Stress-Induced Cognitive Dysfunction: The Hormone-Neurotransmitter Connection by AOR
Several studies have examined the influence of emotions on cognition, but common everyday situations also testify to the prevalence of this phenomenon. Indeed, who has never forgotten something important under the effect of acute stress, or hasn’t witnessed a menopausal relative complaining about becoming forgetful? The mechanisms and neural circuits involved in emotions and cognition are inextricably linked, and the maintenance of this delicate neurochemical balance is easily disrupted from exposure to stress. Stress triggers a cascade of hormone and neurotransmitter release throughout the brain, affecting our thoughts, decision-making process and behavior.
Understanding the Impact of Stress
Hans Selye (1907-1982), a Hungarian endocrinologist who conducted his research in Montreal (Québec), was the first to give a scientific explanation for biological stress. Selye explained that in response to a stressor, the hypothalamic-pituitary-adrenal (HPA) system is activated, leading to a three-stage bodily response.  The HPA system triggers the production and release of steroid hormones (glucocorticoids), including cortisol. Cortisol is considered the primary stress hormone due to its importance in mobilizing systems throughout the body against a stressor. The HPA system also releases certain neurotransmitters (chemical messengers) called catecholamines, particularly dopamine, norepinephrine, and epinephrine. Catecholamines activate the amygdala, an area inside the brain which triggers an emotional response to the stressful event. The brain also releases neuropeptide S, a small protein that modulates stress by increasing alertness, decreasing sleep and generating a sense of urgency and anxiety in the individual facing the stressor.
Effects of Stress on Cognitive Functions
The prefrontal cortex (PFC) is the anterior part of the frontal lobes of the brain that governs higher-level cognitive processes and executive function. The basic activity of the PFC is considered to be orchestration of thoughts and actions in accordance with internal goals.  Under optimal, stress-free conditions, microcircuits within the PFC work in concert to allow nuanced decision-making and inhibit inappropriate responses. During exposure to stress however, catecholamines (mainly norepinephrine and dopamine) and glucocorticoids (mainly cortisol) suppress activity in areas at the front of the brain concerned with short-term memory, concentration, inhibition, and rational thought. Glucocorticoids activate glucocorticoid receptors (GRs) in the hippocampus in order to store the emotionally loaded experience in long-term memory. Cortisol may also indirectly exacerbate working memory impairments through interactions with the catecholamine systems.
Figure 1: Estrogen “ahead of the curve” hypothesis. Estrogens may amplify the stress response in females by raising baseline dopamine D1 signaling, thus making small shifts more apparent in behavioral measures. In this model, high and low estrogen females perform equally well at working memory tasks under no-stress conditions, but mild stress shifts high estrogen animals down into the far end of the D1 inverted U, while only pushing low-estrogens animals slightly across the middle. (adapted from Selye, H., 1976)
This sequence of mental events encountered during stress allows a person to react quickly in the face of a perceived danger, but it also interferes with the ability to handle difficult social or intellectual tasks and behaviors during that time. In primitive times, this brain action would have been essential for survival (long-lasting memories of dangerous stimuli would be critical for avoiding such threats in the future) but in today’s world, the almost chronic activation of these same circuits by non-life-threatening stressors is proving detrimental to daily life. In addition to the alteration of cognitive and emotional processes throughout the brain markedly impairing working memory, the activation of the HPA axis impacts almost every system in our body. Research shows that untreated chronic stress can result in serious health conditions including anxiety, depression, insomnia, muscle pain, high blood pressure, weakened immune system and obesity. The question that begs to be asked is just how prevalent stress really is. According to the American Psychological Association’s Stress in America survey, 40 percent of all adults admit to lying awake at night because of stress. And what’s worse, 33 percent reveal never having discussed ways to manage stress with their healthcare provider.
Sex Differences and Estrogen Effects
Sex differences in basal and stress HPA function and neuropathologies associated with HPA dysfunction suggest that the HPA axis is subject to gonadal influence. For example, stress-related mental illnesses such as major depressive disorder and post-traumatic stress disorder (PTSD) are twice as prevalent in women. Though the exact mechanisms are not yet fully understood (the vast majority of behavioural neuroscience research is conducted in male animals), a growing body of literature points to the role of estrogen in modulating the action of neurotransmitters and glucocorticoids described above.Several mechanisms could explain how estrogens may sensitize the PFC to the detrimental effects of stress. First, high estrogen levels may exacerbate the effects of stress-induced glucocorticoid release. Another means by which estrogens may exert their influence is through the dopaminergic system. In this scenario, both high and low-estrogen females present an increased sensitivity to stress (see figure 1).
Minimizing the Impact of Stress and Hormonal Imbalance
The key to managing stress is recognizing and changing the behaviours that cause it. However, modifying behaviour, lifestyle, or even eating habits can be challenging especially while undergoing stressful events! For example, physical activity is known to increase the body’s production of endorphins (feel-good neurotransmitters in the brain) and can help treat mild forms of depression and anxiety. Unfortunately, prioritizing exercising during intense periods of stress is not something easily achieved by most people. And when it comes down to achieving hormonal balance, the challenge is even greater! But certain herbs and supplements can help modulate our stress response and our estrogen levels.
Figure 2: Stress and its effects on brain function
Adopt the Adaptogens
Rhodiola, ginseng and ashwagandha (to name a few) belong to a class of medicinal herbs collectively known as adaptogens. Adaptogens are defined as a “new class of metabolic regulators which increase the ability of an organism to adapt to environmental factors and to avoid damage from such factors”.  Despite an extensive amount of research in the USSR, the non-specific concept of adaptogens has struggled for acceptance in western countries until recently, due to its contrast with some key concepts of modern pharmacology. However, since 1998 the term adaptogen is allowed as a functional claim by the US Food and Drug Administration and by the European Medicines Agency.
Rhodiola rosea thrives at high altitudes in Arctic areas of Europe and Asia  and can provide a powerful antidote to the stresses of modern day life. Preparations of Rhodiola extracts are used world-wide to strengthen the body’s response to physical, mental, and emotional stressors. For example, it was approved in 1969 by the Pharmacological Committee of the Ministry of Health of the USSR for use as a stimulant against fatigue by patients who suffered asthenic (personality disorder) states and by healthy people who showed astheny during periods of high mental exertion or after intensive physical work, and it is also commonly used in the medical regime of some European countries . A number of studies have shown that Rhodiola can dramatically reduce mental and physical fatigue under stressful conditions. In one study, R. rosea extract (170 mg/day) was given to a group of 56 physicians on night duty. Using measures of cognitive and memory function, such as associative thinking, short-term memory, calculation, and speed of audiovisual perception, the researchers found a statistically significant reduction of stress-induced fatigue after just two weeks of supplementation. A series of studies also revealed that Rhodiola can help increase attention to detail-oriented tasks by improving concentration over a prolonged period. A one-time dose of R. rosea of 300 mg or more, significantly decreased the percentage of errors made in a proofreading test, particularly over an eight-hour period.  Recent research highlights the potent antioxidant effects of Rhodiolaon nervous system cells. The scientists from Jiangsu Institute of Nuclear Medicine in China concluded that salidroside (an active ingredient found in Rhodiola) could be used for the prevention or treatment of neurodegenerative disease implicating oxidative stress.  Other benefits attributed to R. rosea include: enhancing healthy sleep,  relieving anxiety,  lifting depressed mood,  and maintaining blood sugar within an optimal range. 
Ashwagandha (Withania somnifera) is one of the best known medicinal herbs originating from the Ayurvedic tradition. In traditional Indian medicine, ashwagandha is considered a panacea and it is used as a treatment for an array of ailments such as: stress, fatigue, pain, diabetes, gastro-intestinal and rheumatologic disorders.  Clinical studies confirm the neuroprotective potential of this adaptogenic herb. It has been shown to prevent damage to neurons and improves neurological function in the presence of stress.[28,29,30] In a double blind, randomized, placebo-controlled clinical trial assessing the effects of ashwagandha in 130 chronically stressed subjects over a 60-day period (125-500 mg/day), a significant improvement of scores on a standardized measurement of stress intensity, and biomarkers associated with cardiovascular health was reported. Moreover, the subjects that received 500 mg of ashwagandha daily had cortisol levels nearly 30% lower than those in the placebo group, and their DHEA levels were also significantly higher. 
Siberian ginseng (Eleutherococcus senticosus), constitutes another example of a widely known and well-documented adaptogen. While it is not technically a true ginseng botanical, E. senticosus shares similar beneficial properties with its close relatives from the Panax family of plants.  The European Medicines Agency classifies this herb “as a tonic for invigoration in fatigue and impairment, in decreasing capability and power of concentration as well as in reconvalescence”. 
As we have seen, balancing estrogen levels is important in modulating the stress response. Supporting estrogen metabolism by increasing sulforaphane consumption and modulating their activity with phytoestrogen consumption(plant-based estrogen-like substances) can help achieve that goal. Since phytoestrogens resemble estradiol in their chemical structure and function, they can help substitute for a woman’s declining levels of estrogens.  In the case of high estrogen levels, phytoestrogens may offer some protection by blocking the action of endogenous estrogens by interacting with some members of the estrogen receptor family. 
Broccoli is a plentiful source of glucosinolates, which are converted enzymatically into isothiocyanates. One of the primary isothiocyanates in broccoli is sulforaphane. This plant chemical has been shown to increase the production of glutathione S-transferase and other phase II detoxification enzymes, enhance antioxidant status, and protect animals against chemically induced cancer.  These powerful enzymes are responsible for metabolizing estrogens and eliminating other harmful toxins and carcinogens from the body.
Although the hops plant (Humulus hupus) owes most of its fame to its role in brewing beer, it has a long tradition of use as a sedative and hypnotic herb.  More recently, an extract of the hops cone has been found to contain a previously unknown class of nonsteroidal phytoestrogens (prenylflavonoids) of which 8-prenylnaringenin (8-PN) is the most potent. Clinical studies demonstrate that 8-PN is significantly more potent than the isoflavones daidzein and genistein, but marketedly less estrogenic than estradiol.  Hops extract provides the ideal balance between potency and safety when it comes to modulating estrogens levels. Stressful events can lead to immediate and marked impairments in working memory and other cognitive functions which depend on a balanced neurochemical state. Research has shown that this impairment is driven by increased catecholamines signaling, which may be further modulated or exacerbated by changes in steroid hormone levels. A safe and natural strategy to support the body’s capacity to cope with stress through the use of science-based adaptogenic herbs, standardized for their content in active ingredients and combined with the modulation of estrogen level, may help improve cognitive functions.
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