Role of Lateral Septum in Emotional Reactivity During the Postpartum Period

描述（由申请人提供）：母亲的攻击（保护后代）为理解两个重要的心理健康问题提供了联系：产后期间发生的情绪变化和激烈的反应性攻击。母性攻击（也称为母性防御）是一种强有力的反应性攻击形式，在后代的防御中产生，并且在从人类到小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回路。本申请的目的是确定外侧隔（LS）中β肾上腺素能和GABA A受体信号传导如何调节母体攻击性。本申请的中心假设是LS中β肾上腺素能受体信号传导的降低是提高母体攻击性的关键步骤，而LS中GABA A受体信号传导的降低是减少攻击性输出的关键步骤。LS含有大量的GABA阳性神经元，其中许多项目外的LS，我们建议，这些GABA阳性投射神经元含有β肾上腺素能受体和GABAA受体在LS和调节。拟议研究的基本原理是，一旦β肾上腺素能和GABA A受体调节LS中母体攻击的机制已知，我们将获得重要的见解，了解哺乳期间的神经元变化，揭示产后情绪障碍。我们还将根据人类激烈的反应性攻击性爆发获得信息，这些信息有望为新的干预措施提供见解。因此，拟议的研究与NIH的使命有关，即减轻精神疾病和行为障碍的负担。在强有力的初步数据的指导下，将通过追求两个特定目标来测试该假设：1）鉴定在LS中起作用以调节母体攻击的关键受体;以及2）鉴定LS中由β肾上腺素能和GABA A受体调节的神经元群体。在第一个目标下，将使用位点特异性注射方法来调节β肾上腺素能和GABA A受体活性，并测试对母体攻击的影响。已建立的Western印迹和实时PCR技术将用于确定这些受体在多大程度上显示与侵略变化相关的表达改变。根据第二个目标，基因表达的方法将被用来确定GABA合成的变化，发生在LS与侵略的变化。将使用双/三标记方法沿着顺行和逆行追踪来确定LS中GABA阳性神经元含有GABA A和β肾上腺素能受体的程度，并鉴定作为LS中GABA阳性投射神经元靶点的下游脑区域。这项工作是创新的，因为它结合了一系列的行为，药理学，神经生物学和神经化学方法来研究一个重要的，但研究不足的领域的母亲的侵略。这项拟议中的研究意义重大，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，并提供对产后期间情绪变化的见解。

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.