Sex-Specific Neurodevelopmental Programming by Placental Insulin Receptors on Stress Reactivity and Sensorimotor
Stefanie L Bronson1, Jennifer C Chan1, Tracy L Bale1
1Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Insights
Maternal diabetes and obesity can impact offspring neurodevelopment. Placental insulin receptor (InsR) signaling defects in male fetuses disrupt neurodevelopment, increasing risk for disorders.
Area of Science:
- Neuroscience
- Developmental Biology
- Metabolic Disorders
Background:
- Pregnancy complications like diabetes, obesity, and overweight are linked to offspring neurodevelopmental disorders (autism, ADHD, schizophrenia).
- Male individuals exhibit higher vulnerability (3-4x) to these disorders, but underlying sex-specific mechanisms are unknown.
- Defective placental insulin receptor (InsR) signaling is a marker of metabolic dysfunction, potentially linking maternal metabolic state to sex-specific neurodevelopmental risks.
Purpose of the Study:
- To investigate the role of placental insulin receptor (InsR) signaling in sex-specific neurodevelopmental outcomes.
- To explore the mechanistic link between placental InsR function and neurodevelopmental disorder risk in offspring of mothers with metabolic complications.
Main Methods:
- Utilized Cre/loxP transgenic mice to conditionally delete InsRs in placental trophoblasts.
- Assessed adult offspring for neurobehavioral phenotypes (stress response, cognitive function, sensorimotor gating) and prefrontal cortex gene expression.
- Conducted genome-wide expression profiling in placenta and fetal brain to identify sex-specific molecular mechanisms.
Main Results:
- Placental InsR deficiency in male, but not female, mice led to increased stress response and impaired sensorimotor gating.
- These deficits in males were associated with dysregulated nucleotide metabolism in the prefrontal cortex.
- Placental InsR deficiency altered gene expression in male placentas (vasculature, amino acid transport, serotonin, mitochondria) and male fetal brains, suggesting delayed cortical development.
Conclusions:
- Placental InsRs play a critical role in sex-specific fetal neurodevelopment.
- Disrupted placental InsR signaling offers a novel mechanism explaining increased neurodevelopmental disorder risk in male offspring exposed to maternal metabolic disorders.
- These findings highlight placental InsR as a potential therapeutic target for mitigating risks associated with pregnancy complications.
Background:
Diabetes, obesity, and overweight are prevalent pregnancy complications that predispose offspring to neurodevelopmental disorders, including autism, attention-deficit/hyperactivity disorder, and schizophrenia. Although male individuals are three to four times more likely than female individuals to develop these disorders, the mechanisms driving the sex specificity of disease vulnerability remain unclear. Because defective placental insulin receptor (InsR) signaling is a hallmark of pregnancy metabolic dysfunction, we hypothesized that it may be an important contributor and novel mechanistic link to sex-specific neurodevelopmental changes underlying disease risk.
Methods:
We used Cre/loxP transgenic mice to conditionally target InsRs in fetally derived placental trophoblasts. Adult offspring were evaluated for effects of placental trophoblast-specific InsR deficiency on stress sensitivity, cognitive function, sensorimotor gating, and prefrontal cortical transcriptional reprogramming. To evaluate molecular mechanisms driving sex-specific outcomes, we assessed genome-wide expression profiles in the placenta and fetal brain.
Results:
Male, but not female, mice with placental trophoblast-specific InsR deficiency showed a significantly increased hypothalamic-pituitary-adrenal axis stress response and impaired sensorimotor gating, phenotypic effects that were associated with dysregulated nucleotide metabolic processes in the male prefrontal cortex. Within the placenta, InsR deficiency elicited changes in gene expression, predominantly in male mice, reflecting potential shifts in vasculature, amino acid transport, serotonin homeostasis, and mitochondrial function. These placental disruptions were associated with altered gene expression profiles in the male fetal brain and suggested delayed cortical development.
Conclusions:
Together, these data demonstrate the novel role of placental InsRs in sex-specific neurodevelopment and reveal a potential mechanism for neurodevelopmental disorder risk in pregnancies complicated by maternal metabolic disorders, including diabetes and obesity.
More Related Videos
06:11Author Spotlight: Exploring the Long-Term Health Impacts of Intracytoplasmic Sperm Injection on Offspring
Published on: May 17, 2024
04:20Author Spotlight: Exploring Microglial Interactions with Stress-Response Circuitry Using the Limited Bedding and Nesting Model
Published on: July 12, 2024
Related Concept Videos
01:20Pathophysiology of Diabetes
Type 1 diabetes is characterized by autoimmune-mediated destruction of pancreatic β cells, with environmental factors potentially triggering this process in genetically susceptible individuals. Despite many not having a family history, certain genes increase susceptibility,...
01:22Diabetes Mellitus: Type 2 and Gestational