Neurobiological Control of Maternal Anxiety

描述(由申请人提供)：高度的母亲焦虑对母亲的动机、母婴互动和婴儿发育有极大的不利影响。虽然许多妇女在分娩后会经历焦虑的升高，但导致产后高度焦虑或其缓解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、乳突上核和中脑导水管周围灰质)的参与，它们都是调节焦虑的神经网络的传统组成部分。VBST具有最密集的前脑去甲肾上腺素能神经支配，vBST中高去甲肾上腺素能神经紧张与高度焦虑有关。这可能是由于GABA能和谷氨酸能输出的改变，直接或间接地调节下游促进焦虑的大脑区域。我认为，与婴儿接触是一种自然刺激，长期下调vBST中的去甲肾上腺素。这种对vBST去甲肾上腺素的下调被认为是为了增加局部GABA的释放，从而抑制GABA能投射和/或抑制从vBST到大脑广泛区域的谷氨酸投射，从而减少母亲的焦虑。以产后实验室大鼠为模型，将通过以下方式检验这一假设：1)检验vBST中去甲肾上腺素紧张的药物增加或减少对母亲焦虑相关行为的影响；2)使用体内微透析来测量当母亲与婴儿互动或暴露于婴儿的特定感觉提示时，vBST中细胞外去甲肾上腺素的释放；3)使用解剖学示踪来确定vBST和其他BST亚区到中央杏仁核、乳突上核、4)对这三个vBST靶点的GABAA受体活性进行药物调控，以确定这些区域的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。这些实验将首次检验去甲肾上腺素在vBST及其更大的神经网络中的作用，在婴儿接触降低焦虑的效果中。这些信息将极大地强化这样一个概念，即与婴儿的身体接触对母亲的神经化学和情绪状态具有积极的调节作用，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。 公共卫生相关性：产后高度焦虑对母亲的动力、母婴互动和婴儿发育具有破坏性影响。了解产后焦虑如何调节的神经基础对许多妇女和她们的孩子来说至关重要。确定与婴儿的身体接触如何调节母亲的神经化学，以减轻焦虑，将有助于改善对患有产后焦虑症的妇女的诊断和治疗。

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.