Lecture 9: Early life adversity, hormones mood Flashcards
Affective disorders and different hormonal axis
These are the main axis (neuroendocrine axis) or hormones involved in or play a role in the development of mood disorders:
- thyroid
- glucocorticoids
- ovarian hormones
- insulin
- We will focus on the HPA axis so glucocorticoids and insulin.
- But there are a lot of studies that show that early life adversity modifies the hypothalamus pituitary thyroid axis by early life stress in ovarian hormones.
- Stress early in life will influence trajectories of health and disease throughout the life course. These trajectories are different between men and women - what happens in men and and women is different in response to early life adversity - phenotype expression is different (behavior expression).
Research paper: The Lancet (1934) - Exploring the mortality rates in Great Britain and Sweden
- mortality rates in britain
- large data sets
- studying relationships between birth, ealry life conditions and mortality in the long term.
- “We are thus led to a picture which is somewhat unexpected. Each generation after the age of 5 years seem to carry along the same relative mortality throughout adulthood, and even to extreme old ages. The figures behave as if the expectation of life was determined by the conditions which existed during the child’s earlier years”
- Almost 100 years ago, we already had this notion that early life was super important to define health and diseas trajectories over the life course.
- In the 50s, we started to explore these more in terms of animal models and trying to recreate exporsure in the lab that would mimic stress or protective factors early in life and then seing what happens later in life.
Harlow Research 1959: Studying the effects of nurture in monkeys
- studying the effect of nurture or care.
- In monkeys: one fake mother would provide nutrition and the other would provide comfort or care
- The monkey would go to the milk to feed and then quickly come back to the mother that provided the care.
- Care and comfort is as important or maybe more important than nutrition early in life.
Barker Dj: In the 80s, big jump/increment in our understanding these associations in humans
Odds ratio for the metabolic syndrome according to birth weigth among 407 men born in Hertfordshire (adjusted for adult body mass)
- Plot replicating different samples with different outcomes.
- David Barker had evidence of chronic disease in older (late 70s) men and found out that there were registry from the earlier days when these men were born from Ethel Burnside (a nurse) who had visited babies as families were expecting babies and she was incredible at talking notes of what these babies were experiencing (conditions, stressors, socioeconomic status, problems that the mother was facing, birth weight).
- These notes were kept almost 100 years after in the museum of the hospital. Barker wanted to look at these notes to get info about his participants. He was granted access when he said he had family members in the data.
Looked at birth weight collected at that time and the risk for disease in these old men.
Metabolic syndromes = collection of diseases that comprise cardiovascular disease, atherosclerosis, hypertensio, typeII diabetese, glucose intolerance…
- Small babies (decrease in birth rate) = increased risk for metabolic syndrome 80 years after. same for mortality - they have an increased mortality in every single age that you look at.
- Developmental origins of health and disease (dohad) = society that has biannual meetings studying what causes this or other types of events beyond or markers beyond birth weight that you can collect early life - predict risk for disease.
- Problem = using only birthrate as the marker but babies can be born at different gestational ages too (ie, if a baby is born at an earlier gestational age then they are going to have lower birth weight - does not tell you the whole story). It is just correlational.
Long term effects of childhood adversity - classical studies
40s to 90s: better understanding of stress response as well as critical periods of development. Much better understanding of the HPA axis:
* When faced with a stressor, there is a group of responses from the brain. The stressor information is captured by the sensory part of our brain.
* It stimulates the production of CRH and ACTH which go into the blood stream and stimulate the secretion of glucocorticoids. Glucocorticoids go into the bloodstream and carry out their role. But they also go back to the brain and inhibit the axis (negative feedback action). They are both at the level of the hippocampus and pituitary blocking and terminating the response.
* Important to understand this to understand the long term effects of stress.
* Graph representing sensitive critical period of development
* Development of brain finishes at 25 - you should stop seing a pediatrician at 25 - because that is the age when the brain ends development.
* Humans develop the different systems throughout infancy, childhoold and adolescence. Sensory systems like vision and hearing start and end development very early in life. Different slopes in development for different systems. Sensory is the first, then motor, language and then higher cognition.
* Stressor at early age will make the axis work differently = HPA axis programming. This is seen in many animal studies.
* Huge stressor or critical event occuring during a critical period that disrupts the slope will leave a mark in that functioning of that system forever. ex: visual system: during the time of development, the sensitive period of developing vision, the stimuli was not so there was a lack of stimulation = blind.
* If you have a stressor or something very critical that happens during the development of the HPA axis, this will make the axis work differently forever. This is called HPA axis programing (a stimulus or stressor that happens early in life can leave a mark in the way that this system works persistently).
Programming of HPA axis in humans
- Kids 10 -12
- They have to perform a series of task called the trial social stress test: math calculation, talk in front of a commitee to induce stress in the kids. Committe is trying to induce stress in the kids
- Collect biological tissue and measure cortisol levels.
- Kids born smaller had higher cortisol levels to acute stress.
- This small increase in glucocorticoids happens every single event of stress. Every little thing that is ‘stressful’, you secrete a bit more glucocorticoid chronically (throughout the live course). You have a chronic increase of exposure to glucocorticoids.
- An increase of release of glucocorticoids; inhibits digestion, affects immune function, high blood pressure, disturbs sleep, inhibit reproduction, reduced metabolism.
Long term effects of childhood adversity - classical studies - Study delving into the mechanisms of why this happens.
- Observe (no intervention) and watch what the mom’s are doing with their newborns (72 times, 5 times a day). This allows you to observe maternal behavior.
- Licking, grooming and cleaning the pups (providing sensory stimulation to the pups). There was a normal distribution - most mothers had like a median level of licking. There were extremes high care and the low care (stimulating less). No intervention, just natural variation in these pups.
- Let these pups grow up to adulthood and see if the ammount of care they received influenced their HPA axis.
- Both respond to stress but the ones that receive less care respond more and they take longer to shut down stress response - negative feedback is not working as well as the high care animals.
- Most of the negative feedback of the HP axis happens at the hippocampal level so they looked at the hippocampus.
- Larger number of glucocorticoids receptors in the hippocampus of the animals with high care. More receptors to receive glucocorticoids coming from the bloodstream to shut down the axis. Hence, high number of GR facilitates the negative feedback.
- Low care = lower levels of GR. Saw this at the level of the receptor, at the level of gene expression of GR in the area as well.
- They found that there is a difference in the expression of the transcription factor for GR. This is becase there are differences in maculation levels.
- ie: epigenetic changes (beyond the genetic code) - that facilitate or block gene expression. ex: methylation - facilates the gene expression or can make it harder for transcription factor to bind to DNA to express the gene. They found that there was higher methylation in a place where it facilitates or difficulties the gene expression of GR.
- animals with lower maternal care = lower expression of Glucocorticoid receptors in the hippocampus and had difficulties in shutting down the HPA axis.
- They mapped a natural behavior to a molecular finding. They saw that this effect also exist in humans by using post-mortem - they compared people who were exposed to childhood trauma vs not and saw similar alterations in humans as well.
- Opened a line of investigation in behavioural epigenetics.
Chronic exposure to glucocorticoids - increased risk for:
These are the extremes - people who have more chronical stress:
* obesity
* hyperglicemia/insulin resistance
* atherosclerosis
* hypertension
* psychiatric conditions
Acute stress
- Acute stress has an adaptive value. We do all these changes because we need to face whatever it dangerous or perceived as dangerous for us at the moment.
- The problem is that when this becomes chronic and repeated that is when we have the damage and poor outcomes.
- For example, microglia through inflammation they modify the arborization in these cells. Alterations in the fluidity of the cell membrane also because of inflammation, this alters the way neurons talk to each other and how the message is transmitted in the pathways.
- Stress affects glia and neurons
- This figure summarizes that these side of the figure is more associated with depressive life behavioirs and when you are more focused on alterations of long chain fatty acids and fluidity of the membrane, you have more anxiety like behavior.
Perinatal events that program the activity of offspring’s HPA axis peristently:
Perinatal events that program the activity of the offspring’s HPA axis peristently (neonatal events)
* Intrauterine growth restriction - baby doesnt grow as much as it should in the womb
* Chronic diseases during pregnancy
* Natural variations in maternal care
* Use of glucocorticoids during pregnancy
* Smoking during pregnancy
* Postnatal stress - can program the HPA axis because its been formed.
reduction of the material available for the nest (example of this post natal programming of HPA axis)
- This is a common moel that many people use in mice and rats to induce stress at the beginning of life.
- Control: sawdust and everything needed to build the nest for the pups.
- Intervention: take out the nest material and give small pieces of paper for the dam to build the nest (gets wet and not enough to build the nest = stressor for the dam = post natal stress). This causes psychological stress for the dam.
- Result: it effects maternal care. The dams will be stressed in trying to take care of their pups, this leaves them less time to focus on maternal behaviour
- Longer time in pure contact (not nursing of in LG)
- Higher frequency of less efficient nursing positions (1&2).
ELS is associated with anxiety in the NSFT in females
- Let the pups grow up to adulthood and then tested them in an anxiety task.
- The pups with the intervention group were more anxious in adulthood.
Findings of the pups study
- We also saw that they respond more to stress.
- Similar findings as the one from mini: we see an increased secretion of ACH and Cortisol in response to acute stress in adulthood.
- We see classical programming of the HPA axis by a post natal stressor.
- We also saw alterations in the secretion of T3 and T4, so the HPT axis is also affected by the stressor here. This has implication for mood disorders, disorders that resemble things like anxiety and depression.
Growth & Insulin
- Workung with the differences in growth during different periods of life and how that affects development.
- The organs of the baby on the right are all smaller –> anatomical deficit is coupled with the functional deficit.
- ie: she has less beta cells because her pancreas is smaller. She has less nephrons in the kidney because her kidney is smaller.
- These anatomical differences will cause the baby to have an increased risk for developing glucose intolerance, Type2 diabetes, hypertention because of the less nephrons in the kidney throughout her life course.
- The baby is born small but not a pre-term baby, she is born at term (more than 37 weeks gestation), meaning it is an intrautenine growth restriciton: the. baby did not grow as much as expected for that gestational age.
Intrauterine growth restriction (IUGR)
- results from a failure to achieve a higher growth potential
- Causes: different diseases in pregnancy (Hypertension, obesity, diabetes..)
- 10% of all births -This is prevalent in canada too, it is not just a result of under-nutrition. There are many conditions during preganancy that can induce a baby to not grow as much (ie, obesity, diabetes, hypertension can all induce low birth weight/poor fetal growth)
- If the placenta is not working well, the nutrients don’t pass as much as they should so the baby doesnt grow. Behaviours that the mother does (ie, smoking) can impair this transfer of nutrients to the placenta.
- Gestational diabetes is more linked to high birth weight babies. Diabetes that the mother previously has - small birth weight because nutritions do not pass to baby.
- High birth weight is not necessarily good, you always want middle ground.
- SGA as marker
- Long-term risk of being born small for NCDs (type II diabetes, cardiovascular disease, mental health).
- Increased risk for morbidity or mortality in every single age during life course
Brain insulin action
- Role of Insulin that goes beyond the metabolic role.
- Insulin is produced in the pancrease, it is important for the cells in the periphery to make use of glucose. Glucose is in the bloodstream and insulin helps glicose to enter the cells.
- Insulin also enters the brain. There are active mechanisms putting insulin inside the brain and there are receptors for insulin spread throughout the brain. Neurons do not use insulin for using glucose - neurons have glucose transporters so they do not need insulin to use glucose but they have receptors, why? They play a neuromodulatory role, modifying the membrane potention of neurons. It influences synaptogenesis, neurotransmission and in some areas insulin is super important for very prevalent diseases like Alzheimers - Important role for insulin in hippocampus that seems to be influencing the risk for Alzheimers dementia in this region.
- Insulin also acts on more frontal areas and seems to influence behaviors like memory,cognition, impulsivity.
- Does insulin have an effect on babies that were born small? Smaller pancreas when born, so produce less insulin.
Catch up growth (an insulin dependent process) is related to impulsivity in SGA children
- Study to determine if insulin dependent process could have anything to do with impulsivity in babies that are born small: smaller pancreas = less production of insulin.
- Since they have so little insulin being released in the bloodstream, the number of receptors increases. They are born with a high insulin sensitivity.
- There is a facilitation of this insulin signal, so glucose is going to enter the cell, they are going to use glucose a lot more than a normal baby
- So the baby is born small and 3 months after birth they grow up very fast. This is called catch up growth.
- Baby is born small but because of this alteration in insuling, they grow very fast and the degree of catchup growth reflects the degree of alteration in insulin secretion.
- Normally, babies follow their trajectory on the growth chard, but the catch up babies fo from a low percentile to a higher one - not normal. We use the delta - how much they changed in percentile as a measure of insulin function.
- Use differences in growth as a measure for insulin function
Catch up growth
- delta = how mnay lines they have crossed in the first five years.
- white dots = nomal babies, black dots = ones that were born small.
- As catch up growth increases, there is an increase in impulsivity. There is an increase for impulsivity only for those that were born small. The higher the catch up, the more impulsive they are
- Saw this effect in two different cohorts: Canada and Singapore. Still see this effect in different culture and ancestry.
- The degree of catch up growth is directly linked to impulsivity measures of five years of age only in those that were born small.
rPRS Calculation
- Using genotype, a polygenic score that sums up the small effect of many genetic variants that were associated with fasting insulin levels.
GWAS: - Take a large number of participants and divide them according to a feature or characteristic.
- In this study, we used the GWAS that was based on fasting insulin levels.
- Large population, some people had higher fasting insulin, other peiple had lower fasting insulin. Then you take each of the variants of the genome and see associations; one of the variants of the genome associated with your outcome 1 by 1. The purpose of this is to identify which variants of the genome are associated with that outcome (fasting insulin).
- Use this information to calculate the score in the cohort, this will tell them if the child has a higher risk for having higher fasting insulin genetic risk. ie: this child has a lower genetic risk for higher fasting insulin.
- The problem with this is that the original GWAS was done in adults and here we are trying to work in children. Had to transform this to apply in children. Did this by filtering by another study that had fasting insulin in children and seeing what variants were important for adults and children.
- A polygenic score that represents variations in fasting insulin can be calculated in your sample and this is what was done in this study.
Wanted to see if these genetic variations associated with fasting insulin would also predict impulsivity.
- Variations in insulin function predict impulsivity especially in relation to adversity (ie, if the child is small or not small)?
- Here, they did not use birthweight, they used cumulative adversity score: low birth weight + other things (low socio economic status, adding up other stressors - not only being born small).
- As adversity increases, there is an increase in impulsivity only for the kids that had a higher genetic risk for higher fasting insulin.
- Crossing the 3 factors: hihger adversity, higher fasting insulin and higher impulsivity.
Life course perspective of the programming effects of insulin on neurodevelopment
- Alterations in sensitivity to insulin early in life will define growth patterns and trajectories and influence development and risk for disease in the long term.
- This is another version of the figure. Here we are talking about gene environment interaction.
- We are born with a set of genes, eventually you can be born with a set of genes that already puts you at a higher risk for having diabetes, higher fasting, insulin. On top of that, you can have events that happen early in life like being born small or other types of stressors that will also influence the risk.
- You have both of the genetic component and the environmental component that also increases the risk. So of the combination of these two can put you on track to having diseases related to insulin function such as alzeimers and diabetes.
- Events that are happening prenatally and post natally interact with your genome and the genetiuc risk that you have can be additive in increasing the risk.
- Essentially, they are trying to understand behaviors that can put you at a higher risk for developing for example type2 diabetes.
- Try to use these outcomes as a process to understand risk behavior that will put you at a higher risk for these disease and that is where we intervene and interfere.
- Insulin is the snesory for what is happening in the periphery - very true for the hypothalamus - takes in the sensory information.
- After the catch up growth, it is programmed so the system will continue always using more glucose as much as possible. This is what we call the thrifty phenotype, a phenotype that tries to save as much energy as possible because it was exposed there in the past to a condition where energy was not available. So they forever try to store. In adulthood they get increase insulin resistance, so they move from a scenario of high sensitivity at birth to being resistant and having type 2 diabetes later.
- This switch between sensitivity and resistance also happens in the brain, but each brain region will have a different timing for this. For example, hippothalamus is the first one that will become resistant, then you have the other areas. So that is probably why eating behavior is something that we see so early because you have this being programmed very early in life - this shift between sensitivity and resistance.
- This system is involved in the associations between being born small and the risk fo disease. ie: alterations in the release of dopamine when the animal is facing the palatable food. So animals that were bron small and face the sweet food when you give them it they get a dump release of dopamine compared to controls and this is reversed by insulin.
- Alterations in dopaminergic signalling, it is easy to understand why you would have risk for metabolic disease because it is involved in intake of palatable foods and psychopathology, addicitons and other diseases like Alzeihmers and Schizophrenia.
Connectivity and Birth Weight
- Study looking at the activation of the brain in response to different food.
- Looking at resting state connextivity. Interested in comparing the individuals that were born small versus normal birth weight.
- We saw a difference in the connectivity between the orbital frontal cortex which is an area of the PFC involved in winlingness to pay for a reward. Orbitofrontal cortex is very much involved in making decisions, value calculations and reward of values.
- Connections between the orbitofrontal cortex and the PFC or dorsolateral prefontal cortex is altered in kids that are born smaller.
- Wanted to collect blood - so they were fasting the night before, then gave them 20$ to buy food from cafeteria. They can use all the money but if there was something left they had to give it back.
- The ones that gave the money back were the ones that were born smaller.
- They chose cheaper snacks but if you look at the calories it was the same as the normal kids. They chose the cheap calories - they went for the junk food.
Gene networks – environment interactions
- We are born with a set of genes. Our genetic makeup will define the way our biological processes happen.
- Our genes will define how much gene expression happens, how much protein we’re going to produce this receptor more, this receptor less.
- So our biological baseline functioning is defined by our genes right now. Whatever happens in the environment, especially during sensitive periods, will interect with this baseline functioning and modify the way gens are.
- The way the genes are expressed can modify like an induced epigenetic changes, these events can happen during these senstive period and these sensitive period can happen for a prolonged time in human development.
- We’re talking about prenatal stress during fetal life, during birth and post-natally as well. Adolescence is another sentive period and can also leave an impact.
- Several systems will be done developing and so stress will not have an impact anumore on those systems. Some other systems will still be in formation, especially high cognitive function like PFC. So stressors passed adolescence will have an impact on these systems as they are still being developed. You have more chance to impact attention, cognition…
- The interaction between genetic variations and early loife adversity will impact brain development, behavviour and risk for disease.
- Genes do not work alone, they work in networks in biological processes.
- Environment is super complex too.
- It is important to keep a broader perspective, take into account other variables beyond being born small.
