Loss of placental hormone linked to brain and social behavior changes


Date:
August 16, 2021
Source:
Columbia University Irving Medical Center
Summary:
A new preclinical study provides the first direct evidence that
loss of a placental hormone during pregnancy alters long-term
brain development, causing autism-like behaviors in male offspring.



FULL STORY ========================================================================== Preterm birth has been shown to increase the risk of autism spectrum
disorders and other developmental problems, particularly in males. The
more premature a baby is, the greater the risk of either motor or
cognitive deficits. What does the preterm baby lose that is so critical
to long-term outcomes?

==========================================================================
A new study, in mice, suggests that one factor may be the loss of a
placental hormone that the developing brain would normally see in the
second half of pregnancy.

The study is the first to provide direct evidence that loss of a placental hormone alters long-term brain development.

In the study, researchers in the laboratory of Anna Penn, MD, PhD, now
at Columbia University Vagelos College of Physicians and Surgeons and previously at Children's National Hospital in Washington, D.C., found
that reducing amounts of a single hormone, called allopregnanolone(ALLO),
in the placenta caused brain and behavior changes in male offspring that resemble changes seen in some people with autism spectrum disorder.

The study also found that both brain structure and behavioral changes
in the mice could be prevented with a single injection of ALLO in late pregnancy.

"Our study provides new and intriguing insights into how the loss
of placental hormones -- which happens in preterm birth or if the
placenta stops working well during pregnancy -- can lead to long-term structural changes in the brain that increase the risk for autism or
other neuropsychiatric disorders," says lead author Claire-Marie Vacher,
PhD, assistant professor of neonatal sciences in the Department of
Pediatrics at Columbia University's Vagelos College of Physicians and
Surgeons. "What's encouraging is that these disorders may be preventable
if diagnosed and treated early." The study was published online August
16 in the journal Nature Neuroscience.



==========================================================================
The placenta is an organ that provides the fetus with oxygen and
nutrients and removes waste products. It also produces hormones,
including high levels of ALLO in late pregnancy that may influence brain development. Penn, now the L.

Stanley James Associate Professor of Pediatrics at Columbia University
Vagelos College of Physicians and Surgeons and chief of neonatology at
Columbia and NewYork-Presbyterian Morgan Stanley Children's Hospital,
coined the term "neuroplacentology" to describe this new field of research connecting placental function to brain development.

About one in 10 infants is born prematurely (and is thus deprived of
normal levels of ALLO and other hormones), and many more pregnancies
have poor placental function.

For this study, the researchers created a mouse model in which they were
able to selectively decrease the production of ALLO during pregnancy so
that some developing pups were exposed to sufficient placental ALLO while others were not. Although male and female fetuses were both subjected
to ALLO deficiency, only male mice showed autism-like behaviors after
birth. Working with collaborators in Washington, D.C., France, and Canada,
the Penn laboratory analyzed brain development and long-term behavioral outcomes in the offspring.

ALLO reduction led to cerebellum changes, autism-like behaviors The male
mice that lacked placental ALLO had structural changes in the cerebellum,
a brain region that coordinates movement and has been linked to autism,
while their littermates did not.



==========================================================================
"In particular, we observed thickening of the myelin sheaths, the lipid
coating that protects nerve fibers and speeds up neural signaling," Vacher says. The same type of thickening is also known to occur transiently in
the cerebellum of some boys with autism.

The degree of myelin thickening in juvenile male mice correlated with
abnormal behavior, the researchers also found. The more the sheath was thickened (as measured by myelin protein levels), the more the male
mice exhibited autism- like behaviors, such as decreased sociability
and repetitive activities.

"Our experimental model demonstrates that losing placental ALLO alters cerebellar development, including white matter development. Cerebellar
white matter development occurs primarily after birth, so connecting a
change in placental function during pregnancy with lingering impacts on
later brain development is a particularly striking result," says Penn.

"The findings provide a new way to understand poor placental
function. Subtle but important changes during pregnancy or after delivery
may set in motion neurodevelopmental disorders that children experience
later in life." Similarities with human tissue To determine if similar
changes occur in infants, the researchers also examined post-mortem
cerebellar tissues from preterm and full-term infants who had died soon
after birth. Analysis of these human tissues showed similar changes
in brain proteins when cerebellum from male babies born preterm were
compared to male full-term babies.

"This study is an important first step in understanding how placental
hormones may contribute to specific human neurobehavioral outcomes. We
look forward to continuing our collaboration with Dr. Penn and her team
to help define how cerebellar neurons and glia respond to environmental factors, including placental function, that can compromise the developing brain," says study co- author Vittorio Gallo, PhD, interim chief academic officer at Children's National Hospital and interim director of the
Children's National Research Institute.

Hormone injection reduced autism symptoms ALLO's therapeutic potential
was then tested in the preclinical model.

Male offspring of mice given a single injection of ALLO in late
pregnancy had fewer autism-like behaviors, the researchers found. Similar results were seen after an injection of muscimol, a drug that enhances
the function of GABA receptors -- the same receptors that respond to
ALLO. Myelin protein levels in the developing cerebellum also normalized
with the treatment.

"Identifying when key hormone levels are abnormal, and figuring out how
and when to adjust these levels, provides an opportunity to intervene,"
Penn says.

"Performing additional studies with our mouse model, and measuring
hormone levels in moms and babies, may lead to earlier treatment to
reduce or prevent long-term cognitive and behavioral impairments in
high-risk fetuses and newborns." More information The study is titled "Placental endocrine function shapes cerebellar development and social behavior." The other contributors: Helene Lacaille (Columbia), Jiaqi
J. O'Reilly (Columbia), Jacquelyn Salzbank (Columbia), Dana Bakalar
(National Institutes of Health, Bethesda, MD), Sonia Sebaoui (Children's National Hospital, Washington, DC), Philippe Liere (University Paris
Saclay, Le Kremlin- Bice^tre Cedex, France), Cheryl Clarkson-Paredes
(George Washington University, Washington, DC), Toru Sasaki (Children's National Hospital), Aaron Sathyanesan (Children's National Hospital), Panagiotis Kratimenos (Children's National Hospital), Jacob Ellegood
(Hospital for Sick Children, Toronto, ON), Jason Lerch (Hospital for Sick Children and University of Oxford, John Radcliffe Hospital, Oxford, UK),
Yuka Imamura (Pennsylvania State University College of Medicine, PA),
Anastas Popratiloff (George Washington University), Kazue Hashimoto-Torii (Children's National Hospital and George Washington University), and
Michael Schumacher (University Paris Saclay).

The research was funded by grants from the National Institutes of Health (R01HD092593, 3R01HD092593-S1, R37NS109478, F31HD098886, U54 HD090257),
the Simons Foundation, the Children's National Board of Visitors, and
the Research Foundation of Cerebral Palsy Alliance.

The authors declare no competing financial interests.

========================================================================== Story Source: Materials provided by
Columbia_University_Irving_Medical_Center. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Claire-Marie Vacher, Helene Lacaille, Jiaqi J. O'Reilly, Jacquelyn
Salzbank, Dana Bakalar, Sonia Sebaoui, Philippe Liere, Cheryl
Clarkson- Paredes, Toru Sasaki, Aaron Sathyanesan, Panagiotis
Kratimenos, Jacob Ellegood, Jason P. Lerch, Yuka Imamura,
Anastas Popratiloff, Kazue Hashimoto-Torii, Vittorio Gallo,
Michael Schumacher, Anna A. Penn.

Placental endocrine function shapes cerebellar development
and social behavior. Nature Neuroscience, Aug. 16, 2021; DOI:
10.1038/s41593-021- 00896-4 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210816112050.htm

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