20 Responses

  1. runanteldat
    runanteldat at | | Reply

    What I thought would be interesting is how do different types of stress affect newborn brain development, more so, chronic vs. acute stress. Acute stress can be a sudden death in the family whereas chronic stress can be racial discrimination or unemployment. Interestingly, not all the mothers that were studied for acute stress had higher levels of CRP or IL-6, and it is thought that they may have had a better support system compared to the mothers with the elevated proteins. Also, the varying types of chronic stress can affect neurodevelopment. Chronic stress that’s a result of poverty or racial discrimination also coincides with a decreased likelihood of receiving prenatal care.


  2. Amy Hoang
    Amy Hoang at | | Reply

    This study highlights the importance of understanding how maternal immune activation (MIA) can change the brain’s circuitry development within children, predisposing them to mental illness. I particularly found the correlation between maternal immune activation and the risk of schizophrenia to be intriguing. There have been many studies that show that there is a seasonality of birth in schizophrenia, specifically during the winter or spring months where there is a prevalence of influenza infections. Women that are infected with a respiratory infection like the flu, increase their children’s risk of schizophrenia by seven fold. There is an estimate that 14-21% of schizophrenia is due to MIA infections. With these resounding statistical associations, I wanted to understand the mechanism by which MIA and one of its circulating products, cytokine Interlukin (IL-6) was found to be responsible for the alteration brain development that increases risk of schizophrenia.

    A study done on mice in 2008 tested the effects of IL-6. The researchers injected pregnant mice with IL-6 and saw that the offspring exhibited abnormal behavior and Prepulse Inhibition (PPI). PPI is a measure of sensory-motor gating, attention, and distractibility that is also seen in patients with mental illnesses, such as schizophrenia. They also saw that IL-6 injected mothers had 61 genomic differences being expressed in the offspring’s brain development when compared to the control. To show that it is not MIA alone that is the agent of behavioral changes, the researchers genetically modified mice to not express IL-6, and infected them to induce MIA and saw that the behavior of those mice were normal and similar to those of the control group. Interestingly, their data shows that when they injected an antibody to the IL-6 (anti-IL-6) injected mothers, their offspring did not have any transcriptional changes and did not show any behavioral deficits.

    This study shows that IL-6 is critical for mediating behavior and transcriptional changes in the offspring and by eliminating IL-6, the effects of MIA can be less detrimental to the development of the fetus’ brain and predisposition to schizophrenia can be reduced. Possibly, future studies could direct us into the path of the invention of a pharmaceutical agent that could regulate IL-6 secretion when a mother is infected with the flu, or Zika, to allow normal fetal brain development. With that stated, I wonder what critical mechanism C-reactive protein (CRP) play in MIA.


    1. Amber
      Amber at | | Reply

      Though most research on prenatal immune response and CNS disorders centers around schizophrenia, recent research also suggests that Autism Spectrum disroders (ASD) may in part be caused by maternal immune responses. Scientists believe that the maternal immune activation (MIA) model may act as a primer for CNS disorders to develop. Though MIA has been associated with ASD and SZ it is likely that other environmental and genetic factors are also at work. Although a clear universal infectious risk factor has not been established, certain subsets of patients can have a double or triple chance of their children having an ASD after an infection or immune response. Both the timing and severity of the response have been indicated as possibly having influence on whether an ASD is contracted.


  3. MikeandIke
    MikeandIke at | | Reply

    The full idea of immune activation can’t be accounted for without mentioning the importance of cytokines. Cytokines are signaling proteins that play a big role in the regulation of immune responses stemming from an infection. For the most part, the maternal immune system in pregnant women is responsible for protecting the developing embryo from any potential infections that may occur. It is also very interesting to know that cytokines have implications in the development of the brain as well as behavior. Infections within the mother can affect offspring development and cause a variety of neurological disorders.


    1. viva/la/raza
      viva/la/raza at | | Reply

      Cytokines such as IL-6 has had major implications in fetal brain development. Production of IL-6 can transverse the placental barrier and activate fetal immune system which can influence neural development. One such implication is in autisim spectrum disorder. Maternal immune response to pathogens such as the influenza virus seems to indicate propensity of infants displaying a range in ASD. In cases of Alzheimer patients, IL-6 is implicated in the activation of transcriptors (STAT), particularly STAT3 which upregulates the transcription of glial cells. This leads to a sustained inflammation in these cells. IL-6 can also influence neural regulatory genes for the differentiation of neural stem cells. Anomalous expression of this genes are associated with ASD.


  4. dmicul13
    dmicul13 at | | Reply

    The study discussed in the above post states that fetal heart rate and changes in the communication between specific brain regions were looked at in fetus, newborn, and toddlers. Reading through this post, I wondered if there were any observable anatomical changes such as size or other markers of fetal, infant, or toddler brains due to elevated maternal IL-6. One study I came across, found that elevated maternal IL-6 was associated with a larger amygdala and strong bilateral amygdala connectivity to brain regions involving sensory processing, integration, salience detection, and learning and memory. These differences were associated with lower impulse control at 2 years in the child during a snack delay task (to assess impulse control). As researchers continue to conduct studies to better understand intrauterine conditions that influence the fetus beyond the nine months they spend in the uterus, the environment of the fetus is extremely important for psychological development. Furthermore, amygdala activity has been correlated to sexual orientation, social interaction, aggression, fear, alcoholism, anxiety, post-traumatic stress disorder, bipolar disorder, and even political orientation which are aspects of human psychology well beyond the age of 2 years. I wonder the mechanisms in which the maternal environment affects these aspects.


  5. Nicholas McGregor
    Nicholas McGregor at | | Reply

    Firstly, it is my belief that this post on immune activation and infant brain development is vital to understanding the immune system’s role in the earliest years of life and even the development that occurs prior to birth. The researchers measured levels interleukin-6 (IL-6) and C-reactive protein (CRP) to determine the levels of immune activation as both of these markers indicate immune activation.

    I chose to focus on CRP’s role in the immune system to determine if this is truly a good measure of immune activation. In the paper titled “C Reactive Protein (CRP)” by Sara Nehring. She provides a detailed and accurate description of the purpose of CRP. CRP is produced during the acute phase of an inflammatory/ infectious process. It has both anti-inflammatory properties and pro-inflammatory properties. CRP is primary used in recognition of foreign pathogens and damaged cells by binding to phosphocoline arms, when available, and can activate phagocytic cells. This function can actually have negative effects. When it is activated by antibodies that are displaying the phosphocoline arm and can worsen tissue damage in certain cases.

    Reference article: https://www.ncbi.nlm.nih.gov/books/NBK441843/
    It is my conclusion that CRP is an “okay” indicator for immune activation because it is a primary responder when inflammation is present but IL-6 is a more precise indicator of immune response. The potential cyclic cascade that can occur due to CRP’s ability to worsen tissue damage makes its role as a marker possibly inaccurate. IL-6 would be the more important marker to be measured because CRP is produced as a result of IL-6 activation, not produced on its own.

  6. Rahat Mohammad Nayem
    Rahat Mohammad Nayem at | | Reply

    Pregnant women, whom experience infectious diseases during pregnancy, develop an increased risk of disorders such as Schizophrenia and autism initiation in their offspring. Exposure to infections will result in immune system activation during pregnancy. Maternal immune activation, also known as MIA, has a negative affect on offspring’s behavior, development, gene expression and histology in many ways. In other words, MIA serves as a “helping factor” for disorders such as Schizophrenia and Autism. There are several studies done to indicate the direct mechanism of MIA leading to long-term behavioral disorders. However, the direct cause of this process is still not known.


    1. Karishma S
      Karishma S at | | Reply

      A meta-analysis of 300 studies regarding maternal immune activation, maternal stress and child neuropsychiatric risk reviewed the various factors the led to actual mental health development in children stemming from immunological and neurodevelopmental events. The researchers proposed that inflammation is a potential intermediary between the mother’s prenatal stress and their child’s neuropsychiatric risks.
      Psychosocial stress disregulates features of immune function. Various types of stress have been associated with elevated circulating inflammatory markers and impaired immune function. The origin of this relationship between stress and inflammation is the interplay between the hypothalamic-pituitary-adrenal axis and immune system. Glucocorticoids affect both innate immunity, such as inflammation, and adaptive immunity, such as specific T-cell/B-cell mediation. Glucocorticoids also modify the activity of various immune cells, such as monocytes and macrophages, and communicative intermediaries, such as cytokines and chemokines. Despite being considered anti-inflammatory, glucocorticoids also can suppress immune function.
      The meta-analysis found that different types of stress affect different aspects of immune function. For example, “acute laboratory stressors upregulated innate immunity and downregulated adaptive immunity, brief naturalistic stressors such as academic examinations shifted function away from cellular immunity (T helper type 1) and toward humoral immunity (T helper type 2), and chronic stressors, which are pervasive and unrelenting, suppressed both innate and adaptive immunity”.
      A “healthy” or well-regulated glucocorticoid–immune system will respond to stimulation through a temporary rise in pro-inflammatory cytokines in response to acute physiological stress, however a dysfunctional glucorticoid- immune system will prolong that immune response and that chronic stress may result in glucocorticoid resistance.
      Preclinical research states that maternal immune activation (MIA_, particularly involving cytokines IL-6 and IL-17a, is the key link between the mother’s stress and their child’s outcomes. The review also found that maternal IL-6 during pregnancy associates with altered infant brain structure and function along with neurocognitive deficits suggesting that MIAs during pregnancy raise risk by “inducing potentially subtle neurocognitive patterning that may or may not be unmasked later in life depending on environmental factors”.


  7. chrisleah
    chrisleah at | | Reply

    It’s amazing how many factors play a role in fetal development. This article discusses how the immune response and in particular IL-6 and C-reactive protein changes the brain development of a fetus. The fact that inflammation can affect your babies brain and essentially play a factor in their future illustrates how many variables there truly are when one considers starting a family. Twenty years ago, I don’t think such factors were ever taken into consideration. It will be interesting to see what exactly the effects are of inflammation and immune activation in the babies brain. Stress can also cause inflammation and be very dangerous when a woman is pregnant. An article that I found discusses psycho-social stress that can increase cortisol levels which can inhibit vaginal glycogen, leading to inflammation and infection. The vaginal micro-biome is crucial during pregnancy and can affect the fetal membranes and placenta.


  8. Sauveur Barry
    Sauveur Barry at | | Reply

    I found it very interesting that stresses to the mother could shape the brain development of a child. The study above found that significant changes in the communication between specific brain regions correlate with elevated maternal IL-6 and CRP level. This led me to wonder whether other aspects of the mother’s immune system significantly altered other aspects of fetal development. I found a paper that looked at the link between increases in immunoglobulin G and increases in live births in women with recurrent miscarriages. The study found that in women with exhausted T cells and regulatory T cells were at risk for recurrent miscarriages. To combat this, the women were given intravenous immunoglobulin G (IVIG) every four weeks during 32 weeks of gestation. The IVIG decreased the number of exhausted T cells and regulatory T cells. Which in turn, led to a decrease in recurrent miscarriages. This study introduced another link between the immune system and fetal development.

  9. Sauveur Barry
    Sauveur Barry at | | Reply

    I found it very interesting that stresses to the mother could shape the brain development of a child. The study above found that significant changes in the communication between specific brain regions correlate with elevated maternal IL-6 and CRP level. This led me to wonder whether other aspects of the mother’s immune system significantly altered other aspects of fetal development. I found a paper that looked at the link between increases in immunoglobulin G and increases in live births in women with recurrent miscarriages. The study found that in women with exhausted T cells and regulatory T cells were at risk for recurrent miscarriages. To combat this, the women were given intravenous immunoglobulin G (IVIG) every four weeks during 32 weeks of gestation. The IVIG decreased the number of exhausted T cells and regulatory T cells. Which in turn, led to a decrease in recurrent miscarriages. This study introduced another link between the immune system and fetal development.


  10. Fri
    Fri at | | Reply

    The article above used women between the ages of 14-19 years old as participants in their study, to exemplify a group under psychosocial stress, resulting in inflammation receptors affecting their babies brain development. Whether it being short or long term. On the contrary, there are things other than psychosocial stress that can elevate the pro-inflammatory response in pregnant women. Such as things like obesity, which is a serious epidemic in America. They’re a lot of women who are obese ( BMI over 30) that are pregnant. Many articles state how obesity or high lipid levels can impact cancer and the inflammatory response. I was interested to see if this could have any correlation with any impacts on the babies brain development as seen in the other women in the post above.

    One article in which I found, discussed this type of experiment, in which this kind of relationship was shown. To address the manner in which inflammation is noted in the ovaries, a panel of cytokines (IL6, IL10 and TNFα) were analyzed alongside acute phase proteins (C-Reactive Protein (CRP) and sICAM-1) from the ovarian follicular fluid. The women the fluid was obtained from were lean, overweight and obese. The results showed that the adipokines and pro-inflammatory cytokines expressed were not directly related to BMI index. Meaning there was no direct relationship seen with definition obese women (BMI over 30). However there was a positive correlation with the lipid levels in the follicular fluid and the amount of cytokines and acute phase proteins expressed. Specifically with triglyceride and free fatty acids. The inflammatory markers that were associated with intra-follicular lipids were both pro-inflammatory and anti-inflammatory mediators. CRP and IL6 were both pro-inflammatory markers noted in the intra-follicular lipids. The exact impact these findings have on an ovarian microenvironment with high lipid levels and inflammatory mediators is unknown.

    In reference to the above blog post, this just shows that there are multiple things that should be taken into consideration when evaluating pro-inflammatory release during pregnancy. This experiment just shows that even a person without a high BMI (so the atypical obese person) can still have high levels of lipids (triglycerides and free fatty acids) in their blood streams. A woman who looks slim could very well fit into this category. More research could be done with women to see if there are any test that can be run during pregnancy to test for lipid levels or other pre-disposing factors. This is also good information for other woman to understand that simple things like high lipid level can have a chain event affecting pro-inflammatory mediators, which could play a part in their babies brain development.


    1. Carl Dalmeus (AKA the wondering scientist)
      Carl Dalmeus (AKA the wondering scientist) at | | Reply

      I just read your comment, it seems to focus on the weight, high lipid molecule levels, and the types of diseases that can be produced by them such as obesity. It reminds me of a concept I learned a while ago called metabolic syndrome. This is where the body can have multiple problems and conditions such as: increased weight, hypertension, increased cholesterol or triglyceride, and increased amounts of blood glucose. When you have this disorder, it can make you susceptible to many different other diseases like diabetes, some type of cardiovascular diseases, even obesity. Do you think that mothers that are obese also have metabolic syndrome that can affect the inflammatory signals?

      In addition, I also read that exercise, being active, and a change in diet can help people lighten or even reverse the effects of disease like obesity, diabetes, and high blood pressure. These seem to be all a part of some form of metabolic syndrome. In the study below, this is shown. Do you think there is a way for a mother with these diseases or metabolic syndromic affects could have decreased inflammation without it being too strenuous or harmful to the mother and baby? This way their newborn child could as healthy as possible, like speeding up the mother’s metabolism to in order to decrease sugar levels and fat moles in the mother (maybe even decreasing weight).


      1. Fri
        Fri at | | Reply

        Yes, in-fact you have brought up some key points. Metabolic syndrome seems to be a very good way to describe the characteristics of what is going on in the body of a lot of individuals. Especially the facts you listed: increased weight, hypertension, increased cholesterol and high amounts of glucose all seem to have a cycling effect on the body. Hence the term syndrome, the exposure to one definitely leads to the exposure of others. It will be very interesting to see if hopefully sometime in the future there can be some kind of underlying key to solve this cycling problem. I do believe though, as you mentioned, the underlying cause of this is diet. As well as some other minute genetic predisposing factors. Maybe sometimes we do not take into account how gravely we are a product of what we eat. The stress the body goes through during pregnancy, especially if experiencing gestational stress can surely have some impacts on the baby. Do you think things like this really play that big of a deal when it comes to embryo development with brain and even after birth?

        I read in an article that was talking about this kind of issue at hand. Females that experience gestational stress during pregnancy have a high chance at developing postpartum depression. Depression has been shown to be accompanied by the activation of the inflammatory response system. The study looked into this by seeing the effect gestational stress had on female fisher-rats. It was suggested in the study that gestational stress leads to an onset of post-partum depression-like behavior. The stressed group of rats were analyzed for concentrations of pro-inflammatory cytokines interleukin-1beta and the anti-inflammatory cytokine interleukin-10 via whole-blood cultures. The stressed groups of rats showed higher levels of all 3 cytokines.

        These findings can then lead one to wonder if the same mothers that experience a rise in cytokines from gestational stress, can they be transferred to baby via breastmilk or via placenta? It will be interesting to see the kind of response the babies immune system will give based on this. This definitely gives rise for future evaluation in human studies. Although ethical issues will surely have to be ironed out. Do you think this is something that metabolic syndrome findings can play a key role in? Even just educating mothers on the implications gestational stress has on the body and growing baby. Diet should not just be looked at for size or weight, but total body and reproducing health in a whole.


  11. Karishma S
    Karishma S at | | Reply

    This post discusses how maternal immune activation (MIA) affects the brain neural development of the fetus. A study referenced in the blog, the Journal of Neuroscience states that “maternal immune activation during the third trimester is associated with neonatal functional connectivity of the salience network and fetal to toddler behavior” and the study sought to assess potential associations between “markers of inflammation in the mothers’ blood” with changes in the neural processes of the fetus/infant. Researchers evaluated brain development from fetal stage through delivery and through toddlerhood. Teenage expectant mothers were selected as teenage pregnancy carries higher risks of psychosocial stress. The subjects were assessed during their second trimester and they had inflammation.

    During their third trimester, the expectant teenage women had blood work done, along with fetal heart monitoring. The blood work measured levels of interleukin-6 (IL-6) and C-reactive protein (CRP) to assess immune activation. The fetal heart rate served as a gage for fetal nervous system development. Post-birth, at 14 months old, the infants then had anatomical brain scans and cognitive behavioral assessment done. The study found that “the presence of CRP during the third trimester correlated with variability of the fetal heart rate, indicating that maternal inflammation was already beginning to shape brain development.” The brain scans that determined neural development revealed that significant deviations in the “communication between specific brain regions correlated with elevated maternal IL-6 and CRP levels.” The brain regions or the salience network filter incoming stimuli and chooses which stimulus information requires the brain’s attention. Also at the 14 months mark, the infants were assessed for their motor skills, language development, and behavior. This assessment indicated significant changes in toddlers born to the teenage mothers who had the elevated levels of both IL-6 and CRP, thus suggesting that markers of inflammation have lasting implications of the brain development of the fetus/child.

    I wondered if preterm infants (premies) had more concerns for these neural developmental changes as their fetal incubation and/or delivery tends to be more challenging. The study “Chronic inflammation and impaired development of the preterm brain” was a meta-analysis study of premature infant brain development. The literature stated that 50% of preterm infants will have cognitive and behavioral challenges. They stated that inflammation is hypothesized to be one of the “primary mediators of white matter dysmaturation” or stunted white matter development. Infants in that 50 % had a high occurrence of “inflammatory lesions, and both acute and chronic chorioamnionitis, and funisitis, signifying a strong association between perinatal inflammation and impaired neurodevelopment”. The maternal lifestyle choices, such as smoking, drug and alcohol use, and diet; and health status, such as obesity, respiratory compromise and access to standard clinical care all served as stressors that has impacts on preterm infant brain development.


  12. Capricorn86
    Capricorn86 at | | Reply

    When reading this article I found it interesting that they examined young mothers due to the high psychological stressors in their life. I found an article that examined young mothers that had early intervention for their psychological stressors to see the impact it had on their babies cognitive development. These babies were examined at birth, 12 months, two and four years old. The results that early intervention for these mothers while they were pregnant had no affect on the babies cognitive development. I am interested in other environmental factors or influences that might alter the levels of IL6 and CRP in the mother’s blood due to inflammation.


    1. Tate
      Tate at | | Reply

      I also found it interesting that the study mentioned in the post used mothers ranging from age 14 to 19. It made me wonder if being a teen mother typically led to children with more developmental issues. Most research we see indicates that children of teen mothers do have developmental issues, but this study I found concluded the opposite. They found that when comparing the health and development of children of teen mothers to the children of older mothers (mothers over the age of twenty) of the same socioeconomic background, there was not much of a difference. This brought about the conclusion that a mother’s age (in regards to a mother being young) does not solely determine the health and development of the child but that socioeconomic status plays a role as well.


  13. Hadeel
    Hadeel at | | Reply

    When I was reading this post, I wondered about the outcomes of maternal inflammation on the neurodevelopment event? What are the consequences on the behavioral side! And what phenotypes we are expected from babies with maternal inflammation? I found this review article about what the role of maternal inflammation on the neurodevelopment in preclinical outcomes. What this paper concluded is early pregnancy inflammation can later develop physiological and neural development in newborns. Some outcomes are changes in the cellular and molecular process in the babies’ brains. Due to the fact that prenatal development is critical in the activation of microglia and brain development, prenatal inflammation can result in anxiety or depression or some sort of social behavior. It is also associated with mood disorders, and autism spectrum disorder. It is critical to consider the psychological health as well as the physical health for pregnant women to reduce the risks of neurodevelopmental and brain deficiency.


  14. viva/la/raza
    viva/la/raza at | | Reply

    In the reemergence of Zika Virus (ZIKV) in late 2015, there was a correlation of high birth rates of infants with microcephaly, to the regions of endemic ZIKV infection. At the time, the correlation couldn’t be tied to the virus, but there were signs of strong support for that relationship. It was interesting to note how a mild, and sometimes asymptomatic infection can result in such a disastrous effect on pregnant women. I wondered in what metabolic pathway was this deleterious effect achieved. While it is a common notion, backed by science, that good mental health and good overall health is beneficial to a fetus, it was significant to realize just how dangerous this virus could be. I wanted to understand, mechanistically, how maternal hormones or inflammation can disrupt fetal brain development.

    This paper has elucidated that an increase in serotonin hindered fetal forebrain development in mice. They induced mice to an immunostimulant, Poly(I:C). This resulted in sustained levels of inflammatory cytokines such as IL-6. They found that these sustained levels increased the concentration of placental tryptophan (TRP), which then led to an upregulation of tryptophan hydroxylase (Tph1) and increase in Tph1 activity. This resulted in increased levels of placental and tissue serotonin (5-HT). 5-HT affected the forebrain by disrupting the axonal growth.

    This was a study conducted in mice but have broad implications on human brain development. I would like to understand more of the mechanisms relating to immune response and human development, particularly with ZIKV.


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