Related Experiment Video
Updated: Jul 1, 2025
Neurobehavioral Assessments in a Mouse Model of Neonatal Hypoxic-ischemic Brain Injury
Published on: November 24, 2017
Neonatal hypoxia impairs serotonin release and cognitive functions in adult mice
Karen Ka Yan Lee1, Bidisha Chattopadhyaya2, Antônia Samia Fernandes do Nascimento2
1Neurosciences Department, Université de Montréal, Montréal, Canada; CHU Sainte-Justine Azrieli Research Center, Montréal, Canada.
Insights
Moderate perinatal asphyxia (MPA) impairs serotonin (5-HT) system function in mice, leading to cognitive deficits. Treatments targeting 5-HT pathways show promise for improving memory and cognitive flexibility in adults affected by MPA.
Area of Science:
- Neuroscience
- Developmental Neuroscience
- Neuropharmacology
Background:
- Moderate perinatal asphyxia (MPA) can cause long-term cognitive and behavioral issues in children.
- The prefrontal cortex (PFC), crucial for cognition and emotion, receives serotonin (5-HT) projections.
- The role of 5-HT system dysfunction in MPA-induced cognitive deficits remains unclear.
Purpose of the Study:
- To investigate the impact of MPA on the 5-HT system in the PFC.
- To determine if 5-HT dysregulation contributes to cognitive impairments following MPA.
- To explore potential therapeutic interventions for MPA-induced cognitive deficits.
Main Methods:
- Established a moderate perinatal asphyxia (MPA) mouse model.
- Quantified 5-HT levels and release in the PFC using immunohistochemistry and in vivo microdialysis.
- Assessed cognitive flexibility and memory functions.
- Evaluated the effects of fluoxetine and tandospirone treatment.
Main Results:
- MPA mice exhibited impaired recognition, spatial memory, and cognitive flexibility.
- Reduced 5-HT expression and release were observed in the PFC of adult MPA mice.
- MPA mice showed deficits in body temperature regulation after 5-HT1A receptor agonist administration.
- Chronic treatment with fluoxetine or tandospirone rescued cognitive and memory impairments.
Conclusions:
- Moderate perinatal asphyxia disrupts the development and function of the 5-HT system in the PFC.
- 5-HT hypofunction may underlie long-term cognitive impairments after MPA.
- Targeting the 5-HT system offers a potential therapeutic strategy for cognitive deficits associated with MPA.
Abstract:
Children who experienced moderate perinatal asphyxia (MPA) are at risk of developing long lasting subtle cognitive and behavioral deficits, including learning disabilities and emotional problems. The prefrontal cortex (PFC) regulates cognitive flexibility and emotional behavior. Neurons that release serotonin (5-HT) project to the PFC, and compounds modulating 5-HT activity influence emotion and cognition. Whether 5-HT dysregulations contribute to MPA-induced cognitive problems is unknown. We established a MPA mouse model, which displays recognition and spatial memory impairments and dysfunctional cognitive flexibility. We found that 5-HT expression levels, quantified by immunohistochemistry, and 5-HT release, quantified by in vivo microdialysis in awake mice, are reduced in PFC of adult MPA mice. MPA mice also show impaired body temperature regulation following injection of the 5-HT1A receptor agonist 8-OH-DPAT, suggesting the presence of deficits in 5-HT auto-receptor function on raphe neurons. Finally, chronic treatment of adult MPA mice with fluoxetine, an inhibitor of 5-HT reuptake transporter, or the 5-HT1A receptor agonist tandospirone rescues cognitive flexibility and memory impairments. All together, these data demonstrate that the development of 5-HT system function is vulnerable to moderate perinatal asphyxia. 5-HT hypofunction might in turn contribute to long-term cognitive impairment in adulthood, indicating a potential target for pharmacological therapies.
