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Perinatal Morphine Exposure Leads to Sex-Dependent Executive Function Deficits and Microglial Changes in Mice
Brittany L Smith1, Tess A Guzman2, Alexander H Brendle2,3
1Department of Pharmacology & Systems Physiology, University of Cincinnati, Cincinnati, Ohio 45267 smithb103@nku.edu.
Insights
Perinatal opioid exposure impairs male offspring executive function and alters neuron-microglial signaling, with females showing fewer deficits. This highlights sex-specific vulnerabilities to prenatal opioid effects on brain development.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Prenatal opioid exposure is linked to behavioral issues and executive function deficits in children.
- The prefrontal cortex (PFC) and amygdala (AMG) are crucial for social behavior and executive function, and are sensitive to prenatal opioid effects.
- Opioids can activate microglia via toll-like receptor 4 (TLR4), potentially impacting synaptic pruning during development.
Purpose of the Study:
- To investigate the effects of perinatal morphine exposure on executive function and social behavior in male and female mouse offspring.
- To analyze microglial-related and synaptic-related molecular and cellular changes in response to perinatal opioid exposure.
- To determine sex-specific differences in vulnerability to these developmental effects.
Main Methods:
- Dams received daily subcutaneous injections of saline or morphine (10 mg/kg) from pregestation through lactation until postnatal day 21 (P21).
- Executive function was assessed using the five-choice serial reaction time task in offspring.
- Gene expression in the PFC and protein levels of microglial markers (Iba1, CD68) in the PFC and AMG were analyzed.
Main Results:
- Male offspring exposed to morphine exhibited impaired attention and accuracy, while females were less affected.
- Gene expression analysis revealed alterations in microglial- and TLR4-related genes in the male PFC.
- Immunohistochemistry showed decreased Iba1 and CD68 in adult male PFC and AMG, but increased levels in females. Both sexes displayed increased social preference.
Conclusions:
- Perinatal opioid exposure induces male-specific executive function deficits.
- Opioid exposure disrupts neuron-microglial communication, with distinct sex-specific changes in microglial markers.
- These findings underscore the critical impact of prenatal opioid exposure on neurodevelopment and highlight sex-based differences in vulnerability.
Abstract:
Children exposed prenatally to opioids are at an increased risk for behavioral problems and executive function deficits. The prefrontal cortex (PFC) and amygdala (AMG) regulate executive function and social behavior and are sensitive to opioids prenatally. Opioids can bind to toll-like receptor 4 (TLR4) to activate microglia, which may be developmentally important for synaptic pruning. Therefore, we tested the effects of perinatal morphine exposure on executive function and social behavior in male and female mouse offspring, along with microglial-related and synaptic-related outcomes. Dams were injected once daily subcutaneously with saline (n = 8) or morphine (MO; 10 mg/kg; n = 12) throughout pregestation, gestation, and lactation until offspring were weaned on postnatal day 21 (P21). Male MO offspring had impairments in attention and accuracy in the five-choice serial reaction time task, while female MO offspring were less affected. Targeted gene expression analysis at P21 in the PFC identified alterations in microglial-related and TLR4-related genes, while immunohistochemical analysis in adult brains indicated decreased microglial Iba1 and phagocytic CD68 proteins in the PFC and AMG in males, but females had an increase. Further, both male and female MO offspring had increased social preference. Overall, these data demonstrate male vulnerability to executive function deficits in response to perinatal opioid exposure and evidence for disruptions in neuron-microglial signaling.
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