Psychiatry and Behavioural Neuroscience, McMaster University, Hamilton, Ontario, Canada.
Psychiatry and Behavioural Neuroscience, McMaster University, Hamilton, Ontario, Canada; Department of Psychiatry, St. Michael's Hospital, Toronto, Ontario, Canada.
J Neuroimmunol. 2021 May 15;354:577530. doi: 10.1016/j.jneuroim.2021.577530. Epub 2021 Feb 27.
Many psychiatric diseases can be considered neurodevelopmental in nature and accumulating evidence links immune system dysfunction to disease etiology. Yet, it is currently unknown how the immune system alters brain function through development to increase susceptibility to psychiatric illness. Neonatal immune challenge in rodents is a neurodevelopmental model that has been associated with long-term molecular and behavioural changes in stress-reactivity. As enhanced stress-reactivity is associated with the emergence of depressive-like behaviours concurrent with hippocampal pathology, we measured depressive-like behaviour in the forced swim test and hippocampal neurogenesis in adult mice neonatally exposed to lipopolysaccharide LPS; 0.05 mg/kg, i.p. on postnatal days 3 and 5. As there are important functional differences along the ventral-dorsal hippocampus axis, ventral and dorsal hippocampal neurogenesis were measured separately. Our findings reveal a sexually-dimorphic response to early-life LPS challenge. Male LPS-mice spent less time immobile in the forced swim test, suggesting altered reactivity to swim stress. This was accompanied by an increase in doublecortin-positive cells in the dorsal hippocampus of female mice. These findings demonstrate that exposure to an immune challenge during critical developmental time periods leads to long-term sexually-dimorphic alterations in stress-reactivity that are accompanied by changes to adult hippocampal neurogenesis.
许多精神疾病可以被认为具有神经发育性，越来越多的证据表明免疫系统功能障碍与疾病病因有关。然而，目前尚不清楚免疫系统如何通过发育改变大脑功能，从而增加患精神病的易感性。啮齿动物的新生儿免疫挑战是一种神经发育模型，与应激反应中的长期分子和行为变化有关。由于增强的应激反应与海马病理学同时出现的抑郁样行为有关，我们在成年小鼠中测量了在强迫游泳试验中的抑郁样行为和海马神经发生，这些成年小鼠在出生后第 3 天和第 5 天接受腹腔内注射 0.05 毫克/千克脂多糖（LPS）。由于腹侧和背侧海马轴具有重要的功能差异，因此分别测量了腹侧和背侧海马的神经发生。我们的研究结果揭示了对生命早期 LPS 挑战的性别二态反应。雄性 LPS 小鼠在强迫游泳试验中不动的时间更少，这表明对游泳应激的反应发生了改变。这伴随着雌性小鼠背侧海马中双皮质素阳性细胞的增加。这些发现表明，在关键的发育时期暴露于免疫挑战会导致长期的性别二态性应激反应改变，同时伴随着成年海马神经发生的变化。
