M3-Lectur2 Flashcards
Fetal Brain and HPA Axis
Exposures at critical windows of development can alter vulnerability (or resistance) to disease
True
Hypothalamic-pituitary-adrenal cortex (HPA) axis Neuroendocrine system
Controls synthesis of glucocorticoids:
Steroid hormones (“stress hormones”)
Humans: cortisol, cortisone (inactive)
Rodents: corticosterone, cortisone
How does the HPA axis work:
Stimulus activates neurosecretory (CRH) neurons in the PVN of the hypothalamus - signal anterior pituitary gland to release ACTH by stimulating expression of POMC (precursor to ACTH) - ACTH travels in blood to adrenal cortex and GC secretion
Note: GC inhibit their activity by negative feedback via GR hippocampus, PVN and anterior pituitary & via MR in hippocampus.
Glucoroticoids can cross membrane:
True
Enzyme that converts cortisol to inactive cortisone:
Hydroxysteriod dehydrogenase 2 (11beta-HSD2)
GU binds to either GR or mineralcorticoids receptor (MR) - higher affinity
These receptors are found in the cytoplasm.
Yes
GC can enter the nucleus and bind GRE, regulating transcription of certain genes, affecting metabolism, immune response, stress adaptation:
Yes
GC function:
Mediate stress response (“Fight or flight”)
Regulates energy and metabolism
Cardiovascular regulation
Modulates immune system, inflammation
Emotions and mood
Reproductive and developmental hormone
GCs function gestation:
Provide critical signal for organ maturation required for survival after birth.
Accretion and differentiation
GCs provide critical signals for timing of parturition:
Yes
Two ways of inducing labor:
- Fetal genome - fetal growth - Uterine stretch } Uterine growth that lead to activation of ion channels, gap junctions, Agonist receptor
- Fetal Genome - HPA axis - cortisol - placental endocrine Axis (p to E) that lead to stimulation of oxytocin, stimulatory, prostaglandins
Glucocorticoids (GC) like cortisol come from both the maternal and fetal HPA axes, playing essential roles in pregnancy.
Maternal HPA axis (direct): release cortisol in response to stress & physiological needs. It can then cross the placenta and influence fetal development.
Fetal HPA axis (direct): Fetus develops its own HPA axis, leading to production of cortisol. Prepares the fetus for birth.
Feedforward mechanism: Maternal cortisol stimulate release of CRH from placenta - activate fetal HPA axis - more cortisol from the fetus. Ensures both maternal and fetal systems respond appropriately.
As the fetal HPA axis is developing, so is the placenta
True
Placenta CRH synthesis and secretion ↑ = Increased circulating [cortisol]
Yes
Fetus protected from ↑ [cortisol] by function of placental 11β-HSD-2
Yes
Placental 11β-HSD-2 converts cortisol to inactive cortisone
due to:
15% maternal cortisol crosses unmetabolized
Cortisol levels in the fetal circulation are kept ~10-fold lower than the maternal circulation
- to prevent effects of high cortisol (maternal and also fetal cortisol)
True
to protect the fetus from excessive levels of cortisol
11BHSD-1 (converts cortisone to cortisol)
Yes
Overexposure or exposure of GC at inappropriate times during fetal development may modify:
Fetal HPA axis function
Brain development
Fetoplacental growth
Endocrine and metabolic function after birth
Causes of GC exposure:
Pre-term birth prevention:
Synthetic glucocorticoids like dexamethasone and betamethasone to promote fetal lung maturity & reduce incidence of respiratory distress syndrome.
Prenatal Stress Exposure:
Maternal stress can lead to more GC levels impacting fetal development.
Consequences of GC exposure:
Fetal deve.:
1. LBW, impaired neurodeve., high risk of behav. issues.
- Reduces inflammation & help manage complications with pregnancy.
Risks: Hypertension, metabolic disorders, and high susceptibility to infections.
- Neurodeve effect:
Exposure to elevated levels of glucocorticoids whether from maternal and synthetic can have long-term effect.
Synthetic glucocorticoids like dexamethasone and betamethasone are preferred over natural cortisol because they are more potent, have a longer duration of action, reduced mineralocorticoid effects, and allow for better control over dosing and therapeutic outcomes.
True
Causes of Preterm Birth:
Idiopathic (45-50%): Often multifactorial, including genetics, environmental factors, socioeconomic status, and maternal behaviors.
Preterm Premature Rupture of Membranes (PPROM) (30%): Often linked to infection or inflammation.
Medically Indicated (15-20%): Due to maternal health issues, fetal growth restriction, or congenital anomalies.
Readily cross the placenta as synthetic GCs are poor substrates for 11β-HSD-2
True
Consequences of SGCs (Long Term Outcomes)
sGCs showed no significant differences in body size, blood lipids, blood pressure, plasma cortisol, or the onset of diabetes and cardiovascular disease;
but participants showed increased plasma insulin levels and decreased glucose levels during oral glucose tolerance tests, indicating a potential risk for insulin resistance.
Another study found no improvements in outcomes with multiple courses of sGCs, showed significant reduction in birth weight, body length, & head circumstances
No diff. in risk of death or neurological impairment.
True
Consequences of SGCs (Long Term Outcomes) Brain Deve.
Animal studies shows that sGCs can reduce brain weight, decrease cell proliferation & dendritic branching, & disrupt myelination while altering neural activity.
In human neonates, exposure to sGCs - decrease in cortical volume & complexity of cortical folding affecting limbic & prefrontal region (have high GR and MR receptors)
Consequences of SGCs (Long Term Outcomes) Brain Deve.
In the fetus, glucocorticoids (GCs) influence limbic development and the maturation of the hypothalamic-pituitary-adrenal (HPA) axis.
True
Consequences of SGCs (Long Term Outcomes) Brain Deve.
In adults, GCs impact limbic function and HPA function, affecting behavior, cognition, memory, learning, and emotion.
True
Consequences of SGCs (Long Term Outcomes) Brain Deve.
GC exposure also affects the cardiovascular system, immune system, and glucose regulation,
True
glucocorticoids (GCs) regulate autonomic and endocrine functions in response to emotional stimuli.
True
GC receptors:
Cortex, hippocampus and dentate gyrus (DG), Paraventricular nucleus of hypothalamus (PVN), amygdala (AMG)
MR receptors
LS (hippocampus & DG)
Consequences of SGCs Limbic System Deve.
antenatal synthetic glucocorticoids (sGCs) showed major structural changes, even full-born, bilateral cortical thinning in (ACC)
Yes
Consequences of SGCs Limbic System Deve.
Serves as a critical link between the “emotional” limbic system and the “cognitive” prefrontal cortex, facilitating the ability to control and manage uncomfortable emotions
The anterior cingulate cortex (ACC)
Consequences of SGCs Limbic System Deve.
Dysfunctions in the ACC are associated with mood disorders such as depression, anxiety, and bipolar disorder, and can lead to avoidance of painful emotions, contributing to behaviors like substance abuse, binge eating, and an increased risk of suicide.
True
Consequences of SGCs Limbic System Deve.
Yes, children exposed to antenatal synthetic glucocorticoids (sGCs) may have an increased risk for mental health disorders. How?
Structural changes in the ACC and other regions - can affect emotional regulation & cognitive functioning - thus anxiety, depression, behavioral issues later in life.
Consequences of sGCs HPA system:
lead to reduced basal and stress-induced cortisol secretion in neonates, potentially affecting their stress response. But not conclusive.
Findings: antenatal synthetic glucocorticoid (sGC) exposure is associated with increased cortisol reactivity to acute psychosocial stress, with effects that depend on fetal sex.
Chronic stress exposure consequences:
Dysregulation of stress response
susceptibility to infections
autoimmune disorders
cardiovascular disease
reproductive dysfunction
cognitive decline
Depression
diabetes
poorer wound healing
cancer (shown in animal models, debated in humans)
Prenatal maternal stress (Physiological or psychological stress) can lead to either acute or chronic stress.
Yes
Prenatal stress exposure:
Fetal/placental growth
HPA function
Fetal neurodevelopment
Endocrine/metabolic changes
Risk of non- communicable disease (eg. CVD)
Metabolic dysfunction
Long-term changes in stress reactivity
Neuropsychiatric vulnerability
Prenatal stress exposure can impact Programming effect on organ systems including brain development and HPA axis
Behavioral and cognitive alterations
Animal studies: Altered HPA function, increased basal levels of croticosterone & high stress response.
True
In male rats, prenatal stress exposure can lead to altered stress response in offspring.
True
In Guinea Pig: chronic maternal stress lead to reduced postnatal growth in males.
Yes
In maze when exposed to stress 3X per day during last 10 days of pregnancy:
Males show increased anxiety-like behavior in maze
Females: Reduced anxiety in maze, improved learning compared to control (learned faster)
is a neurotransmitter and potent vasoconstrictor and is critical for fetal brain development
Serotonin (5-HT)
During pregnancy, the placenta synthesizes neuroactive factors that can influence fetal brain development, including 5-HT.
True
The placenta has endogenous biosynthetic pathways that produce serotonin (5-HT) develops what
Early source
Fetal brain
Later source for fetal brain development:
Dorsal raphe (DR) serotonergic neurons in the fetal brain a key source of serotonin (5-HT) production in the brain
Maternal stress causes an increase in serotonin (5-HT) levels in the mother’s brain and blood. This rise in serotonin leads to more serotonin transporters in the placenta, which increases the synthesis of serotonin there [increased maternal stress elevates serotonin levels, prompting the placenta to upregulate serotonin transporters to manage and utilize the excess serotonin] - potentially disrupting the normal migration of important brain cells (cortical interneurons) during fetal development, which can affect how the brain develops.
5-HT metabolized to inactive form (5-HIAA)
monoamine oxidase A (MAO A)
See the formula
rich source of MAO A
Barrier role, regulating fetal exposure to serotonin
Placenta
Offspring of MAO A knockout mice exhibit impaired neurodevelopment and elevated brain serotonin levels. Similarly, maternal stress results in decreased placental expression of MAO A, leading to increased fetal exposure to serotonin, which can negatively impact neurodevelopment.
True
Short-term stress in rat pups leads to decreased HPA activity and reduced stress responses, while prolonged stress results in increased HPA activity and heightened stress responses. This is linked to elevated mRNA levels of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) in the hypothalamus.
A two-year follow-up study of children who lost a parent during the September 11, 2001, terrorist attacks found that, at a mean age of 8.9 years, these children had elevated morning cortisol levels and higher rates of psychiatric disorders, such as anxiety and PTSD, indicating hyperactivity of the HPA axis.
Outcomes for those exposed to childhood adversity vary due to factors like genetics, sex/gender, health conditions, and the nature of the exposure. Protective factors, such as stable and nurturing relationships, can mitigate stress effects and promote long-term benefits in learning, behavior, and health.
↓ GR gene Me in pups from high care moms
↑ GR gene Me in pups from low care moms
High maternal care also associated with ↑ histone tail acetylation and ↑ NGF-A binding
↑ GR gene expression in the hippocampus of adult offspring of high care mothers
Adults from low care moms:
↑ basal circulating [corticosterone] Heighted stress response
Fearful behavior
Involves skin-to-skin contact between infant and caregiver
Thermal regulation
Increased newborn weight gain
Increased breastfeeding success and duration
Increased milk supply
Increased immunity
Reduced fetal stress and pain
*Increased paternal bonding
*Decreased postpartum depression
Kangaroo Care
Significant decrease in neonatal mortality
Kangaroo care for preterm infants:
Improved body temperature, respiration rate, heart rate and oxygen saturation
Analgesic properties
Heel stick procedure
Reduced HPA activity and decreased cortisol levels in infants
Increased IQ scores at 12 months
Improved executive functioning (5 and 10 yrs)
HPA axis can be programmed during development and infer risk to the offspring later in life
Inappropriate exposure to GC and other stress hormones, maternal inflammation and the postnatal environment are stimuli for programming of the HPA axis
