Analyzing the role of developmental programming of the adult hippocampal neurogenic niche in prenatal stress-induced vulnerability to psychiatric disease

怀孕期间的母亲压力，也被称为产前压力(PS)，与后代出现心理健康问题的风险增加有关。导致这种风险增加的病理生理机制尚不完全清楚。然而，目前的数据表明，PS改变了参与调节压力和情绪行为的神经回路的发展，从而使他们在以后的生活中更容易受到侮辱。海马齿状回在调节学习过程和调节焦虑状态方面起着重要作用，即在PS相关的精神障碍中受到影响的功能。与大多数其他脑结构不同，成年齿状回提供了一个独特的信号环境，允许其主要神经元，即齿状颗粒神经元(DGNs)的终生生成。因此，齿状回不仅由胚胎和出生后早期产生的DGNs组成，也由成年期出生的DGNs组成。重要的是，发育中出生的神经元和成年出生的神经元之间的功能平衡对齿状回信息处理至关重要。在这个高度合作的项目中，我们将在啮齿动物模型中调查假设，即PS破坏发育中出生的DGNs的成熟和终生DGNs所需的独特信号环境，从而破坏这些神经元群体之间的功能平衡，并使精神疾病相关的行为障碍成为可能。为了验证这一假说，我们将结合分子、遗传学、解剖学、光遗传学和行为学方法在小鼠中应用i)分析PS在形态、功能和行为水平上对发育中的与成人出生的齿状颗粒神经元(DGNs)的特定影响，ii)破译驱动成人齿状回特定信号环境出生后异常发育的分子动力学，以及iii)探针调控的异常Wnt/β-catenin信号，作为介导PS对成人神经发生和精神疾病易感性的长期影响的候选方法。我们期待这个项目的结果将大大加深我们对大脑发育关键期不良事件如何建立精神疾病易感性的病理生理学机制的理解。

Maternal stress during pregnancy, which is also termed prenatal stress (PS), is associated with an increased risk of the offspring to develop mental health problems. The pathophysiological mechanisms leading to this increased risk are not fully understood. Current data, however, suggest that PS modifies the development of neural circuits involved in the modulation of stress and emotional behavior, thereby rendering them more vulnerable to insults in later life. The dentate gyrus of the hippocampal formation plays a fundamental role in regulating learning processes and in modulating anxiety states, i.e., functions that are affected in PS-linked psychiatric disorders. In contrast to most other brain structures, the adult dentate gyrus provides a unique signaling environment that allows for the life-long generation of its principal neurons, i.e. the dentate granule neurons (DGNs). As a consequence the dentate gyrus is composed not only of DGNs that are generated during the embryonic and early postnatal period but also of DGNs that are born during adulthood. Importantly, the functional balance between developmentally-born and adult-born neurons is crucial for dentate gyrus information processing. In this highly collaborative project we will investigate in a rodent model the hypothesis that PS disrupts both the maturation of developmentally-born DGNs and of the unique signaling environment necessary for the life-long generation of DGNs, thereby disrupting the functional balance between these neuronal populations and enabling psychiatric disease related behavioral disturbances. To test this hypothesis, we will apply a combination of molecular, genetic, anatomical, optogenetic and behavioral approaches in mice to i) analyze the specific impact of PS on developmentally- vs adult- born dentate granule neurons (DGNs) at a morphological, functional, and behavioral level, ii) decipher the molecular dynamics driving the aberrant postnatal development of the adult dentate gyrus specific signaling environment, and iii) probe dysregulated Wnt/beta-catenin signaling, an essential regulator of DG development and critical signaling pathway in the adult dentate gyrus neurogenic niche, as a candidate to mediate long-term effects of PS on adult neurogenesis and vulnerability to psychiatric disease. We expect that results from this project will significantly further our understanding of the pathophysiological mechanisms of how adverse events during critical periods of brain development establish vulnerability for psychiatric diseases.