Drop Date: March 2012

In This Drop: Sex Hormones in Saliva and Differences in Learning and Memory

It is a common experience for humans to have vivid and long-lasting memories of events or periods in their lives that were stressful or emotionally arousing. In order to understand the influence that stress has on memory, scientists have looked extensively into the interactions between the hypothalamic-pituitary-adrenal axis and various cortical and sub-cortical regions of the brain.(1-5) Additionally, researchers have noted that women and men seem to differ in some mental processes that affect learning and memory.(6,7) Sex differences have also been observed in the susceptibility to certain psychosomatic and psychiatric disorders, including depression, chronic fatigue syndrome, and PTSD, which are also related to HPA axis function. In their investigations of why these conditions are more common in women than men, researchers have looked at interactions of factors such as circulating sex hormones levels, steroid binding protein levels, and corticosteroid receptor function.(8,9)

Neuroscientists have also been actively exploring differences in brain circuitry and function between men and women.(7,10,11) Sex hormone receptors have been identified in the hypothalamus and other areas of the brain, and studies have shown that these receptors are targets for non-protein-bound steroids in the general circulation that can pass through the blood-brain barrier.(10-13) Numerous recent studies have discussed ways that the sex steroids participate in the regulation of connectivity and function of brain regions, which in turn may affect cognitive processes such as learning and memory.(14-19)

This issue of the Salivary Bioscience Bulletin is devoted to a presentation of several recent articles involving sex differences in learning and memory from the laboratory of Dr. Larry Cahill, who has written extensively about the importance of sex in neurobiological studies. (See additional reading below.) In recent studies, Dr. Cahill’s lab has incorporated measurements of salivary estradiol and progesterone, which permit a more detailed analysis of hormone effects than does relying on self-report for menstrual cycle phase.

Featured Article

Review: Sex Influences on the Neurobiology of Learning and Memory

Andreano, J.M. & Cahill, L. (2009). Learn Mem,16(4), 248-66.

The view that sex differences exist in certain memory-dependent verbal and spatial behaviors, as noted in 1974 by Maccoby and Jacklin, is now generally well accepted. The authors of this review point out, however, that the overall conclusion of Maccoby and Jacklin’s landmark survey was that the two sexes were basically similar in brain function, and they observe that there is still a general assumption among many neuroscientists that few, if any, meaningful differences exist between male and female brain function.

In recent years, however, a growing number of neurobiological studies have revealed that multiple differences do exist between men and women in terms of neuroanatomy, neurochemistry, and physiology. The volumes of numerous brain structures, the metabolism of multiple neurotransmitters and receptors, and key neural circuits involved in learning and memory have all been shown to have differences between the sexes. This review presents and discusses the evidence that supports sex differences in brain function in relation to several specific types of memory, with particular reference to emotional memory and the influences of the sex hormones.

The evidence surveyed generally supports the common view that males are better at tasks that involve spatial memory, while females have an advantage in tasks that involve verbal memory. Under closer scrutiny, however, the male spatial advantage seems to exist mainly in tasks for which spatial information is the primary available cue. In a subset of spatial tasks such as object location, small-scale navigation, and landmark-based navigation, the female advantage in verbal memory may allow strategies of internal verbalization to come into play, eliminating the male superiority in these tasks.

Women also have more accurate and detailed recall of life events than men, and this difference has often been associated with enhanced memory for emotional events. Neuroimaging studies have suggested that sex differences exist in neural circuitry during the encoding, processing, and retrieval of emotional material. Differences also exist between men and women for neutral memories, however, indicating that emotional memory by itself cannot explain all of the female superiority in this area. The authors discuss evidence that suggests that the female advantage in verbal memory also likely contributes to sex differences observed in autobiographical and other forms of episodic memory.

A significant section of the review is devoted to recent research that has examined the interaction of sex and stress hormones with memory and learning. Studies with both animals and humans indicate that differences in male and female performance on tasks that are related to emotional memory are due in part to differences in circulating sex hormone levels, which can modulate the effects of stress hormones on memory. The effects of sex on memory are complicated, however, and they appear to differ according to whether the stress is acute or prolonged. For example, acute stress generally improves male memory for numerous tasks, while chronic stress has an impairing effect on certain tasks. In contrast, female performance on these measures is improved following chronic stress. Additionally, changes in ovarian hormone levels during the menstrual cycle in women also seem to modulate the effects of stress on memory.

The significance of the differences in brain circuitry that have been observed between men and women is also discussed in some detail. Several laboratories have reported a sex-related hemispheric lateralization of amygdala function that may be involved in women’s enhanced memory for emotional events. This difference, which exists under both stress and resting conditions, implies that all studies of the human amygdala’s role in memory must consider potential sex influences. Additionally, studies of hippocampal physiology and function have shown some differences by sex, which may also be related to the differing effects of various stresses on memory. A number of neuroimaging studies that involved visuospatial and verbal measures have also reported that male and female brains sometimes use significantly different networks of activation to perform the same tasks, but without any observable behavioral differences by sex.

In summary, the review suggests that the growing body of evidence from recent studies has challenged the common view that significant differences between male and female brain function are limited. In the view of the authors, the burden of proof regarding sex influences on brain function, learning, and memory has shifted, and neurobiological researchers must now consider the possibility of sex influences in their experimental designs. Studies that fail to consider these sex factors run the risk of producing conclusions that are incomplete or incorrect.

Stress, Behavior & Development
Focus: Stress & HPA Axis, Social Behavior & Emotions

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Additional Reading

Menstrual Cycle Modulation of Medial Temporal Activity Evoked by Negative Emotion
Andreano, J.M. Cahill, L. (2010). Neuroimage, 53(4), 1286-93.

Previous studies have shown menstrual phase-related differences in activity of the HPA axis and amygdala in women. The response of the amygdala to negative emotional images has been observed to be reduced during phases of the menstrual cycle when estradiol levels are high, while administration of exogenous progesterone has been shown to have the opposite effect, increasing amygdala activity. This study used fMRI scans to examine brain activity in naturally cycling women in order to study the effects of naturally elevated levels of estradiol and progesterone during the mid-luteal phase of the menstrual cycle. Measurements of salivary estradiol and progesterone were used to determine actual hormone levels. The results confirm that amygdala activity during the encoding of negatively arousing material is increased by higher progesterone levels during the mid-luteal phase. The study also presents new evidence of a similar increase in activity in the hippocampus during the mid-luteal viewing of negative material.

Research Area: Stress, Behavior & Development
Focus: Stress & HPA Axis, Social Behavior & Emotions

Progesterone at Encoding Predicts Subsequent Emotional Memory
Ertman, N., Andreano, J.M., Cahill, L. (2011). Learn Mem, 18(12), 759-63.

Numerous studies have documented a relationship between stress hormones and memory, and changes in memory have also been related in women to menstrual cycle phase. This study examines the effects of menstrual cycle position on emotional memory in women, using salivary measurements of estradiol and progesterone to quantify hormone levels. Memory for emotional items was significantly better than for neutral stimuli across the entire menstrual cycle, but this memory enhancement was further increased during the high-hormone luteal phase. A positive relationship between progesterone levels and emotional memory was found in both free recall and recognition memory tests. No such relationship was found for estradiol.

Research Areas: Stress, Behavior & Development; Wellness & Aging; Health & Inflammation
Focus: Stress & HPA Axis, Social Behavior & Emotions; Aging; Disorders (PTSD, Depression)

Influences of Menstrual Cycle Position and Sex Hormone Levels on Spontaneous Intrusive Recollections Following Emotional Stimuli
Ferree, N.K., Kamat, R., & Cahill, L. (2011). Conscious Cogn, 20(4), 1154-62.

In a previous study, the authors reported that women in the luteal phase of the menstrual cycle reported significantly more spontaneous intrusive recollections after exposure to emotional films, compared to men or to women in the follicular phase of the cycle (based on the women’s self-reported position in the menstrual cycle). This investigation was intended to extend the earlier findings by including analysis of hormone levels through measurement of salivary estradiol and progesterone. In this study, women in the luteal phase again reported significantly more SIRs per film than did women in the follicular phase, and analysis revealed a significantly positive correlation between mean SIR frequency and salivary progesterone levels. No correlation was observed between mean SIR frequency and salivary estradiol levels.

Research Areas: Stress, Behavior & Development; Health & Inflammation
Focus: Stress & HPA Axis, Social Behavior & Emotions; Disorders (PTSD)