Lecture 6: Stress and Hormones Flashcards
Review of transcription and genetic translation
- In order to synthesize mRNA, the two strands of DNA must be unraveled by enzymes called helicases;
- A gene consists of a unique linear sequence of DNA (there are special marker sequences denoting the start and end points of each gene).
- Promoter or facilitatory region, marks the start of the gene;
- The binding of a transcription factor (can be a hormonal complex) to the promoter allows the enzyme RNA polymerase to attach to the promoter and begin the process of RNA synthesis;
- The sequence of RNA nucleotides, determined by the sequence of nucleotides along the DNA, eventually determines the sequence of amino acids in the protein product of the gene;
- DNA methylation and histone modification are epigenetic processes;
- DNA methylation is a process of long-term gene silencing that involves attaching a methyl group to cytosines in the promoter region of a gene
Transcription - starts the process of reading mRNA, uses transcription factors.
Translation - translate mRNA to protein
- hormones can have transcriptional effect/signalling
- can distinguish categories of hormones that have a transcriptional effect and others that are working in the cytoplasm.
Stress and its consequences
- Stress is hard to define but its consequences are well noted at the individual and at the populational level;
- homeostasis is fundemental in defining whether a situation is stressful or not - something that throws you out of homeostasis can be described as stressful.
- About half (48%) of acute myocardial infarctions (AMIs; heart attacks) can be associated by patients to specific triggers; something that starts the event.
- Wars, natural disasters, and anxiety-provoking events are associated with an increase in heart attack rates.
- after 2 weeks of the superbowl, increase in death by cardiac attack…crazy
Main questions in the behavior endocrinology of stress:
- Why are some groups and individuals affected more severely by a potentially stressful event than others?
- Are there differences among individuals in perception of stressors, perturbations to homeostasis, and physiological, psychological, andbehavioral responses to stressors? Individual differences…have an impact on how stress effects a human.
- Are stress responses always detrimental, or can they be adaptive in some circumstances?
- How can we measure stress?
Stress and Homeostasis
- Homeostasis is the ability to maintain optimal conditions in the body, and hormones are critical to this process. These hormones may be influenced by the stress response.
- It involves the regulation of fluid and sodium balance, as well as energy balance, eating, and body mass and temperature regulation.
- All living organisms currently exist because they have evolved adaptations that allow individuals to cope with energetically demanding conditions
- Stressors typically disrupt homeostasis, which affects brain and behavior, but it is important to note that the brain itself can perceive psychological factors as stressful and evoke a stress response
What are the sources of stressors?
Environmental factors: temperature extremes or noise are often perceived as stressors.
Physiological factors: insufficient food quality or quantity or water deprivation.
Psychosocial factors: maltreatment, social subordination, novel situations, lack of control. All evoke anxiety.
The stress response
The systems involved in the mediation of stressors (e.g., glucocorticoids, sympathetic and parasympathetic transmitters, cytokines, metabolic hormones) operate as a nonlinear, interactive network in which mediators down- and upregulate one another, depending on such factors as concentration, location in the body, and sequential temporal patterning.
Definition of stress
Stress: Any significant disturbance of homeostasis, as by extreme temperatures or psychological factors
Definition of stressor
Stressor: A condition, agent, or other stimulus that causes stress to an organism.
Defenition of stress-response
Stress-response: A suite of physiological and behavioral responses that help to reestablish homeostasis.
The body wants to reestablish homeostasis after a stressful situation.
Defenition of Flight-or-flight response
Fight-or-flight response: The automatic and endocrine responses that prepare an individual to battle or flee from real or perceived attack, harm, or threats to survival.
What are the major components of the stress response?
Two endocrine systems, one primarily involving epinephrine (adrenaline) from the adrenal medulla and the other primarily involving glucocorticoids from the adrenal cortex, constitute the major components of the stress response.
- distinguished as the short term stress response and long term stress response.
- chronic stress (chronically exposed several times to a stressfull response and will have a chronic effect on individual) is NOT the same as long term stress response (mediated by glucocorticoids, observed after the stressful event occurs, helps recover from situation).
What is the “Emergency theory”?
“Emergency Theory”: Within seconds of perceiving a stressor, the sympathetic nervous system begins to secrete norepinephrine, and the adrenal medullae begin to secrete epinephrine. This immediate, nonspecific
component, are involved in physiological changes in cardiovascular tone, respiration rate, and blood flow to the muscles from the trunk that can support the behaviors needed in the Fight-or-flight response.
Examples of hormonal variations in response to stressful or arousing situations
Modern perspectives on stress are less likely to focus on fight or flight than on a psychological feature of stress, namely, the degree of control the stressed individual has over the situation
- During the finals, peak in epinephrine release.
- People that are learning to parachute jump have increase in cortisol
- GH is inhibited with recurring stress
- GH drops in stressful situation and then reestablishes as the individual gets more used to the stress.
Founder of modern stress research
Hans Selye (1930s) is considered the founder of modern stress research. He was the first to observe the epinephrine and glucocorticoids are released in response to virtually any stressor. He was the first to observe that this system is activated for many different forms of stress.
- not the injection of the ovarian hormone was causing this but probably the manipulation of the animals was causing this response. Probably delt with animals in an aggressive way.
Other stressors as diverse as frostbite, exposure to formaldehyde, or hemorrhage could also elicit these symptoms observed by Selye. The common endocrine event underlying these very different stressors was the release of glucocorticoids from the adrenal cortex. Mediated by glucocorticoids
Epinephrine and cortisol are commonly known as the stress hormones, despite the fact that their major endocrine functions involve metabolism and that circadian variation in these hormones occurs even in the absence of exposure to stress.
Prolonged Stress Response
General Adaptation Syndrome: what are the 3 stages of general adaptation syndrome?
The General Adaptation Syndrome consists of three stages:
1. Alarm Reaction Stage: Initial phase of the body’s response to stress. When a stressor is perceived, the body activates its “fight or flight” response, which involves the release of stress hormones such as epinephrine and cortisol. Physiological changes occur rapidly, including increased heart rate, heightened awareness, and mobilization of energy reserves to prepare the body to cope with the stressor.
2. Stage of Resistance: If the stressor persists beyond the initial alarm reaction stage (with prolonged stress), the body enters the stage of resistance. During this phase, the body attempts to adapt to the ongoing stressor by maintaining elevated levels of hormones and physiological responses. The body tries to cope with the stressor and restore homeostasis.
3. Stage of Exhaustion: If the stressor persists for an extended period or if the body’s resources become depleted, the stage of exhaustion occurs. During this phase, the body’s ability to cope with the stressor diminishes, and physiological resources become depleted. Can lead to death.
Finally, what is “Stress”?
- Most definitions employ some of the prevailing homeostatic notions of stress
- “The recognition by the body of a stressor and therefore, the state of threatened homeostasis. This way stressors are threats against homeostasis; and adaptive responses are the body’s attempt to counteract the stressor and reestablish homeostasis” (Chrousos et al., 1998).
- Defined stress as: Anything that throws your body out of homeostatic balance. Considered together, stress is the sum of all nonspecific effects of factors that can act on the body to increase energy consumption above some resting, or basal, level. but there are limitations to this concept…
- In the short term, the stress response is adaptive and helps individuals cope with emergency situations; in the long term, the stress response tends to be maladaptive (Sapolsky, 1992).
What are the limitations of the homeostatic concept of stress?
- It does not address the issue that psychological stressors, can evoke a full physiological stress response; indeed, this psychological stress response actually causes homeostatic imbalance in an individual rather than restores it.
- Does not account for individual variation in the perception of stressors.
- In order for a definition of stress to be useful, it must address how the same stimulus can be stressful to one individual and pleasurable to another. This needs developmental inquiry to figure this out.
What is stress?
Integrate the notion of homeostasis and looking at when responses of stress are no longer adaptive anymore:
(1) Predictive homeostasis is the response range that comprises daily and seasonal variation in a given hormone
(2) Reactive homeostasis is the range of mediator fluctuations necessary to respond to threats.
(3) Homeostatic overload represents values above the reactive homeostasis range.
(4) Homeostatic failure represents mediator values below the predictive homeostasis range. Failure in bringing back the organism to the homeostatic state.
Detrimental effects of stress:
- sick more easily
- change in circadian rhythm
- digestion slows down, parasympathetic system doesnt work very well.
- blood pressure increases
- loss of menstruation - impacts HPG axis
- hair loss - due to GH
Physiological Effects of the Stress Response
Several other hormones, including prolactin, urocortin, glucagon, thyroid hormones, and vasopressin, may also be secreted from various endocrine tissues during a stress response.
1) release of noreponephrine in the CNS. epinephrine has 6x greater effect than norepinephrine but it takes longer to release.
3) related to the more prolonged physiological response.
Steps of acute stress response
1- Need a quick energy supply in order to sustain the sprint back to a safe place.
2 – The immediate release of catecholamines (NE and EP) raises respiration and cardiovascular rates within seconds; its body requires increased energy availability to sustain these high rates. Immediate increase in available levels of glucose and oxygen in the blood. Epinephrine increases the delivery of oxygen to the tissues and raises sympathetic tone.
3 – Glucocorticoids, which are secreted within minutes, though probably not until the zebra is back to a safe situation, act on metabolic pathways to replenish the energy reserves used to escape the predator. Will help cope with metabolic needs and restore the suply of energy.
4 – Rapid effects of glucocorticoids operate via nongenomic pathways to affect behavioral stress responses, although genomic pathways mediate some of the long-term effects of stressors.
5 – Responses to injuries that might curtail movement (e.g., pain, inflammation) are inhibited by the stress-induced release of endorphins and endocannabinoids.
6 – Energetically expensive activities such as growth, reproduction, and some components of immune function are also suppressed until after the emergency has passed.
7 – Other components of immune function, such as trafficking of immune cells to the skin where injuries might occur, are enhanced during stressful events.
After stress response subsides, parasympathetic tone increases, and metabolic rate returns to baseline.
Stress Hormones and Behavior: Corticotropin Releasing Hormone (CRH)
But not only glucocorticoids, CRH (a polypeptide) also acts in the central nervous system and HPA axis
- this reaches the adrenal gland but outside of the pituitary gland we also have receptors for CRH. evidence for neurosignalling of stress.
Glucocorticoids and Glucocorticoids Receptors
Types of corticosteroid receptors in the hippocampus:
o Type I receptors, which are mineralocorticoid receptors (MRs), MRs have higher affinity for circulating glucocorticoids and are usually engaged under baseline conditions MRs. Activation of these receptors is thought to modulate homeostatic balance. However, as glucocorticoids increase during a stress response, he low-affinity GRs are activated.
o Type II, which are glucocorticoid receptors (GRs). It’s a low-affinity receptor (e.g., more specific to cortisol) which provides negative feedback and brings the stress response back under control.
Some hormones can cross-react: one hormone binds to the receptor of another hormone.
- People with stress show high blood pressure and therefore higher risk for heart attack - aldosterone and cortisol are involved in these.
- Higer level of inflamation leads to thickening of blood vessels which leads to higher risk for blood vessels.
Glucocorticoids and Endocannabinoids interactions
- Endocannabinoids (neuromodulator) also are involved in mediating the effects of glucocorticoids on stress responses via synaptic mechanisms (in CNS)
- Glucocorticoids bind to membrane-bound glucocorticoid receptors, a G protein signaling cascade induces endocannabinoid ligand production (this is not genomic signalling). There is no gene transcription in this process.
- Endocannabinoid ligand molecules are released into the synapse and bind to CB1 cannabinoid receptors on GABAergic terminals to inhibit GABA secretion (GABA is inhibitory).
- The decrease in GABA disinhibits norepinephrine secretion and modulates stress responses. The neurons that are supposed to be inhibitory become less inhibitory and release the Norepinephrine (CNS) that is related to the short term stress response. This is how cortisol plays a role in the rapid stress response by mediation of GABA and endocannabinoids.
Other pathways involved in the Stress response
Pathological Effects of the Prolonged Stress Response!!
- Prolonged stress shift starts to change to a pathological condition!!
Ideally, the stress response is initiated by stressful stimuli, then the system is deactivated. This is called adaptive-stress response. The event, we cope with it and then we return to homeostatsis.
Chronic stress, genetic differences in glucocorticoid receptor numbers or subtype, or other individual differences in endocrine secretion, responsiveness, carrier-binding proteins, or other factors can dysregulate the normal stress response and provoke inappropriate or pathological stress responses.
- We can have this just by chance, some people are prone to cope with stress less well. Individual differences are involved. The main cause of stress response system is the prolonged activation: Prolonged stress shifts the useful, adaptive short-term stress response to a pathological condition that can jeopardize health, economics, and survival.
For example: 8 most costly chronic diseaseses are associated with childhood diversities. cardiovascular, diabetes, depression and asthma.
Pathological Effects of the Stress Response: acute stress response vs pathological state associated with chronic stress
- More common for stress to cause cummulatative damage over the years
- Stress response in animals does not translate well to what we see in humans… we see the cummulative effect over the years.
- Having these disproportianal responses in every day life is not beneficial. We need to distinguish what is beneficial and what is detrimental of the stress response.
Growth and repair processes
Growth and repair processes: You might notice that your fingernails are more likely to be flimsy or brittle, or that your hair grows more slowly, during stressful periods in your life. For example, chronic stress delays cutaneous wound healing (See figure)
Brain and Behavior
Brain and behavior. Chronic stress alters the structure and function of the brain, especially in the hippocampus, amygdala, and prefrontal cortex.
- Reduced neurogenesis
- Retraction of the dendrites of hippocampal and cortical neurons, but the opposite is seen in the amygdala = physical expansion in the basolateral amygdala
- Increased inflammation in the brain.
These changes in the brain following chronic stress are potential ways in which stress can lead to cognitive dysfunction and depression.
Hippocampus and HPA regulation - Hypercortisolism
- Chronic stress leads to hypercorisolism.
- When the HPA axis is disrupted the stress response does not act as it is supposed to.
- The ** hippocampus** is one of the key sites of HPA axis negative feedback and is damaged by chronic stress, thus a vicious cycle can develop. That is, prolonged elevated glucocorticoids cause hippocampal dysfunction and impair negative feedback, which in turn leads to ever-increasing glucocorticoid concentrations, and so on (Sapolsky et al., 1984).
- Chronic stress leads to hypercorticolism when the HPA axis is disrupted. Increase in glucocorticoid.
- Disrupted negative feedback response of cortisol: the response does not peak as expected and the reduction is much slower. The leves of cortisol is higher for a more prolionged time as well. This leads to hypercortisolism - there is a disregulation of the negative feedback of cortisol.
- Hipothalamus activates the anterior pituitary and then the adrenal glands release cortisol and this feedbacks to the hypothalamus and then the reaction stops. Sometimes the hippocampus will help the hypothalamus to stop the CRH release to help in the negative feedback. When we have disruption of this functioning of the hypothalamus, we see that the negative feedback response is not so accentuated and then we see this maladaptive response.
- Alterations in the negative feedback is one aspect that leads to hypercortisolism.
Hippocampus and HPA regulation – Differences due to social Dominance:
The feedback system implicated in cortisol response can vary due to the social position of individuals.
* We need to consider context when thinking of stress.
Stress has different effects on dominant or subordinate baboons:
* After a stressful experience, dominant animals display an elevated cortisol, but because they possess an efficient HPA axis feedback system, the cortisol concentrations are returned to baseline faster.
* Subordinate individuals have blunted sensitivity to CRH in the anterior pituitary (prolonged cortisol response), thus, a similar stressful stimulus results in low cortisol response, but also long-term elevation of glucocorticoids, which may ultimately harm those individuals.
Specificities of Stress Research in Humans
- We have seen that for stress to be considered a stressful individuals must perceive it as aversive. But humans are exposed to different circumstances that are not necessarily perceived as stressful but can have deregulatory effects on physiological responses that aim to restore homeostasis.
- Adversity (or exposure to adversities) has been used to better capture the developmental risks involved in unhealthy environments. Adversity does not always “count” as a stressful situation - stress research is more complex in humans and so we need to broaden the definition of stress.
- Adversity can be conceived as the exposure to harmful or threatening stimuli, or the absence of stimulation needed for typical development.
Adverse Exposures forms
Exposure to harmful or threatening stimuli or the absence of stimulation needed for typical development, which in turn will require significant adaptation by the infant. When does adaptation become unhelpful?
* forms of adversity can have different levels. Direct vs contextual (more broad) effects
Romenia’s tragic example of negligence - example of how we can study this in humans
- During the 70’s and 80’s President Nicolae Ceausescu created a policy aimed at increasing the country’s population. His plan was to increase the number of Romanians from 23 million to 30 million by the year 2000.
- Prohibition of contraceptive methods, such as condoms and contraceptive pills, and criminalization of all types of abortion; crazy birth rate increase
- Specific State Laws for Women’s Health - required all women to be examined by state doctors;
- With little money to support the family, mothers and fathers began to abandon their children.
- The government then created orphanages to house these children left on the street.
- Employees of these shelters have been instructed not to show any kind of affection for babies. If they were crying, they should be ignored until they learned they wouldn’t attract attention. All were sleeping and they slept in similar cradles, lined up in large sheds.
The Bucharest Project
Research group investigated this group: A randomized controlled trial of foster care as an alternative to institutional rearing for abandoned children –> assigned babies in different intervention groups.
- started to see the impact of the childhood of these children in their own offspring.
Changes in ANS and HPA axis measures during three tasks:
* Two social stressors [the Trier Social Stress Test
(TSST), which includes preparation, speech, and math
portions;
* Nonsocial stressor (a frustration task).
The Bucharest Project: Stress response results
RESULTS:
institutional care;
* got a blunded HPA axis reaction
* differences in the autonomic system response to stress
* showed acronicity between respiratory and heear beat
* differences in systolic blood pressure.
* showed a blunted sympathetic response - were not responding as they should.
Strange situation Experiment
- Observational assessment in which the mother and child are separated. The child is left alone in the room with age-appropriate toys in the presence of a stranger.
- Children were classified with secure attachment if a pattern of relaxed and mutually enjoyable interaction between the dyad was observed.
- Children were considered insecure attachment if a pattern of physical and affective avoidance towards the parent was exhibited, or verbal exchanges between them are often short and lacks affection.
