, but I would imagine that it could affect memory bias, depending on the form and dose.

Would you recommend changes to the way studies involving memory tasks are conducted in light of your results?

I would certainly note that researchers studying memory in women or female mammals should control for hormone levels.

RG: What led you to look into the effects of hormones on memory bias?

Brake: It’s about bloody time that we start understanding more about the female brain. Every mental disorder or disease, every single one, has a sex bias.

Yet, we still mostly only study the brains of men. Since researchers began studying the brain, they’ve known that studying the female brain is messy. There was more variability, which people suspect could be accounted for by changes in circulating ovarian hormones, so many people couldn’t be bothered with all that extra variability in their studies.

DOI: 10.1016/j.psyneuen.2016.05.008

Aside from the likelihood of significantly misleading data that undoubtedly has been arising from various navigation studies and attempts to understand hippocampal function, we note the related issues of lesser importance but one with which we can identify: Getting around via Digital Maps and Navigational Aids:

Why Your Maps Should Get in Touch with Their Feminine Side

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