The markers of fear recall differ between men and women


A new study shows that markers of fear recall differ between men and women, but in a hormone-dependent manner.

Aberrant fear-memory processing in the brain is thought to underlie anxiety disorders, which affect hundreds of millions of people worldwide.

The neurobiological mechanisms underlying these disorders remain poorly understood, but recent studies suggest that neural oscillations in the prefrontal cortex can reflect the strength of fear recall activity, providing a physiological measure.

Women suffer from anxiety disorders at twice the rate of men and indeed the literature shows that there are sex differences in fear recall behaviors, but this area of study has not been extended to neural oscillations.

Additional studies suggest a modulatory role for the female sex hormone estradiol (E2) for fear recall and extinction recall.

The new study led by Ursula Stockhorst, PhD, at the University of Osnabrück, Germany, specifically shows that peripheral and brain markers of fear recall differ in a hormone-dependent manner between men and women.

The work appears in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging.

Cameron Carter, MD, Editor of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, said of the work: “This study sheds light on the well-known differences between men and women in their vulnerability to anxiety disorders and shows that aspects of fear learning and extinction that contribute to vulnerability in women are related to differences in estrogen levels.”

For the study, first author and PhD student Philipp Bierwirth, MSc, and colleagues examined 20 men, 20 women using oral hormonal contraceptives (OC) and 20 free-cycling women during their mid-cycle (MC). Women taking OC have suppressed and thus low endogenous E2 levels, whereas free-cycling MC women have higher levels of E2.

Participants underwent a fear-conditioning paradigm in which two of four photographs of neutral male faces were paired with a loud burst of white noise. Following the conditioning, the subjects underwent fear extinction, in which two photographs – only one of which had been paired with the noise – were again presented, but this time with no noise stimulus.

The next day, subjects were shown all four photographs again, including the two that had been presented in the extinction phase and thus ready for extinction recall, and two of them without previous extinction – thus subject to fear recall.

During all presentations, the researchers measured skin conductance responses (SCR), a peripheral readout of fear expression, and brain oscillations measured by electroencephalography.

Mr. Bierwirth said: “We found stronger peripheral fear expression (via SCR) during fear recall and extinction recall under low-E2 conditions, that is, in men and in OC women, compared to mid-cycle women with higher E2 levels.

Most importantly, we also observed enhanced theta oscillations in the medial prefrontal cortex and especially in the dorsal anterior cingulate cortex (dACC), in men and OC women compared to MC women.”

Importantly, the authors also point out that subjects were examined during their natural E2 status. They were not randomized to experimentally manipulated estrogen levels and so causal inferences about estrogen cannot be drawn.

Fear recall-related dACC theta oscillations were attenuated in women with higher E2 levels, which, importantly, supports previous findings suggesting a protective role for E2 against fear overexpression during the recall of fear and extinction memories. The data demonstrate that peripheral and brain oscillatory correlates of fear memory recall do not differ between the sexes per se but vary with E2 status, even among women.

Oestrogens, androgens and progestogens are most commonly associated with their roles in reproduction, despite their involvement in a broad range of physio- logical and neural functions. One particular realm in which these sex steroid hormones exert wide-ranging effects is that of learning and memory.

In particular, considerable effort has been devoted to understanding how 17β-oestradiol (E2), the most potent and prevalent circulating oestrogen, regulates the function of the hippocampus, a bilateral medial temporal lobe structure with extensive connections to numerous cortical and subcortical brain regions.

Although the hippocampus is not the only brain region important for memory, damage to or dysfunction of this structure leads to deficits in the formation and retention of numerous types of memories, including those used for spatial navigation, recognizing objects and conspecifics, and recalling fear-associated contexts. However, the roles of sex steroids in regulating the function of mnemonic brain regions such as the hippocampus have rarely been considered by scientists other than neuroendocrinologists.

In the early 1990s, a series of articles describing the effects of oestrogens on neuronal morphology and plasticity in the hippocampus were paradigm shifting for the field of neuroendocrinology1–5. These publications demonstrated that dendritic spine density on CA1 pyramidal neurons in the hippocampus fluctuates across the reproductive (oestrous) cycle of female rats, and is increased in bilaterally ovariectomized female rats by exogenous E2 treatment3.

Box 1 | A role for hippocampally synthesized oestrogens in memory
Although the gonads are a primary source of oestrogens in both sexes, oestrogens are synthesized in numerous tissues, including the brain. Of most relevance to learning and memory, the enzyme aromatase, which converts testosterone into 17β-oestradiol (E2), is widely expressed in the brain and has been shown to produce E2 locally in regions such as the hypothalamus and hippocampus17,18,200,237,238.

In the hippocampus, neuron-derived de novo E2 supports multiple aspects of synaptic plasticity, including synaptogenesis and long-term potentiation19,204,239,240. In hippocampal cultures from female rats, pharmacologically blocking de novo E2 synthesis with the aromatase inhibitor letrozole results in reduced spine density, decreased expression of synaptic proteins and impaired long-term potentiation19,204,239.

Neural E2 synthesis seems to be regulated by neuronal activity. For example, activation of NMDA receptors in cultured hippocampal neurons or in hippocampal slices increased E2 synthesis200,203, and exposure to a learning stimulus in ovariectomized mice increased de novo E2 synthesis in the hippocampus, an effect blocked by letrozole226. In vivo, systemic letrozole treatment decreased CA1 dendritic spine density and levels of hippocampal synaptic proteins in both ovary-intact and ovariectomized females240, demonstrating that neuron-derived E2 contributes to hippocampal synaptic plasticity regardless of other sources of the hormone.

The central importance of de novo hippocampal E2 synthesis in both sexes is illustrated by studies in which letrozole infusion into the dorsal hippocampus of gonadectomized male or female mice impaired consolidation of spatial and object recognition memory215,226. Similarly, hippocampal implants of the aromatase inhibitor 1,4,6-androstatriene-3,17-dione impaired spatial memory in male zebra finches241, suggesting that the importance of hippocampal E2 synthesis is conserved across species. Supporting this conclusion are recent data showing oral letrozole treatment impaired spatial working memory and reduced hippocampal intrinsic excitability in male and female marmosets228.

Aromatase outside the hippocampus also seems to be important for memory consolidation, as infusion of letrozole into the perirhinal cortex of gonad-intact male mice impaired short-term and long-term memory in an object placement memory task224. In humans, letrozole is an approved treatment for oestrogen receptor (ER)-positive breast cancer; however, women taking letrozole may experience a number of adverse side effects that affect memory242. For example, women taking letrozole for ER-positive breast cancer exhibited episodic memory deficits, supporting the idea that brain-synthesized oestrogens are crucial in memory processes227.

Other contemporaneous work showed that E2 potentiates hippocampal excit- atory synaptic plasticity5–7 and protects hippocampal neurons from drug-induced excitoxicity8. Collectively, this body of work unlocked a new research frontier that has broadened understanding of how E2 regulates hip- pocampal function to modulate memory.

Since their publication, these findings have inspired much research examining the actions of E2 and other sex steroid hor- mones in non-reproductive, procognitive brain regions, including the hippocampus and prefrontal cortex (PFC). A subset of this newer research has unveiled very rapid actions of E2 on molecular and cellular mechanisms in the hippocampus, PFC, amygdala and other regions that facilitate memory-consolidation processes.

Although the myriad effects of oestrogens such as E2 on hippocampal function have been intensely studied by neuroendocrinologists for nearly three decades, oestrogens have yet to be widely accepted in neuroscience as general neuromodulators of cognitive processes.

As oestrogens exert numerous effects in multiple cognitive brain areas in both sexes9–13, elucidating how these hormones regulate memory could result in better mental health outcomes in people of both sexes by identifying potential therapeutic targets for neurodegenerative diseases, mood disorders and other conditions in which memory dysfunction features prominently.

Effective treatments for memory loss are sorely lacking, highlighting an urgent need to characterize the neural mechanisms underlying memory formation, including those mediated by oestrogens. Moreover, such information will greatly inform our general understanding of how memories are formed.

Thus, more broadly considering oestrogens and related sex steroid hormones as impor- tant neuromodulators of memory formation will provide fundamental insights into the neurobiology of memory and new avenues for drug development.

The goal of this Review is to highlight the importance of E2 as a critical modulator of synaptic plas- ticity and memory circuitry. Although other sex steroid hormones can regulate memory, the influence of E2 on learning and memory is the most extensively doc- umented, and thus E2 is the focus of this Review.

The discussion will centre on the effects of E2 in rats and mice because their size and short lifespans make them convenient mammalian systems in which to explore molecular mechanisms of E2 action in the brain, and thus the preponderance of data are from these species. However, non-human primate studies (reviewed in11–13) have also provided insights into oestrogenic regulation of memory and neuronal morphology that corroborate findings from rodent studies, highlighting the trans- lational potential of this work.

Here we first outline molecular mechanisms underlying E2 signalling in the rodent brain, including both classical and non-classical signalling. Next, we describe several forms of learning and memory modulated by E2 in rodents, and the mech- anisms thus far identified that underlie this mediation.

Although findings from female rodents are the primary focus, data from males are also discussed, as are sex differences in the neural mechanisms through which E2 influences memory. Last, we conclude by discuss- ing the broad health implications of considering E2 as a neuromodulator, and speculate about the next steps necessary to further advance knowledge of oestro- genic regulation of memory.

We hope readers will be convinced of the importance of E2 as a general neuro-modulator that, like stress hormones and growth factors, should be considered in mainstream models of the neurobiological mechanisms underlying memory.
E2 signalling Unlike neurotransmitters, which are stored in vesicles after synthesis for later release, steroid hormones are generated in response to a stimulus and released imme- diately. Sex steroid biosynthesis begins with the catabolism of cholesterol to progesterone, which is then broken down into the androgens testosterone and androstenedi- one, which are subsequently converted to the oestrogens E2 and oestrone, respectively14,15. In this synthesis path- way, E2 is generated from testosterone via the enzyme aromatase.

The primary sources of sex steroids in both sexes are the gonads, which synthesize progestogens, androgens and oestrogens in differing sex-dependent amounts (with more androgens in males, and more progestogens and oestrogens in females). Hormones synthesized in the gonads can exert paracrine effects on adjacent cells in the gonads, or endocrine effects on distant tissues via the bloodstream16.

However, other tissues synthesize sex steroid hormones as well14, including adipose tissue, the adrenal glands and numerous brain areas, including the hippocampus16–19 (BOX 1). In the brain, steroids including E2 exert rapid paracrine or synaptocrine effects on neighbouring cells20,21.

In female mammals, circulating E2 is synthesized by the ovaries, which release fluctuating levels into the bloodstream as part of the reproductive cycle. During the human menstrual cycle and rodent oestrous cycle, oestrogen levels rise to promote follicle maturation in advance of ovulation, peak to stimulate ovulation and then return to the baseline as the degenerating folli- cle secretes progesterone in preparation for implanta- tion of a fertilized egg. In mice and rats, the oestrous cycle consists of four approximately 12–24-h-long stages: proestrus, oestrus, metoestrus and dioestrus22,23.

E2 levels surge during proestrus and remain high through early oestrus, after which they plunge in late oestrus and remain low throughout metoestrus, rising again during late dioestrus. These fluctuations are reflected in the hippocampus, where E2 levels are substantially higher during proestrus than during other phases24, as is CA1 dendritic spine density2 and neurogenesis25.

Hippocampal E2 levels in ovariectomized rats are similar to those of ovary-intact rats in dioestrus and metoestrus24, reflecting hippocampal E2 synthesis in the absence of the ovaries. As discussed in BOX 1, de novo hippocampal E2 synthesis is activity dependent and cru- cial for rapid synaptic plasticity and memory formation. Oestrogen receptor (ER) expression is also influenced by the oestrous cycle26.

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reference link: DOI: 10.1038/s41583-020-0362-7

Original Research: Open access.
Prefrontal theta oscillations are modulated by estradiol-status during fear recall and extinction recall” by Philipp Bierwirth et al. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging


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