Neurobiological Control of Maternal Anxiety

描述（由申请人提供）：母亲的高度焦虑对母亲的动机，母婴互动和婴儿发育有非常不利的影响。虽然大量的妇女在分娩后经历焦虑升高，但对产后焦虑或缓解焦虑的神经生物学事件知之甚少。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。我建议调查与婴儿接触如何调节母体神经化学以减少焦虑的神经基础。我特别感兴趣的是终纹腹侧床核（vBST）及其三个主要靶点（中央杏仁核、乳头体上核和导水管周围灰质）的参与，它们都是调节焦虑的神经网络的传统组成部分。vBST具有前脑的一种密集的去甲肾上腺素能神经支配，并且vBST中的高去甲肾上腺素能张力与高度焦虑相关。这可能是由于改变了GABA能和谷氨酸能输出，直接或间接地调节下游大脑区域，促进焦虑。我建议，与婴儿接触是一种自然的刺激慢性下调去甲肾上腺素能紧张的VBST。vBST去甲肾上腺素能张力的这种下调被认为增加了局部GABA释放，这解除了GABA能投射的抑制和/或抑制了从vBST到大脑广泛区域的GABA能投射，导致母亲焦虑减少。使用产后实验室大鼠作为模型，将通过以下方式检验该假设：1）检查vBST中的去甲肾上腺素能张力的增加或减少对母亲的焦虑相关行为的影响，2）当母亲与婴儿相互作用或暴露于来自其婴儿的特定感觉提示时，使用体内微透析来测量vBST中的细胞外去甲肾上腺素释放，3）利用解剖示踪确定神经化学表型vBST和其他BST亚区向中央杏仁核、乳头体上核的投射（GABA能或GABA能），和中脑导水管周围灰质;在这三个vBST靶位点中操纵GABAA受体活性，以确定这些区域中的GABAA受体调节是否可以防止或模仿婴儿接触对母亲焦虑相关行为的影响。这些实验将是第一个研究去甲肾上腺素在vBST及其更大的神经网络中的作用，在婴儿接触的焦虑减少作用中。这些信息将大大加强与婴儿的身体接触积极调节母亲的神经化学和情绪状态的概念，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.