Sex differences in adult social, cognitive, and affective behavioral deficits following neonatal phlebotomy‐induced anemia in mice

Matveeva, Tatyana M.; Singh, Garima; Gisslen, Tate; Gewirtz, Jonathan C.; Georgieff, Michael

doi:10.1002/brb3.1780

Cited by 7 publications

(13 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The finding that anemia alters brain inflammatory gene expression is unique and concerning if translatable to human infants because of the deleterious effect of inflammation on the developing brain. The findings of the study provide several potential mechanisms to explain the sex-dependent differences in neurobehavioral performance reported in this model 12 and in clinical studies of anemic preterm infants. 23 – 25 …”

Section: Discussionmentioning

confidence: 75%

“…We previously demonstrated that neonatal PIA negatively affects learning, memory, and social behavior in adulthood and does so differently between males and females. 12 In the current study, large-scale dysregulation in gene pathways and networks important for neurodevelopment was present in mPIA and sPIA males and sPIA females. Both mPIA and sPIA males showed a similar degree of dysregulation of genes critical for embryonic, organismal, and tissue development in the hippocampus ( Supplementary Table 3 ).…”

Section: Resultsmentioning

confidence: 99%

“…The objectives of this study were to determine whether neonatal PIA alters neuroinflammatory and neurodevelopmental pathways in the developing hippocampus in a dose- and sex-dependent manners and whether such changes in pattern of gene expression can account for the long-term social and memory behavioral deficits previously documented in this model. 12 …”

Section: Introductionmentioning

confidence: 98%

“… 7 , 8 Compromised hippocampal oxidative metabolism during this critical developmental period is detrimental to overall neuronal growth and differentiation 9 and mitochondrial motility, 10 in turn altering neural networks and connectivity, 11 and resulting in short- and long-term neurobehavioral abnormalities. 12 …”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Dose- and sex-dependent effects of phlebotomy-induced anemia on the neonatal mouse hippocampal transcriptome

et al. 2021

Self Cite

View full text Add to dashboard Cite

Background: Phlebotomy-induced anemia (PIA) is universal and variable in degree among preterm infants and may contribute to neurodevelopmental risk. In mice, PIA causes brain tissue hypoxia, iron deficiency, and long-term sex-dependent neurobehavioral abnormalities. The neuroregulatory molecular pathways disrupted by PIA underlying these effects are unknown. Methods: Male and female pups were phlebotomized daily from postnatal day (P)3-P14 via facial venipuncture to target hematocrits of 25% (moderate, mPIA) and 18% (severe, sPIA). P14 hippocampal RNA from non-bled control and PIA mice was sequenced by Next-Generation Sequencing to identify differentially-expressed-genes (DEGs) that were analyzed using Ingenuity Pathway Analysis. Results: mPIA females showed the least DEGs (0.5% of >22,000 genes) whereas sPIA females had the most (8.6%), indicating a dose-dependent effect. mPIA and sPIA males showed similar changes in gene expression (5.3% and 4.7%, respectively), indicating a threshold effect at mPIA. The pattern of altered genes induced by PIA indicate sex-specific and anemia-dose-dependent effects with increased pro-inflammation in females and decreased neurodevelopment in males. Conclusion: These gene-expression changes may underlie the reduced recognition memory function in male and abnormal social-cognitive behavior in female adult mice following neonatal PIA. These results parallel clinical studies demonstrating sex-specific behavioral outcomes as a function of neonatal anemia.

show abstract

Section: Discussionmentioning

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Dose- and sex-dependent effects of phlebotomy-induced anemia on the neonatal mouse hippocampal transcriptome

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the clinical population, there is evidence supporting sexspecific outcomes for iron-deficient individuals or its treatment during early life, including differential effects on fecal microbiota (5), brain development (6), verbal fluency (7), and risks of cognitive disorders such as schizophrenia (2). Sex-specific physiologic and behavioral effects are also observed in preclinical models (8)(9)(10)(11). Early postnatal ID anemia causes sex-specific neuroinflammatory responses (8), seizure vulnerability (9), social and affective behavioral abnormality (10), and vasculature dysfunction (11).…”

Section: Introductionmentioning

confidence: 99%

Sex-Specific Effects of Early-Life Iron Deficiency and Prenatal Choline Treatment on Adult Rat Hippocampal Transcriptome

Liu

Fredrickson

Gisslen³

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Fetal-neonatal iron deficiency (ID) causes long-term neurocognitive and affective dysfunctions. Clinical and preclinical studies showed that early-life ID produced sex-specific effects. However, little is known about molecular mechanisms behind the sex-specific effects of early-life ID on neural gene regulation. Objective: To illustrate sex-specific transcriptome alteration in adult rat hippocampus induced by fetal-neonatal ID and prenatal choline treatment. Methods: Pregnant rats were fed iron-deficient (4 mg/kg Fe) or iron-sufficient (200 mg/kg Fe) diet from gestational day (G) 2 to postnatal day (P) 7 with or without choline supplementation (5 g/kg choline) from G11-18. Hippocampi were collected from P65 offspring of both sexes and analyzed for changes in gene expression. Results: Both early-life ID and choline treatment induced more transcriptional changes in female rat hippocampus than males with a less than 10 percent overlap between sexes. While both sexes showed alterations in gene networks related to increased risks of neurocognitive disorders, males also showed enhanced anti-inflammatory activities in response to ID, contrary to activated pro-inflammatory responses in females. Prenatal choline treatment to ID animals partially rescued ID-induced dysregulations in males but showed less effects in females. However, choline treatment to iron-sufficient rats showed more negative effects on the regulation of genes associated with cognition and affective behaviors, especially in females. Conclusions: This study provided unbiased global assessments of gene expression regulated by iron and choline in a sex-specific manner, with greater negative effects in female than male rats. Our new findings highlight potential sex-specific gene networks for further investigation.

show abstract

Sex-specific association between maternal mild anemia and children’s behavioral development: a birth cohort study

Hao,

Guo,

et al. 2024

Eur Child Adolesc Psychiatry

View full text Add to dashboard Cite

Sex differences in adult social, cognitive, and affective behavioral deficits following neonatal phlebotomy‐induced anemia in mice

Abstract: While multiple factors contribute to this increased neurodevelopmental risk, the degree of neonatal anemia is one that is controllable by the healthcare team. However, two randomized trials that

Cited by 7 publications

References 66 publications

Dose- and sex-dependent effects of phlebotomy-induced anemia on the neonatal mouse hippocampal transcriptome

Dose- and sex-dependent effects of phlebotomy-induced anemia on the neonatal mouse hippocampal transcriptome

Sex-Specific Effects of Early-Life Iron Deficiency and Prenatal Choline Treatment on Adult Rat Hippocampal Transcriptome

Sex-specific association between maternal mild anemia and children’s behavioral development: a birth cohort study

Contact Info

Product

Resources

About