Lecture 10: Stress - Epigenetics, neuroalterations and mental health Flashcards
Early life adversities can alter neuroendocrine development
- We have seen that for stress to be considered a stressful individuals must perceive it as aversive (requires activation of the HPA axis). 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 is not only stress, we also observe the effects of deprivation and threat.
- Human beings are exprience-dependent individuals
- Adversity can be conceived as the exposure to harmful or threatening stimuli, or the absence of stimulation needed for typical development.
- High threat vs low threat and threat is more present in institutionalization, physical abuse, sexual abuse and domestic violence, community violence. As well as poverty and neglect (absence of resources).
Romania’s tragic example of negligence
- The government was ecouraging couples to have babies…but pore country so a lot were institutionalized.
- 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. - 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. They were not cared for.
- Probably one of the main causes of physical and mental health issues that this population faced.
Documentary Romanian Orphanages
- physical abuse - beating with rope
- “belonged to no one”
- dogmatic vision - increase population to drive economy
- romanian people were left hungry
- dictator was executed due to the revolution
- 100 000 children left abadoned
- Cleaned with hose and broom
- Disabled people were not accepted.
- all institutions are closing - to reduce abuse and exploitation. They do not offer family, love and belonging which is what the children need most.
- Will be relocated from state institution care into homes but this is difficult.
- These will cause alterations at the level of hippocampus and frontal cortex area
The Bucharest Project
A randomized controlled trial of foster care as an
alternative to institutional rearing for abandoned children (these romanian children).
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).
!Effects of Timing of Neglect
- A lot of changes at the level of the HPA axis
- Timing of placement and HPA axis reactivity. Children placed earlier had an enhanced cortisol response (Placement at 24 months).
- Children that stayed in the orphanage showed no cortisol response - it is blunted because of the timing they were put in institutional care. Timing is important - the longer they stayed in the care the worse.
- In general, they have higher cortisol levels and they are also blunted and does not react as expected.
- Earlier age of placement also predicted greater
vagal engagement (Placement at 18 months). - RSA - when people are disynchronized …. !!!
- The best scenario would be the normal breathing with heart rate (that is typically faster than the breathing rate). If you are really stressed, your breathing is faster and hence is synchronized with your heartbeat = BAd.
- Children in the neglecting situation show more synchrony between the heart rate and the breathing.
- In both cases, patterns among children placed earlier in appropriate care, more closely resembled those in the typically developing children.
- HPA axis feedback seems to be altered. Probably happening because of epigenetic alterations.
Review of genomic transcription and translation events
- DNA has several areas.
- Promoter - contains binding sites for TFs. When the hormone binds to the promoter, this complex acts as a TFs. Hormones/ hormone complexes act as TFs.
- Binds to promoter and captures RNA polymerase
Review of genomic transcription and translation events
- TFs facilitate RNA polymerase which is responsibe for synthesizing RNA.
- RNA polymerase opens the DNA and start to see transcription
- The more RNA molecules that we observe is an indicator that we have gene activity.
- Not all of the genes are active - we need regulatory mechanisms to turn on and off the genes. This is where epigenetics plays a role.
Review of genomic transcription and translation events
- Enzyme responsible for synthesizing an RNA molecule from a DNA template during transcription. RNA polymerase binds to the promoter region of a gene with the assistance of transcription factors and begins the synthesis of an RNA molecule complementary to the DNA template
Review of genomic transcription and translation events
!Translation
The mature mRNA moves from the nucleus to the cytoplasm, where the actual process of translation occurs. Translation is carried out by ribosomes, which are composed of protein and ribosomal RNA (rRNA). The mRNA molecule binds to a ribosome, and the process of decoding its sequence to produce a protein begins
* Sequence of RNA is translated into proteins. This happens outside of the cell nucleus.
* The mature RNA will be organized in terms of triplets of amino acid - the building blocks of proteins.
* Specialized cells that produce a simple….!
* Dopamine neurons have activation of dopamine gene.
* The main output of the gene determines whether it is dopaminergic, cholinergic, serotonergic…
Epigenetics – definitions and measures
The promoter and the accessibility of the DNA can be alterned by epigenetics.
* Epigenetics is not altering the sequence –> you are not changing the gene. Epigenetic mechanisms are mediating whether the sequence is accessible or not.
The study of how behaviors and the environment can cause changes that affect the way your genes work.
* Genetic sequence is unchanged
* Environment physically modifying the functioning
of the DNA = modification of gene expression
The two most common forms of epigenetics mechanisms are DNA methylation and histone modifications
!Epigenetic mechanisms are affected by:
Epigenetic mechanisms are affected by:
* Development (in utero, childhood…)
* Environment chemicals
* Drugs
* Aging
* Diet
* Stress exposure
These changes in gene activity or function are not associated with any change in the DNA sequence itself.
Certain tissues are more influenced/vulnerable at certain times. ie: brain is more influenced early in life.
Dry FEB:
- epigenetic modification in liver. Get drunk faster!!
Gene Regulation trough Epigenetic Processes – Histone modifications
ON EXAM
- DNA is constructed by histones - they give the structure to DNA. They are the proteins that coil the DNA and can make the DNA more or less accessible (tighly packed vs not tightly packed.
- less accessible = deactivation.
- Acetylation by HAT (Histone acetyltransferse): Unfold DNA = more accessible = activation
- Deacetylation by HDAC (Histone deacetylase): coiling of DNA = less accessible because more tighly packed = deactivation
- Coiling of the DNA is not a precise mechanism. Acetylation and Deacetylation (histone modifications) is less precise mechanism compared to methylation.
Gene Regulation trough Epigenetic Processes - Methylation
- DNA methylation is the transfer of a methyl group to the fifth carbon in a cytosine nucleobase (C).
- For this to occur DNA methylation is catalyzed by a family of DNA methyltransferases (Dnmts) that transfer the methyl groups to cytosine base in the DNA strand
- Transcription factor can not access the promoter region of the gene, resulting in lower levels of expression
- Binding of methyl group to promoter region of the genes makes it more difficult for TFs to bind (physical barrier) and hence lower levels of gene expression - but some TFs can be inhibitory so it leads to an increase.
Gene Regulation trough Epigenetic Processes - Methylation
Gene Regulation trough Epigenetic Processes - methylation
- Measuring histone modifications is less precise.
- Can locate glucocorticoids receptor gene and estimate with methylation for example.
Developmental Origins of Health and Disease Hypothesis
- DoHaD proposes that environmental exposures during critical periods of prenatal and early postnatal development can influence long-term health outcomes.
- These early-life exposures may alter developmental pathways, leading to an increased risk of chronic diseases, such as obesity, diabetes, and cardiovascular disorders, later in life.
- “The new science of epigenetics reveals how the choices you make can change your genes – and those of your kids” TIME magazine. There is still a struggle to explain epigenetics.
- They are changing your gene function (more or less activated)
- Certain forms of adversity in the whomb could be observed in the long term even if the child ends up in an adoptive setting. It can alter certain systems.
- Different phenotypes are impacted because of the environment they are exposed to
- Chronic stress could be alterning several systems through epigenetics.
Dutch Famine Birth Cohort Study
Conducted after World War II, it investigated the longterm health effects of prenatal famine exposure. Findings
revealed that individuals exposed to famine during early gestation had higher rates of obesity, cardiovascular disease, and psychiatric affective disorders.
Developmental Origins of Health and
Disease Hypothesis
- During gametogenesis, the process of forming sperm and egg cells, extensive epigenetic reprogramming occurs in both male and female germ cells. This reprogramming includes the erasure of numerous DNA methylation marks and histone modifications.
- Some epigenetic patterns can be transfered to the offspring - transgenerational trauma.
- Certain epigenetic markers are also transferred.
- However, certain regions of the genome, known as imprinting control regions, escape this reprogramming and maintain their parental methylation patterns. This phenomenon allows for the transmission of environmentally induced changes in DNA methylation (acquired during the lifetime of the parent) to subsequent generations, potentially impacting the phenotype and
disease susceptibility of offspring.- gestational period is very sensitive period of development
Developmental Origins of Health and
Disease Hypothesis
Take home.
* Experience alters the accessibility to our gene.
* Some can be transferred to offspring.
Classical studies
- The Agouti mice carry a mutation in the Agouti gene, resulting in overexpression of the Agouti protein. As a result, agouti mice exhibit traits such as obesity, hyperphagia, and coat color.
- Agouti gene is constantly turned “on” in mutant mice. It is always expressing the protein which leads to fat and different fur colour. Phenotype characteristics :yellow, obese, susceptible to heart disease and diabetes
- They were able to measure methylation levels by using variations in phenotype.
- Methylation patterns is associated with deactivation of the agouti gene and change of coulour of the fur.
- Agouti moms (dams) if they are fed with Dietary methyl supplementation with extra folic acid, vitamin B, choline, and betaine, it will alter the phenotype of their offspring via increased CpG methylation. They show innactivation of the problematic gene.
- Relating genetics and the environment of the offspring.
!!Maternal care and epigenetics of glucocorticoid receptors - stufy
- Was able to categorize epigenetic programming in terms of maternal behaviour
- Maternal care is important for regulation of HPA axis - prob the phenotypes are alterned becasue they didnt receive proper care.
- Specific types of maternal care evoke changes in DNA methylation and chromatin structure that result in relaxed histone proteins and therefore increased GR gene expression.
- These changes emerged in early life, they could be reversed by cross-fostering to mothers who displayed low levels of licking/grooming and arched-backed nursing, and they persisted into adulthood. High maternal care vs poor maternal care.
- low licking and grooming group showed epigenetic alternations in the glucocortical receptor promoter (higher methylation in the promoter region of the GR gene).
- The net result of these actions is a GR gene that is more readily accepting of the NGF1-A transcription factor, which leads to more GRs in the hippocampus of the offspring.
- Methylation in the GR gene of bad maternal care group was higher in comparison to the ones with the good maternal care group.
- In the good maternal care, we dont have methylation and the TFs can easily bind to the gene to produce the GR and appropriate feedback mechanisms of the HPA axis.
Maternal care in mice is related to epigenetic alterations.
Crossing these pups with the low maternal care alters the epigenetic processing leading to less methylation…!!
Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse - Study.
- They examined epigenetic differences in a neuron-specific glucocorticoid receptor (NR3C1) promoter between postmortem hippocampus obtained from suicide victims (only the ones that have hung themselves because other ways of suicide could have change the brain function) with a history of childhood abuse and those from either suicide victims with no childhood abuse or controls.
- They found decreased levels of glucocorticoid receptor mRNA (less mRNA of GR), as well as mRNA transcripts bearing the glucocorticoid receptor 1F splice variant
- Increased cytosine methylation of an NR3C1 promoter region - suicide and child abuse victims.
- Hippocampus acts as auxiliary, helping hypothalamust with negative feedback in response to cortisol. Less receptors which leads to less feedback from hippocampus to hypothalamus . This alters the HPA axis functioning.
Early life adversities can alter neuroendocrine development
Stress during the Perinatal Period in Humans
We have evidence that prenatal stress alters the structure and function of the brain, especially in the hippocampus, amygdala, and prefrontal cortex. We can correlate this with elevated cortisol levels during pregnancy. Cortisol can cross the placenta and impact the penis.
- Reduced neurogenesis
- Retraction of the dendrites of hippocampal and cortical neurons, but physical expansion in the amygdala
- Elevated cortisol values during early pregnancy were associated with increased right amygdalar development and poor emotional development in girls, but not boys, before puberty
- These effects may be mediated by changes in brain-derived neurotrophic factor (BDNF) (alterned by cortisol), a growth factor that is reduced by stress and is important for promoting neurogenesis and dendritic branching. Importantly, antidepressant drugs can prevent the development of stress-induced depression by buffering the reduction in BDNF levels. We also showed that genetic variation of BDNF is related to differences in response to prenatal adversity.
Young humans also require tactile stimulation provided by physical contact with their caregiver for normal somatic growth and development
- Psychosocial dwarfism is a relatively rare syndrome found among human infants who are reared in situations in which they experience little or no physical contact.
- They have compromised growth and development despite adequate nutrition, disruption of normal sleep cycles, a disruption of GH secretion, and an absence of tissue responsiveness to exogenous GH.
- This distinguishes psychosocial dwarfism from hypopituitary dwarfism, in which treatment with GH restores normal growth.
Importance of child attachment for the HPA Axis
- Children that are securely attached showed less alterations in stress response…!
- Interventions seem to help with cortisol response. Leading to better functioning of HPA axis with attachement based intervention.
- Estimate cellular aging –> telomers and epigenetic mechanisms
- children with secure attachement show less aging compared to insecure children.
Stress Effects on Reproductive Function in Males
- Stress inhibits testosterone production, and low testosterone concentrations reduce both sexual motivation and performance. We have glucocorticoid receptors in the testes that can influence this.
- The release of CRH and endogenous opioids can directly suppress the release of GnRH.
- Additionally activation of CRH receptors in ACTH –releasing cells stimulates the protein kinase A pathway, which leads to changes in gene transcription and other cellular functions. CRH and its receptors have also been identified in the testes and ovaries, suggesting that this releasing hormone may also directly inhibit steroid production.
Stress Effects on Reproductive Function in Males - Glucocorticoids can inhibit reproduction in several ways
- Glucocorticoids at high concentrations can suppress GnRH and LH secretion
- Glucocorticoids have also been reported to inhibit the formation of proteins necessary for the production of hormone receptors, steroidogenic enzymes, and several intracellular signaling molecules.
Male behavior
- Cortisol inhibits testosterone secretion in men by acting on testicular LH receptors (cross-reaction).
- Additionally, Leydig cells (produces testosterone) have GRs that appear to be involved in the normal process of cell growth, metabolism, and energy use. However, when glucocorticoid are elevated for a long period, especially in subordinate animals, an enzyme that normally neutralizes glucocorticoids at basal concentrations is overwhelmed, and testosterone production is curtailed.
- Social position might influence HPA axis. Dominant individuals show less secretion of cortisol to stress so they are able to cope with stress better.
Male reproduction
- Glucocorticoids suppress spermatogenesis more directly by acting on testosterone levels. The resulting low testosterone may fail to support spermatogenesis such that sperm counts fall and stressed individuals become infertile. Social status appears to affect testicular enzymes that,
in turn, mediate androgen production and fertility.
Stress Effects on Reproductive Function in Females - Glucocorticoids can inhibit reproduction in several ways
- Successful ovulation and the onset of mating behavior in females typically depend on the precise timing of neuroendocrine events. Stress, however, often disrupts this timing. Stress can impact/alter menstrual cycle.
- Stress can interrupt estrous cycles and cease the menstrual cycle.
- Women with functional hypothalamic amenorrhea (no menstrual cycles and no pulsatile release of GnRH from the hypothalamus), display elevated cortisol concentrations
- Current activiation of the adrenal glands result in hypothrophy.
- This can be associated with hyperandrogenism - happense because u have the adrenylcorticol hormone over active…!
- signs = acne, balding, abnormal hair growth
- Increased androgens also disrupt gonodotroping-releasing hormone.
- equivalent of taking steroids but is just caused by stress.
Mammals have mechanisms to inhibit reproduction when they fall into a negative energy balance. Women who diet rigorously or exercise strenuously often have problems with
fertility. EX: LH pulses are less frequent in women who are longdistance runners
Stress and the Brain
- Stress hormones like cortisol can influence the structure and function of key brain areas for learning, like the amygdala, the hippocampus, and the prefrontal cortex – all part of the brain’s limbic system.
- hippocampus helps with the negative feedback so not helpful for HPA axis if there are reductions.
- Lower neurogenesis
- Increase in amygdala volume - exerts a postive feedback to the hypothalamus. Reduction in the hippocampus and frontal cortex and increase in amygdala.
- These structures become primed to be on high alert for danger, and to react quickly. These changes affect an individual’s ability to regulate emotion, attention, and behavior, and to learn and remember – all key components of academic success, and health outcomes
Hormones and Mood Disorders
- Many mood disorders emerge during adolescence, when hormone concentrations are changing dramatically. The interactions of these hormones with still-maturing brains can trigger dysregulated affective responses in susceptible individuals, who have some combination of genetic and
environmental pressures for disordered moods. - Sex differences in mood disorders begin at puberty, and generally women are at twice the risk compared with men.
- Hypomania - burst of energy, disorganized actions and speech
Hormones and Mood Disorders
Depression
According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), to be diagnosed with major depressive disorder (MDD), an individual must experience five or more of the following symptoms during the same 2-week period, and at least one of the symptoms should be either
(1) depressed mood or (2) loss of interest or pleasure:
1. Depressed mood most of the day, nearly every day.
2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day,
nearly every day.
3. Significant weight loss when not dieting, weight gain, or decrease or increase in appetite
nearly every day.
4. Insomnia or hypersomnia nearly every day.
5. Psychomotor agitation or retardation nearly every day.
6. Fatigue or loss of energy nearly every day.
7. Feelings of worthlessness or excessive or inappropriate guilt nearly every day.
8. Diminished ability to think or concentrate, or indecisiveness, nearly every day.
9. Recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a
suicide attempt or a specific plan for committing suicide.
Hormones and Mood Disorders
Depression & Thyroid Hormones
It was recognized over a century ago that depressed people tend to have low thyroid function. What is interesting is that although TRH and TSH are usually within the normal range in depressed patients, the thyroid response to TSH is significantly lower in depressed patients than in nondepressed individuals, suggesting some subclinical endocrine malfunction.
Depressed patients often exhibit:
(1) a very high level of antibodies against the thyroid gland
(2) high TRH concentrations in the cerebrospinal fluid
(3) enhancement of antidepressant efficacy by cotreatment with triiodothyronine (T3)
(4) The mood of depressed patients with hypothyroidism
improves when they begin thyroid hormone treatment - thyroid treatment only works in patients that have hypothyroidism.
Hormones and Mood Disorders
Depression & Estradiol
Deficits in estrogen have been associated with
depression. In one double-blind study, estrogen
treatment was given to women who were hospitalized
with severe depression. None of the women who received
placebo treatment showed changes in their mood; in fact,
47% of those patients deteriorated in mood. However,
over 90% of the depressed women treated with estrogen
significantly improved.
* Women with a history of past depression who were
crossed over from estradiol to placebo patches
experienced a significant increase in depression symptom
* Women with past history of depression = scores seem to be higher when they stop estradiol replacement
Stress & PTSD: Findings in Holocaust survivors and Combat Veterans
Findings in Holocaust survivors and Combat Veterans
* Holocaust survivors with PTSD displayed low urinary cortisol excretion and impaired memory compared with Holocaust survivors without PTSD or healthy
Jewish adults. Combat veterans displayed similar dysregulation in the HPA axis
* In cognitive tests, Vietnam veterans with combat-related PTSD also displayed significant deficits in short-term memory.
Several fMRI studies have revealed that persons suffering from PTSD have smaller hippocampi than age matched individuals without PTSD
- Correlations of hippocampal volume and severity of PTSD symptoms reveal similar relationships in Vietnam combat veterans and their non-combat twin brothers. The results suggest that having a small hippocampus might be a
risk factor for PTSD, rather than a result of PTSD. - Veterans with PTSD showed less GABA-benzodiazepine binding (yellow areas) in a PET scan throughout the brain, but especially in the hippocampus, insula, and thalamus and the prefrontal, temporal, and parietal cortices. GABA is the principal inhibitory neurotransmitter in the brain, exerting control over excitability in most brain areas. Alterations in GABAergic systems have been implicated in the pathogenesis of anxiety disorders, including posttraumatic stress disorder (PTSD) and depression.
Hormones and Mood Disorders
Seasonal affective disorder - Serotonin and melatonin correlation
1 - Tryptophan, an amino acid that normally circulates in the blood at low concentrations, is converted to serotonin (it is necessary for the production of serotonin) in the brain. Needs to cross the blood brain barrier to be converted to serotonin.
2- Diet consumption of carbohydrates stimulate the pancreas to secrete insulin, which in turn facilitates the uptake of sugars and nontryptophan amino acids into peripheral cells. This action leads to higher tryptophan in blood It is typically available in low concentrations in blood.
3- Thus, carbohydrate ingestion seems to result in more tryptophan crossing the blood-brain barrier, and thus higher production of serotonin. Serotonin is generally associated with a decrease in appetite
- balanced link between serotoning, eating carbs and tryptophan available.
- more transporeter, less serotonin in the synpatic cleft and this reuptake of serotonin is higher during the winter season.
- serotonin is converted to melatonin in the pineal gland.
Hormones and Mood Disorders
Androgens and Affective Disorders
Androgens are increasingly abused by men and boys to enhance body muscle mass and athletic performance.
* Adverse behavioral effects of anabolic steroid abuse include hyper aggressiveness(including criminal violence) as well as a number of major psychiatric symptoms. Mania or hypomania is common among abusers of androgens.
* know the differences
Psychological variables that modulate stress physiology
- understanding your context helps you cope with stress
- we are always trying to revise and review the events.
