early life adversity, hormones and mood Flashcards
lecture outline
early studies in ELA
HPA programming
prenatal adversity
insulin as key player in relationship between ELA and adult disease
affective disorders and different hormonal axes
- thyroid
- glucocorticoids
- ovarian hormones
- insulin
modulation of these hormonal axes can result in affective disorders
early papers: “the long-term prognosis for prematurely born children”, “a study on birthweight and intelligence”
approaching notion that early life is super important for health across lifetime
Kermak et al quote from The Lancet
“we are thus led to a picture which is unexpected. each generation after 5 years of age seems to carry along the same relative mortality throughout adulthood and even extreme old ages. figures behave as if expectation of life was determined by conditions which existed during a child’s earlier years”
Harlow Zimmerman monkey studies
monkey studies showed:
baby monkeys prefer the cloth “mother”
over the cage with the bottle
animal study looking at early development
Barker and Burnside
huge jump in the field - looking at HUMANS
used Burnside’s detailed notes on birth conditions of now old men
noticed association between BIRTH WEIGHT and risk for DISEASE in adulthood
arrived at METABOLIC ODDS RATIO
small babies = higher risk of mortality 80 years later
one problem with Barker/Burnside analysis
only examines birthweight
not other factors like if the baby was born at term or premature
there are also other factors that affect birthweight (ie. size of mother) that need to be considered
Barker/Burnside odds ratio
as birthweight increases, lower odds ratio for metabolic syndrome
among 407 men born in Hertfordshire
5.5 and lower = at a MUCH higher risk
in the 1940’s-1990’s, developed a better understanding of…
- stress response
- critical periods of development
HPA axis quick overview
when faced with stressors, there’s a sequence of responses
- sensory mechanisms of brain interpret stressor
- CRH and ACTH are released
- glucocorticoids travel through bloodstream
- but glucocorticoids travel back to brain and inhibit the axis
negative feedback!
classical studies: understanding of stress response
progressed during 1940’s-1990’s
negative feedback and glucocorticoid response unveiled
classical studies: critical periods of development
progressed during 1940’s-1990’s
- birth
- sensory development
- motor/language development
- higher cognition
develop different systems throughout infancy, childhood and adolescence
discovered that if animal is in early sensitive period (sensory stage) and experiences a big disruption, systems will be altered forever
like a scar in that system
example of effect of disrupting event/insufficient stimuli during critical period
myopia
if part of visual field doesn’t receive info early on, that part of field will be blind forever
HPA axis is subject to this all well
what happens if a stressor occurs during the development/programming of HPA axis?
will make the axis work differently forever
Liu et al important study SETUP
revolutionized the field
observed rats in cages and how their mothers cared for them - no intervention
let pups grow to adulthood
examined their HPA response to stress (ACTH secretion)
Liu et al important study FINDINGS part 1
- found a NORMAL DISTRIBUTION of maternal behaviour
a) HIGH care mothers and LOW care mothers
- both high and low maternal care receivers respond, but…
a) low care receivers respond MORE and it takes LONGER for their stress response to be shut down
negative feedback of low childhood care receivers is LESS EFFICIENT
Liu et al important study FINDINGS part 2
- looked at HIPPOCAMPUS
a) more glucocorticoid receptors in HIGH CARE rats - this facilitates NEGATIVE FEEDBACK
b) gene expression was different: transcription factor for glucocorticoid receptor gene
in high care rats, there were more ______ ______, which facilitates _____ _____
glucocorticoid receptors
negative feedback
gene expression different in LOW CARE rats
hippocampus of LOW CARE rats had different gene expression
transcription factor for glucocorticoid receptor gene
DNA methylation (epigenetic change) makes it harder for transcription factor to bind to gene
higher methylation in a place that made transcription harder for glucocorticoid receptors in rats who had received LOW CARE
programming of HPA axis in humans chart SETUP
birth weight is associated with cortisol stress response
- gave 10-12 year olds a social test that induced stress
- collected biological tissue and measured cortisol
programming of HPA axis in humans chart RESULTS
- those born small had higher cortisol response to acute stress
- with every single daily stressful event, there’s an increase in glucocorticoid response
a) chronic exposure to glucocorticoids has all sorts of effects
chronic exposure to glucocorticoids = increased risk for…
- obesity
- hyperglycaemia/insulin resistance
- atherosclerosis
- hypertension
- psychiatric conditions
and ELA leads to chronic exposure to glucocorticoids
acute versus chronic stress
acute stress has adaptive value
but chronic stress is damaging
can cause DEPRESSIVE-LIKE and ANXIETY-LIKE behaviour
chronic stress effects on brain
neuron growth in extended amygdala
dendritic shrinkage
alterations in inhibitory synapses
etc
perinatal events that persistently program activity of offspring’s HPA axis
- intrauterine growth restriction
- chronic diseases during pregnancy
- natural variations in maternal care
- use of glucocorticoids during pregnancy
- smoking during pregnancy
- postnatal stress
study: reduction of the material available for nest SETUP
study tried to postnatally induce ELA
CONTROL: lots of nesting material
INTERVENTION: bad quality material
study: reduction of the material available for nest - intervention does what to mothers?
less material STRESSES out the dams, they have less attention to give to maternal behaviour
- longer time in pure contact (not nursing)
- higher frequency of less efficient nursing positions
study: reduction of the material available for nest RESULTS
- ELS is associated with anxiety in the NSFT in female adults
a) rats responded more to stressors if they’d experienced ELS
- T3 and T4 expression was different in rats with ELS
a) implications for depression and anxiety
small babies have…
smaller organs
increased risk for glucose intolerance, hypertension, diabetes etc
specifically talking about small babies born AT TERM
premature babies are different
IUGR
intrauterine growth restriction
IUGR results from…
a failure to achieve a higher growth potential
causes: diseases in pregnancy (hypertension, obesity, diabetes)
generally caused by placenta not functioning optimally - impaired nutrient transfer to fetus
IUGR occurs in what % of all births?
10%
SGA
small for gestational age
SGA is a marker of…
IUGR
IUGR puts you at long-term risk for…
- noncommunicable diseases
a) type II diabetes, cardiovascular disease, mental health issues, lung disease etc
- puts you at higher risk for morbidity/mortality at every age
a) not deterministic, but probabilistic
SGA as model of altered brain insulin function
observation that babies born small are more IMPULSIVE towards rewarding foods
this behaviour, over life course, contributes to increased risk for obesity, diabetes, cardiovascular disease
observation that babies born small are more IMPULSIVE towards rewarding foods
- marshmallow test with 3 year olds
a) kids born small can’t wait for the sweet reward
b) increased intake of palatable food, independent of current body weight
- neuroimaging study of adolescents of varied birth weights
a) showed different pictures (hamburgers, broccoli, and neutral ie. table)
b) measured brain activation in responses
c) when adolescents who were born small see palatable food, they activate more areas of INHIBITORY control
what happens to adolescents who were born small when they see palatable food?
neuroimaging shows they activate more areas of INHIBITORY CONTROL
trying to refrain from an impulse
brain insulin action
neuromodulator - modifies membrane potentials, influences synaptogenesis and neurotransmission
affects the VTA (ventral tegmental area)
insulin action within the VTA
- fusiform gyrus
a) object recognition (including food)
b) processing of positive emotions
c) reward - hippocampus
a) memory formation - PFC
a) integration of sensory info
b) inhibitory control of eating - hypothalamus
a) central regulator of whole-body energy homeostasis
b) homeostatic control of food intake
catch up growth is dependent on what?
insulin
catch up growth is related to what in children?
impulsivity
and catch up growth is an insulin dependent process
smaller pancreas means…
less insulin production
means that sensitivity of peripheral insulin cells will INCREASE
increase in sensitivity means MORE RECEPTORS
so small babies are born with HIGHER INSULIN SENSITIVITY
higher insulin sensitivity means…
glucose will be used a lot more than normal
so baby is born small, and then grows super FAST
degree of catch up growth is an indirect way of measuring…
how altered insulin secretion is
can look at graph and look at the delta/change in percentiles as a measure of insulin function
degree of catch up growth is directly linked to impulsivity levels…
only in those who were born small
(and who also have insulin-sensitivity)
insulin rPRS calculation
trying to estimate insulin sensitivity using genotypes
GWAS study - identify which gene variants are related to high fasting insulin levels
can they say, ok, this child has a higher/lower risk for high fasting insulin
GWAS
genome wide association study
take large number of participants, divide them according to a feature/characteristic
map that onto another measure (ie. high fasting insulin levels)
as adversity increases, there’s a ____ in impulsivity only in which kids?
impulsivity
kids with higher risk for fasting insulin
higher adversity = higher fasting insulin = higher impulsivity
neuroimaging study: resting state connectivity
resting state connectivity: people look at cross on screen, empty mind
get data on connectivity between diff areas
compare resting connectivity of SMALL versus NORMAL birth weight
difference in connectivity between orbital PFC and other parts of PFC
small/normal birth weight: diffs in resting state connectivity
difference in connectivity between ORBITAL PFC and other areas of PFC
area involved in willingness to wait for/work for a reward, economic tasks, calculating rewards/costs
study to complement resting state connectivity data SETUP
saw that smaller-born individuals had different resting state connectivity between orbital PFC and other areas of PFC
wanted to map this onto behaviour
had them fast the night before, because they were having their blood taken
afterwards, gave them cafeteria voucher
told them to return any remaining money
study to complement resting state connectivity data RESULTS
small-born adolescents…
a. gave more money back (as if they didn’t catch onto the value of it)
b. gave more money back (went for the cheaper, more junk-food options)
caused by alteration in the brain areas that make value attributions?
