Wednesday, November 25, 2015

Cesarean section and brain development

These immune changes — or perhaps something else about the experience of birth — may affect the brain, too. Castillo-Ruiz and her advisor, neuroscientist Nancy Forger, had noticed a strange spike in cell death right around the time of birth in baby mice. That sounds alarming, but it's not: As the nervous system grows, it overproduces brain cells, only to kill off the ones it doesn't need.
"We were struck by this peak of cell death right at birth," Forger said. It happens across the brain, she said, in the hippocampus, the prefrontal cortex, the hypothalamus and more.

Forger and Castillo-Ruiz wondered if birth itself was kick-starting this process. Some recent work suggests that the immune system plays a role in this cell destruction, and birth is an immunological experience. Not only are babies introduced to mom's microbiome during delivery, but are also exposed to inflammatory signals in the uterus as the process of labor begins.

The researchers bred mice and watched them like hawks 19 days after conception, when delivery was imminent. Forger's team made hourly, round-the-clock checks on the pregnant mothers. When one began to give birth, she selected another mouse at the same point in gestation that wasn't yet in labor. Then she conducted a mouse-y cesarean to deliver that mother's litter. In this way, the researchers could compare the effects of delivery method without any confounding data on gestational length.
The project is still ongoing, but the researchers presented some preliminary results at the annual meeting of the Society for Neuroscience in October. Early analysis of the mice brains suggests that the delivery method mattered. Three hours after birth, baby mice born by C-section show decreased cell death compared with mice born vaginally, she said.

The team has also measured physical development of the offspring. The method of birth didn't seem to affect initial body weight or time of eye-opening in juvenile mice. But later on at weaning age, the researchers observed an increase in body weight in cesarean born mice, which is in line with reports of higher body mass index and risk of adult obesity in humans born by cesarean section, the researchers said.

Looking at the behavior of baby mice, the researchers found that cesarean-born mice made softer cries when separated from their mothers at 9 days old than mice born vaginally. This could be meaningful for a little mouse's life and survival, Forger said, because other research has found that moms pay more attention to the mouse babies when they're louder.

As for the change in the rate of naturally occurring neuronal death, the researchers are planning to get to the bottom of the underlying mechanism. They are now investigating whether the microglia, the immune cells of the brain, have a role in neuronal cell death and whether their function is altered depending on how a baby mouse is born. That focus on a potential mechanism for the changes is a strength of the study, said John Cryan, a neuroscientist at University College Cork who was not involved in the research but who has studied the long-term neurobehavioral effects of cesarean sections and found changes in anxiety and social behavior in mice.

"Early-life manipulations can have long-term effects in sculpting behavior later on, and this is a very important area both in basic science, but also in clinical medicine," Cryan said.
The effects of birth aren't all immunological, either — babies about to be born are exposed to a massive flood of hormones during labor. If labor never starts, that hormonal influence never happens. One of these hormones is oxytocin, a poorly understood compound, which nevertheless seems to have a variety of effects in the brain. For example, it has been found to switch the function of the neurotransmitter GABA in mice—In fetal mice brain, GABA has an excitatory influence on neurons. Shortly before delivery, oxytocin triggers a chain of events that causes GABA to have inhibitory actions in the mature brain. This shift doesn't happen in some rodent models of autism, Aix-Marseille University researcher Yehezkel Ben-Ari and colleagues found in a 2014 paper published in the journal Science. Cryan and his colleagues, too, have also looked at the effects of oxytocin exposure on the newborn brain. They found that a post-delivery dose of oxytocin can reverse some of the behavioral effects seen in mice born by C-section, they reported in October at the Society for Neuroscience as well.

In the face all these potential effects just coming to light, other researchers have started to look into ways to make cesareans seem a little bit more like vaginal birth. The World Health Organization estimates that about 10 percent to 15 percent of births need to end in C-section in order to prevent the deaths of both moms and babies. Researcher Maria Dominguez-Bello of the New York University School of Medicine and her colleagues have been conducting an experiment in which a piece of gauze is placed in the vagina of a mother about to undergo a cesarean, and then used to swab the baby's skin after birth. Her research suggests that this strategy can partially restore the baby's skin microbiome to what it would look like after a vaginal delivery.

There are caveats, of course. We still know too little about the long-term, real-world neurological effects of birth in humans, Cryan said. In fact, some mothers may not have a vaginal microbiome you'd want a baby introduced to. In Dominquez-Bello's work, the team tries to control for such unknowns by testing mothers to ensure their vaginal microbiome is Lactobacillus-dominated, strep-B negative and otherwise healthy.

And there are mothers' needs to consider. Choosing the method of giving birth is not just a medical but also a personal decision, which makes it all the more important to continue investigating the true effects of birth methods, so moms can make informed birth choices.

"The last thing we want to do is go blaming moms," Cryan said. But in some places, medical policy has pushed cesarean rates sky-high. In the United States, the C-section rate is about 30 percent. Although this is considered a high rate by medical societies such as The American College of Obstetricians and Gynecologists, rates are even higher elsewhere. In Brazil, for example, 85 percent of private hospital births are done by cesarean, as are 45 percent in public hospitals. Those high numbers make a close look at consequences necessary, Forger said.
Courtesy of Doximity


  1. Birth: An overlooked event in brain development?
    Georgia State Univ., Atlanta, GA
    Neuroscience 2015


    Birth involves dramatic changes in a newborn’s environment and the processes associated with birth (labor and parturition) trigger an ‘adaptive stress’ response which prepares key peripheral organs for the transition to postnatal life. However, little is known about how birth influences the brain. Cell death is an important feature of nervous system development. In mice, there is increased cell death across many brain regions around the time of birth. Whether cell death is induced by parturition has not been addressed. In addition, mode of birth might be important for the normal course of cell death in the brain, because 19 days post-conception, Cesarean (C) born mice show decreased cell death in several brain regions (e.g., dentate gyrus, oriens layer of the hippocampus, and suprachiasmatic nucleus) relative to mice born vaginally (V) the same day. To systematically study how birth influences cell death, we manipulated birth mode (V vs C) in timed-pregnant mice and collected the brains of male and female offspring in utero at embryonic day (E)18.5 and E19 and ex utero (V and C birth carefully matched for time of delivery) at postnatal day (P)0 (3h after birth), P1, P3, and P23 (the latter three groups were cross-fostered to unrelated dams). We monitored the morphometric development (body weight and eye-opening) of these mice and assessed affective state by measuring ultrasonic vocalizations in an isolation test at P9. Birth mode did not affect gross development of newborn or juvenile mice. We did observe slightly increased body weight in C mice at weaning, which is consistent with clinical reports of higher body mass index in humans born by C-section. We also found that birth mode may alter neurobehavioral/affective development because C mice had significantly softer (lower amplitude) calls than V mice in the isolation test. Interestingly, call amplitude is reported to be the most salient feature of an infant’s call for eliciting maternal behavior in mice. We are currently processing the brains for the histochemical detection of cell death (activated caspase-3) and microglia (Iba1) markers. Microglia, the brain’s resident immune cells, may play an active role in neuronal cell death. Parturition activates the peripheral immune system and birth mode influences the degree of this activation. Whether the immune activation at birth extends to the brain it is not known and will be investigated here. Taken together our work (previous and current) suggests that birth may be an important event for brain development and deviations from the natural mode or timing of birth may alter brain development and behavior.

  2. Tyzio R, Nardou R, Ferrari DC, Tsintsadze T, Shahrokhi A, Eftekhari S,
    Khalilov I, Tsintsadze V, Brouchoud C, Chazal G, Lemonnier E, Lozovaya N,
    Burnashev N, Ben-Ari Y. Oxytocin-mediated GABA inhibition during delivery
    attenuates autism pathogenesis in rodent offspring. Science. 2014 Feb


    We report that the oxytocin-mediated neuroprotective γ-aminobutyric acid (GABA) excitatory-inhibitory shift during delivery is abolished in the valproate and fragile X rodent models of autism. During delivery and subsequently, hippocampal neurons in these models have elevated intracellular chloride levels, increased excitatory GABA, enhanced glutamatergic activity, and elevated gamma oscillations. Maternal pretreatment with bumetanide restored in offspring control electrophysiological and behavioral phenotypes. Conversely, blocking oxytocin signaling in naïve mothers produced offspring having electrophysiological and behavioral autistic-like features. Our results suggest a chronic deficient chloride regulation in these rodent models of autism and stress the importance of oxytocin-mediated GABAergic inhibition during the delivery process. Our data validate the amelioration observed with bumetanide and oxytocin and point to common pathways in a drug-induced and a genetic rodent model of autism.