Neurobiological Control of Maternal Anxiety

描述（由申请人提供）：母亲高度焦虑对母亲动机、母婴互动和婴儿发育有极大的不利影响。尽管大量女性在产后焦虑升高，但导致产后焦虑升高或减轻产后焦虑的神经生物学事件却知之甚少。与婴儿的身体接触可以减少产后妇女和其他哺乳动物的焦虑，对健康的母亲情绪状态至关重要。我建议研究与婴儿接触如何调节母亲的神经化学以减少焦虑的神经基础。我对终纹腹侧床核（vBST）及其三个主要靶点（杏仁核中央、乳上核和导水管周围灰质）的参与特别感兴趣，它们都是调节焦虑的神经网络的传统组成部分。vBST有最密集的去甲肾上腺素能神经支配的前脑之一，高的去甲肾上腺素能张力与高焦虑有关。这可能是由于gaba能和谷氨酸能输出的改变直接或间接地调节了促进焦虑的下游脑区。我认为与婴儿接触是一种自然刺激，慢性下调vBST中的去肾上腺素能张力。这种vBST去甲肾上腺素能调的下调被认为增加了局部GABA的释放，从而去抑制GABA能投射和/或抑制vBST向大脑广泛区域的谷氨酸能投射，从而减少了母亲的焦虑。以产后实验大鼠为模型，对这一假设进行检验：1)检验在药理学上增加或减少vBST中去甲肾上腺素能张力对母亲焦虑相关行为的影响；2)使用体内微透析测量母亲与婴儿互动或暴露于婴儿的特定感官提示时vBST中去甲肾上腺素的细胞外释放；3)通过解剖追踪确定从vBST和其他BST亚区向杏仁核中央、乳上核和导管管周围灰质投射的神经化学表型（gaba能或谷氨酸能）；4)药理学上操纵这三个vBST靶点的GABAA受体活性，以确定GABAA受体在这些区域的调节是否可以预防或模拟婴儿接触对母亲焦虑相关行为的影响。这些实验将首次检验去甲肾上腺素在vBST及其更大的神经网络中，在婴儿接触后减少焦虑的作用。这一信息将极大地加强与婴儿的身体接触积极调节母亲神经化学和情绪状态的观念，并将改善每年受产后焦虑症影响的数百万妇女及其婴儿的诊断和治疗。

DESCRIPTION (provided by applicant): High maternal anxiety has tremendously detrimental effects on maternal motivation, mother-infant interactions, and infant development. Although a large number of women experience elevated anxiety after giving birth, the neurobiological events responsible for high postpartum anxiety or its alleviation are very poorly understood. Physical contact with infants can reduce anxiety in postpartum women and other mammals, and is vital for healthy maternal emotional states. I propose to investigate the neural basis of how contact with infants modulates maternal neurochemistry to reduce anxiety. I am specifically interested in the involvement of the ventral bed nucleus of the stria terminalis (vBST) and three of its primary targets (central amygdala, supramammillary nucleus, and periaqueductal gray), which are all traditional components of the neural network regulating anxiety. The vBST has one of the densest noradrenergic innervations of the forebrain, and high noradrenergic tone in the vBST is associated with high anxiety. This is likely due to altered GABAergic and glutamatergic output that directly or indirectly modulates downstream brain areas promoting anxiety. I propose that contact with infants is a natural stimulus chronically down-regulating noradrenergic tone in the vBST. This downregulation of vBST noradrenergic tone is proposed to increase local GABA release, which disinhibits GABAergic projections and/or inhibits glutamatergic projections from the vBST to widespread areas of the brain, resulting in reduced maternal anxiety. Using postpartum laboratory rats as a model, this hypothesis will be tested by: 1) examining the effects of pharmacologically increasing or decreasing noradrenergic tone in the vBST on mothers' anxiety-related behaviors, 2) using in vivo microdialysis to measure extracellular norepinephrine release in the vBST while mothers interact with infants or are exposed to particular sensory cues from their infants, 3) using anatomical tracing to determine the neurochemical phenotype (GABAergic or glutamatergic) of projections from the vBST and other BST subregions to the central amygdala, supramammillary nucleus, and periaqueductal gray and 4) pharmacologically manipulating GABAA receptor activity in these three vBST target sites to determine if GABAA receptor modulation in these areas can prevent or mimic the effects of infant contact on mothers' anxiety-related behaviors. These experiments will be the first to examine the role of norepinephrine in the vBST, and its larger neural network, in the anxiety-reducing effects of infant contact. This information will greatly reinforce the notion that physical contact with infants positively modulates maternal neurochemistry and emotional state, and will improve the diagnosis and treatment of the millions of women and their infants affected each year by postpartum anxiety disorders. PUBLIC HEALTH RELEVANCE: High postpartum anxiety has devastating effects on maternal motivation, mother-infant interactions, and infant development. Understanding the neural basis of how anxiety is regulated during the postpartum period is critically important for many women and their children. Determining how physical contact with infants modulates maternal neurochemistry in a way that alleviates anxiety will help improve the diagnosis and treatment of women suffering from a postpartum anxiety disorder.