Alcohol, clinical & experimental research · 2026
Third Trimester-Equivalent Alcohol Exposure Induces Alterations in Locomotor Activity, Anxiety and Risk-Related Behaviors, and Susceptibility to Mechanical Allodynia in Adulthood in Mice.
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Villicana Estrella, Sun Melody S, Chen Haojie, Paez-Beltran Luis E, Milliken Carissa J, Balmer Erik J, Fletcher Danika E, Linsenbardt David N, Morton Russell A, Milligan Erin D, Valenzuela C Fernando, Vue Tou Yia
Аннотация
BACKGROUND: Prenatal alcohol exposure (PAE) can lead to the development of fetal alcohol spectrum disorders (FASDs), which are neurodevelopmental conditions characterized by behavioral dysregulation, learning deficits, and cognitive inflexibilities. Alcohol exposure is harmful at all stages of human gestation, including the third trimester. This developmental window-characterized by rapid brain growth, myelination, and neural circuit formation-may be particularly vulnerable, yet the long-lasting behavioral and sensory consequences of exposure during this period remain poorly understood.
METHODS: In this study, neonatal mouse pups were exposed to Air or ethanol (EtOH) vapor from postnatal day (P) 4 to P8, which is equivalent to a third trimester alcohol exposure (TTAE) in humans. Blood ethanol concentrations measured at P8 reached approximately 250 mg/dL, consistent with binge-level exposure. Air- and EtOH-exposed mice were then assessed as adults at 5-6 months of age for spontaneous locomotor activity and gait control, exploratory and anxiety-related behavior, recognition memory and novelty preference, and susceptibility to neuropathic pain following minor chronic constriction injury (mCCI) of the sciatic nerve.
RESULTS: TTAE produced long-lasting behavioral outcomes in adulthood, several of which differed between males and females. EtOH-exposed males exhibited increased spontaneous locomotor activity in a single-housed cage and increased open-arm exploration in the Elevated Zero Maze, with significant Sex × Treatment interactions for both measures. In the Novel Object Recognition task, EtOH-exposed males exhibited a strong preference for the familiar rather than the novel object. EtOH-exposed males also exhibited stronger alterations in gait parameters than EtOH-exposed females. Following mCCI, both EtOH-exposed male and female mice developed persistent mechanical allodynia that was largely absent in Air-exposed controls.
CONCLUSIONS: These findings demonstrate that TTAE may permanently disrupt behavioral regulation and increase susceptibility to neuropathic pain in adulthood. The differential responses between males and females indicate that some long-term behavioral consequences of TTAE are sex-dependent.
METHODS: In this study, neonatal mouse pups were exposed to Air or ethanol (EtOH) vapor from postnatal day (P) 4 to P8, which is equivalent to a third trimester alcohol exposure (TTAE) in humans. Blood ethanol concentrations measured at P8 reached approximately 250 mg/dL, consistent with binge-level exposure. Air- and EtOH-exposed mice were then assessed as adults at 5-6 months of age for spontaneous locomotor activity and gait control, exploratory and anxiety-related behavior, recognition memory and novelty preference, and susceptibility to neuropathic pain following minor chronic constriction injury (mCCI) of the sciatic nerve.
RESULTS: TTAE produced long-lasting behavioral outcomes in adulthood, several of which differed between males and females. EtOH-exposed males exhibited increased spontaneous locomotor activity in a single-housed cage and increased open-arm exploration in the Elevated Zero Maze, with significant Sex × Treatment interactions for both measures. In the Novel Object Recognition task, EtOH-exposed males exhibited a strong preference for the familiar rather than the novel object. EtOH-exposed males also exhibited stronger alterations in gait parameters than EtOH-exposed females. Following mCCI, both EtOH-exposed male and female mice developed persistent mechanical allodynia that was largely absent in Air-exposed controls.
CONCLUSIONS: These findings demonstrate that TTAE may permanently disrupt behavioral regulation and increase susceptibility to neuropathic pain in adulthood. The differential responses between males and females indicate that some long-term behavioral consequences of TTAE are sex-dependent.