The Neurobiology of Stress: Cortisol and Beyond

Under stress, many changes take place in your body to help you cope with internal or external threats or stressors. The neurobiology of stress involves a complex interplay of neurological pathways, hormones, and chemical mediators that help the body respond to demands. This stress system involves pathophysiological steps that prepare the body to respond to perceived dangers or other demands or threats. 

This stress response involves the activation of neuroendocrine responses coordinated by the brain and adrenal glands as well as hormonal mediators. Cortisol is a key stress hormone that helps to carry out many of the body’s responses to stress. 

This response is designed to help you survive in the short term. But when this physiologic stress response is repeatedly provoked over time and sustained chronically, it can take a toll on your physical and mental health. Therefore, it is crucial to identify chronic stressors and practice effective techniques to help you manage inevitable stressors in daily life to present disease and maintain an optimal quality of life. 

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The Stress Response System

Stress is defined as your body’s response to demands. When you perceive a threat or demand, your body responds with a carefully coordinated physiologic response to prepare to respond and keep you safe. This involves complex mechanisms that integrate responses from your brain and body.

Your body’s stress response involves coordination carried out between key areas of the brain, autonomic nervous system (ANS), and adrenal glands. These systems are involved in integrating information and activation of two key players in the stress response: the sympathetic-adreno-medullar (SAM) axis and the hypothalamus-pituitary-adrenal (HPA) axis. These systems enact a neurohormonal response that helps you cope with stressors.

The ANS influences largely automatic functions like heart rate, blood pressure, digestion, dilation and constriction of the pupils of the eyes, kidney function, and temperature control that are usually adjusted without your conscious input to keep the body in a balanced state. 

The ANS consists of the sympathetic division, which helps you mount the stress response to fight or flee from danger, and the parasympathetic division which helps balance out the body to return to a state of resting, repairing, and digesting after the danger has passed. The sympathetic nervous system helps to increase involuntary body functions such as breathing, blood pressure, heartbeat, and the dilation or constriction of key blood vessels and small airways in the lungs called bronchioles during stress, adding gas when needed to fuel fighting or fleeing from danger. 

The limbic system in the brain senses threats and sends signals to the hypothalamic-pituitary-adrenal (HPA) axis via these autonomic nervous system responses. This leads to the secretion of cortisol, epinephrine, and norepinephrine from the adrenal glands which help facilitate physiological aspects of the stress response. 

Cortisol: The Primary Stress Hormone

When your brain identifies a threat, it triggers the activation of the stress system. This results in a series of responses and communication that leads to the release of hormones and neurotransmitters that mediate how your body responds to the stressor at hand. 

A key component of this stress response involves sending signals via the hypothalamus-pituitary-adrenal (HPA) axis that results in the secretion of glucocorticoids such as cortisol. The hypothalamus in the brain responds to signals of danger by releasing corticotropin-releasing hormone (CRH). This hormone acts on the nearby pituitary gland to stimulate it to release adrenocorticotropic hormone (ACTH). ACTH then leaves the brain and travels to the adrenal glands where it stimulates them to release cortisol.

Cortisol is one of your body’s primary stress hormones and impacts many functions throughout the body that help you respond to stress. Cortisol receptors are found throughout the body, allowing this hormone to have wide-ranging effects causing inflammatory, immune, metabolic, hormone, circadian, and gastrointestinal changes. 

Cortisol helps to prepare the body to handle the demands of stress. Cortisol helps you maintain prolonged alertness when dealing with stress and triggers the release of sugar (glucose) from your liver so that you have fast energy to deal with stressors. 

In addition to being a key regulator of the physiological changes involved in the acute stress response, cortisol influences the immune system. In the short term, cortisol can suppress inflammation to boost the immune response, but if chronic stress results in prolonged elevation of cortisol, inflammation can increase and immune function can become suppressed. 

Beyond Cortisol: Other Neurochemical Players

When the brain senses danger, it sends signals via the hypothalamus to activate the sympathetic division of the autonomic nervous system. This activation of the sympathetic-adreno-medullar axis leads to the secretion of adrenaline (epinephrine) and noradrenaline (norepinephrine) from the adrenal glands. 

This neuroendocrine signaling is key for the early acute stress response and preparing the body to deal with danger. Adrenaline (epinephrine) and noradrenaline (norepinephrine) enter the bloodstream and trigger several physiological changes throughout the body that help the body be able to fight or flee. These hormones increase heart rate and blood pressure to propel more blood to your muscles, heart, and other vital organs and increase breathing rate and dilation of airways in the lungs so that you can take in as much oxygen as possible to increase alertness. These neurotransmitters also trigger the release of blood sugar (glucose) and fats from temporary storage sites in the body to supply energy to the body.

If the acute stressor continues, the brain activates further coordination of the stress response by starting the cascade of signals discussed above that leads to the release of cortisol. 

Dopamine is another neurotransmitter that is involved in your body’s response to stress. This neurochemical is important for mediating the rewarding aspects of certain stimuli and influencing motivation and attention processes underlying the behavioral responses to such stimuli. Chronic stress may contribute to dysregulation in the dopamine system that can contribute to the development of psychiatric and neurological disorders, including schizophrenia, Parkinson's disease, substance abuse, and major depressive disorders.

The Brain's Role in Perceiving and Modulating Stress

Several key areas of the brain are involved in perceiving and responding to stress. This involves communication and feedback mechanisms between the brain and the HPA axis that mediate alterations in physiology and behavior to help you adapt and survive. 

The first step in triggering the stress response is the perception of a stressor which involves different circuitries in the brain depending on the nature of the stressor. You take in information from your internal environment via autonomic feedback mechanisms and information about the external environment via your eyes and ears. 

These sensory organs then send this information to the amygdala. This brain region is part of the limbic system that helps to sense danger and contributes to behavior, emotional processing, and learning. Other areas associated with the limbic system such as the prefrontal cortex (PFC), the nucleus accumbens (NAc), and the hippocampus are also involved.

When the amygdala perceives danger, it sends a distress signal to the hypothalamus, a control and coordination center deep within your brain. From here, signals are sent to the autonomic nervous system and pituitary gland to coordinate hormonal responses from the adrenal glands via the HPA axis.

For example, physical stressors like blood loss activate mainly structures related to vital functions like blood pressure that are controlled by areas of the brainstem and hypothalamus. This triggers autonomic stress responses to help try to keep vital physiological functions stable. 

Psychological stressors evoke a combination of physical and cognitive stress responses. These involve the integration of inputs from areas of the limbic system like the amygdala and hippocampus along with the hypothalamus. Together these systems help to regulate the stress response by sending signals throughout the body via the HPA axis and autonomic nervous system.  

Long-Term Effects of Stress on Neurobiology

While these stress responses are beneficial when you need to respond to acute danger, chronically activated stress physiology can have detrimental impacts on the body. Chronic stress effects include impacts on neuronal plasticity, neuroinflammation, and alterations in neurotransmitter systems that can have wide-reaching effects on mental health, cognitive function, and physical health. 

Over time, cumulative chronic stress has been linked to a range of chronic health issues including hypertension, atherosclerosis, metabolic syndrome, type 2 diabetes, infertility, immune dysregulation, osteoporosis, psychiatric disorders, and neurodegenerative diseases.

Chronic stress results in physiologic changes to the body and brain. The impacts of chronic stress on the nervous, endocrine, and immune systems have wide-reaching implications. When the stress response is prolonged, it can have long-term consequences on brain circuits, behavior, and mental health that can contribute to abnormal behavior and psychiatric disease. 

One way chronic stress impacts the brain is via the process of neuroplasticity. Neuroplasticity involves ways in which the brain is modified at the cellular and circuit levels to allow for learning and memory. Due to these impacts, prolonged stress can impair memory, impair cognitive function, and cause deficits in decision-making. In addition, these impacts of stress on neuroplasticity can result in changes to innate and adaptive behavioral responses.

In addition, chronic stress impairs immune function and increases susceptibility to infectious diseases due to chronically elevated cortisol. Similarly, repeatedly elevated epinephrine surges damage blood vessels and arteries and increase blood pressure, resulting in a heightened risk of heart attacks or strokes. 

Metabolic consequences can also result due to chronically elevated stress hormones. Since cortisol counters the effects of insulin on glucose metabolism, chronically elevated levels of cortisol can lead to persistent elevations in blood sugar (hyperglycemia) that can contribute to increased abdominal (visceral) fat, metabolic syndrome, and type 2 diabetes over time. 

Further corticotrophin-releasing hormone (CRH) that is released from the hypothalamus during stress inhibits gonadotropin-releasing hormone, growth hormone, thyrotropin-releasing hormone, and thyrotropin secretion, leading to suppression of reproductive functions, growth, and thyroid function. 

Glucocorticoids like cortisol also impact the bone causing osteopenia and osteoporosis with chronically elevated levels due to inhibition of osteoblastic activity.

Coping Mechanisms and Stress Resilience

Normally, unexpected acute stressors kick off the stress response described above in your body to help you cope with the stressor and adapt via activation of the hypothalamic-pituitary-adrenal axis resulting in a peak of serum cortisol about 30 minutes following stress exposure. When the stressor has been dealt with and the danger has passed, there is normally a relatively quick recovery in about 60-80 minutes after the stress as the body shifts into a more parasympathetic state. 

To help facilitate this stress recovery and boost your body’s resiliency to cope with stress, you can implement certain coping mechanisms. Research shows that psychosocial factors like positive emotions and optimism, cognitive flexibility, religion and spirituality, life meaning, social support, and active coping styles are protective ways to boost stress resilience.

To mitigate some of these detrimental effects of chronic stress on the body and mind, it is important to implement mindfulness and other strategies to enhance stress resilience. Mind-body practices, exercise, and social support can enhance your ability to cope with stress by balancing out the neurobiological impacts on your body.

Mindfulness and other practices like deep abdominal breathing, soothing mantras such as peace or calm, visualization of tranquil scenes, repetitive prayer, yoga, and tai chi can help strengthen your body’s relaxation response. This helps your body more readily return to a relaxed parasympathetic state after stress. 

Moving the body regularly with physical exercise helps to favorably modulate the body's response to stress. Regular moderate exercise has a favorable impact on the function of your HPA and nervous system response to stress. It is important to avoid over-exercising or stressing the body further with exercise that is too intense for your unique body. The beneficial impacts of exercise on stress resiliency are also greater when you sync movement with a healthy circadian rhythm, keeping more high-intensity exercise for the morning and low-intensity exercise later in the day.

Maintaining a strong social support system is also essential for maintaining stress resiliency for optimal physical and psychological health. Having friends, family, and/or community that makes you feel safe and supported positively impacts the HPA axis and adrenal function. These impacts have been shown to boost resilience to stress.

Therapeutic Interventions Targeting Stress Neurobiology

Current and emerging therapeutic interventions aimed at modulating the neurobiological response to stress can contribute to personalized medicine for stress resilience. Based on individual neurobiological profiles, potential therapeutic interventions including pharmacotherapy, psychotherapy, and lifestyle interventions can help target stress neurobiology to bring the body back into balance. 

Serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter and hormone that plays key roles in emotion, mood, digestion, appetite, and sleep. Stimulating the main inhibitory serotonergic receptor 5-HT1A can reduce stress-induced behavioral symptoms like anxiety and depression. Partial 5-HT1A receptor agonists such as buspirone and benzodiazepine medications like diazepam are used to reduce anxiety and block stress-induced changes involving activation of the HPA axis.

Oxidative stress increases when stress hormones are elevated over a prolonged period. This results in free radicals that can cause damage to DNA, lipids, proteins, and other cells. Chronic stress-induced oxidative stress has been implicated in the development of diseases like depression and Alzheimer’s disease. 

Since prostaglandins help to mediate how HPA axis activation during stress impairs the immune system, they have been targeted to help block some of the impacts of chronic stress. Non-steroidal anti-inflammatory drugs (NSAID) including the non-selective cyclooxygenase (COX) inhibitor naproxen and selective COX-2 inhibitor rofecoxib are known to reduce oxidative stress by inhibiting COX to reduce the release of prostaglandins. 

Antioxidants are also used to mitigate oxidative stress and prevent the impacts of increased free radicals that occur with chronic stress. Eating a balanced anti-inflammatory diet rich in colorful fruits and vegetables helps mitigate chronic stress by supplying antioxidants like beta-carotene and vitamins C, E, and A that help combat free radicals.

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Key Takeaways

Taking a holistic approach to stress management is key to boosting resilience and mitigating the numerous adverse impacts of chronic stress. Implementing lifestyle practices, mind-body exercises, and dietary choices can help boost resilience to stress by balancing neurobiology.

Chronic stress has significant impacts on physiology that can impact all systems of your body. Integrating this comprehensive understanding of the neurobiology of stress with a knowledge of mindfulness and other lifestyle and mind-body strategies that can support a healthy stress response and recovery can support long-term psychological and physical health. 

Ongoing research is furthering our understanding of the neurobiological response to stress allowing us to implement targeted and personalized interventions to bring the body back into balance.