Role of Lateral Septum in Emotional Reactivity During the Postpartum Period

描述(由申请人提供)：母性攻击(保护后代)为理解两个重要的心理健康问题提供了联系：产后情绪变化和激烈的反应性攻击。母性攻击(也称为母性防御)是一种强大的反应性攻击形式，产生于对后代的保护中，在从人类到老鼠的哺乳动物中高度保守。我们的长期目标是了解母性攻击的功能性神经元回路。这项应用的目的是确定外侧隔区(LS)中的β肾上腺素能和GABA A受体信号如何调节母亲的攻击行为。该应用的中心假设是，LS中β肾上腺素能受体信号的降低是提高母亲攻击性的关键步骤，而LS中GABA A受体信号的降低是减少攻击性输出的关键步骤。LS内含有大量的GABA阳性神经元，其中许多投射到LS外，我们认为这些GABA阳性投射神经元在LS内含有β肾上腺素能和GABAA受体，并受其调节。提出这项研究的基本原理是，一旦了解了β肾上腺素能和GABA A受体调节LS母亲攻击性的机制，我们将获得关于哺乳期神经元变化的重要见解，从而阐明产后情绪障碍。我们还将根据人类激烈的反应性攻击性爆发获得信息，预计这将为新的干预措施提供见解。因此，这项拟议的研究与NIH减轻精神疾病和行为障碍负担的使命相关。在强大的初步数据的指导下，这一假说将通过追求两个具体目标来检验：1)确定在LS中作用于调节母体攻击的关键受体；2)确定LS中受β肾上腺素能和GABA A受体调控的神经元群体。在第一个目标下，将使用特定部位注射方法来调节β肾上腺素能和GABA A受体的活性，并测试对母亲攻击的影响。建立的蛋白质印迹和实时聚合酶链式反应技术将被用来确定这些受体在多大程度上表现出与攻击性变化相关的表达变化。在第二个目标下，基因表达方法将被用来识别LS中与攻击性变化相关的GABA合成的变化。双/三标记方法以及顺行和逆行追踪将被用来确定LS中GABA阳性神经元含有GABA A和β肾上腺素能受体的程度，并确定LS中GABA阳性投射神经元的下游脑区。这项拟议的工作具有创新性，因为它结合了一系列行为、药理学、神经生物学和神经化学方法来研究一个重要但未被充分研究的母亲攻击领域。这项拟议的研究意义重大，因为它将提供关于如何产生激烈的反应性攻击的关键缺失信息，并提供对产后情绪变化的洞察。

DESCRIPTION (provided by applicant): Maternal aggression (protection of offspring) provides a nexus for understanding two important mental health issues: emotional changes that occur during the postpartum period and fierce reactive aggression. Maternal aggression (also called maternal defense) is a powerful form of reactive aggression that is produced in the defense of offspring and is highly conserved in mammals ranging from humans to mice. Our long-term goal is to understand the functional neuronal circuitry of maternal aggression. The objective of this application is to determine how beta adrenergic and GABA A receptor signaling in lateral septum (LS) act to regulate maternal aggression. The central hypothesis of the application is that lowering of beta adrenergic receptor signaling in LS is a key step for elevating maternal aggression, while lowering GABA A receptor signaling in LS is a key step in reducing aggressive output. LS contains a large number of GABA-positive neurons, many of which project outside of LS, and we propose that these GABA-positive projection neurons contain and are regulated by beta adrenergic and GABA A receptors in LS. The rationale for the proposed research is that once the mechanisms by which beta adrenergic and GABA A receptors regulate maternal aggression in LS are known, we will gain important insights into neuronal changes during lactation that shed light on postpartum mood disorders. We will also gain information on the basis of fierce reactive aggressive outburst in humans that is expected to provide insights into new interventions. Consequently, the proposed research is relevant to NIH's mission to reduce the burden of mental illness and behavioral disorders. Guided by strong preliminary data, the hypothesis will be tested by pursuing two specific aims: 1) Identify the key receptors that act in LS to regulate maternal aggression; and 2) Identify the neuronal population in LS that is regulated by beta adrenergic and GABA A receptors. Under the first aim, site-specific injection approaches will be used to modulate beta adrenergic and GABA A receptor activity and test effects on maternal aggression. Established Western blotting and real-time PCR techniques will be used to determine the extent to which these receptors show altered expression in association with changes in aggression. Under the second aim, gene expression approaches will be used to identify changes in GABA synthesis that occur in LS in association with changes in aggression. Double/triple labeling approaches along with anterograde and retrograde tracing will be used to determine the extent to which GABA-positive neurons in LS contain GABA A and beta adrenergic receptors and to identify the downstream brain regions that are targets of the GABA-positive projection neurons in LS. The proposed work is innovative because it combines an array of behavioral, pharmacologic, neurobiological, and neurochemical methods to examine an important, but understudied area of maternal aggression. The proposed research is significant, because it will provide critical missing information on how fierce reactive aggression is produced and provide insights into mood changes during the postpartum period.