Effects of chronic stress in pregnancy on hypothalamic gene expression patterns: interference with antidepressants and identified pathways

复杂的围产期适应在神经内分泌、神经元和行为水平上都得到了很好的确立，这对于母亲为分娩和母亲的成长做好准备是必要的。这包括糖皮质激素反应性减弱，尽管同时存在基础皮质醇亢进、催产素能系统活动增加、母性行为发作和焦虑缓解。这些变化对后代的健康发展以及母亲的心理健康都是至关重要的。这些适应的干扰，例如慢性压力，可能会增加产后情绪障碍的易感性，但潜在的机制尚不清楚。最初资助期的数据表明，大鼠的慢性妊娠应激(PS)阻止了这些与妊娠和哺乳相关的适应。在这些和最近的结果的继续，我们首先旨在全面表征下丘脑室旁核(高度参与母体和压力适应的区域)内与生殖相关的基因表达模式的变化，以及PS是如何改变这些基因表达模式的。反过来，药物操作或通过慢性抗抑郁药物治疗恢复被发现由PS改变的神经元靶向通路/系统将揭示它们在PS诱导的适应不良中的因果作用。这一结果将首次在遗传和细胞水平上增加我们对适应性和非适应性围产期变化的理解。

Complex peripartum adaptations at neuroendocrine, neuronal and behavioural levels are well-established, which are necessary to prepare the mother for birth and motherhood. This includes attenuated glucocorticoid responsiveness, despite a concurrent basal hypercorticism, increased activity of the oxytocinergic system, onset of maternal behaviour, and anxiolysis. These changes are essential for both the healthy development of the offspring as well as for the maternal mental health. Disturbances of these adaptations, for example by chronic stress, are likely to increase the vulnerability of postpartum mood disorders, but underlying mechanisms are unknown. Data from the initial funding period demonstrate that chronic pregnancy stress (PS) in rat dams prevents these pregnancy- and lactation-associated adaptations.In continuation of these and recent results we first aim to fully characterize reproductionrelated alterations in gene expression patterns within the hypothalamic paraventricular nucleus (a region highly involved in maternal and stress adaptations), and how these gene expression patterns are altered by PS. In turn, pharmacological manipulation, or restoration by chronic antidepressant treatment, of neuronal target pathways/systems identified to be altered by PS would reveal their causal role in PS-induced maladaptations. The results will importantly increase our understanding of adaptive and maladaptive peripartum alterations for the first time at the genetic and cellular levels.