Maternal Influence Over Prefrontal Cortex and Transition to Independence - Revision - 2

母亲对前额皮质的影响和向独立的过渡 - 修订版 - 2

• 批准号: 10505206
• 负责人: REGINA Marie SULLIVAN
• 金额: $ 13.09万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-16 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10505206
• 关键词: Address; Adult; Age; Amygdaloid structure; Animal Experimentation; Animal Model; Animals; Area; Award; Behavior; Behavioral; Brain; Brain imaging; Caring; Cells; Child; Clinical; Cognition; Communication; Cues; Dependence; Development; Dopamine; Electroencephalography; Electrophysiology (science); Emotions; Etiology; Event; FRAP1 gene; Failure; Food; Fright; Functional Magnetic Resonance Imaging; Functional disorder; Human; Infant; Injections; Lasers; Learning; Life; Light; Literature; Maps; Measures; Memory; Mentors; Metabolic Marker; Modification; Molecular; Mothers; Neuronal Plasticity; Neurons; Odors; Parents; Pathology; Pathway Analysis; Postdoctoral Fellow; Prefrontal Cortex; Procedures; Process; Rattus; Recording of previous events; Research; Rewards; Rodent; Role; Shock; Signaling Molecule; Stimulus; System; Techniques; Testing; Transgenic Animals; Ventral Tegmental Area; Western Blotting; base; conditioned fear; conditioning; dopaminergic neuron; experience; flexibility; genetic manipulation; infancy; infant maltreatment; insertion/deletion mutation; maltreatment; metabolic imaging; molecular marker; neural circuit; neural network; neurobehavioral; novel; optogenetics; parental role; preservation; pup; receptor; relating to nervous system; response

Abstract Infant attachment occurs in species that require parental care for survival, such as children and rodents, and permits the use of animal models to explore mechanisms for both attachment and attachment dysfunction. Here we propose to use infant rats to understand the brain mechanisms for the attachment figure to reduce fear in the infant (i.e. parent functioning as a safe base). Using an approach involving behavior and brain assessment at the network level (communication between brain areas), circuit level (specific set of neurons) and molecular level (events within neurons) to ask, what is different during learning about a threat when the infant is alone or with the mother? How does the infant’s brain lose the ability to use the mother as a safe base with age or pathology? Since clinical literature shows the parent has limited functions as a safe base when the infant experiences rough treatment from the parent, we ask how is it possible for the brain to lose processing of the parent as a safe base? To address these questions, we use odor-shock fear conditioning because it is a robust neurobehavioral system across children and infant rats, has proven translational value, and the neural network is well-defined. The first five years of this award has shown that, during a sensitive period, maternal cues interface with the threat learning circuit in at least two ways. First, the mother’s presence changes the infant’s network processing of threat by adding in a node (brain area), the ventral tegmental area (VTA), which suppresses another node, the basolateral amygdala (BLA) via dopamine release (DA). Second, the mother’s presence suppresses pups’ immature cascade of intracellular signaling molecules (e.g., ERK) critical for plasticity underlying learning and memory. We expand this research on typical-rearing to infants that have experienced rough maternal care and behaviorally show significant reduction in using the mother as a safe base. We ask how this adversity-reared infant’s brain differs from the typically-reared infant within our behavior-to-neuron-to-molecule approach. In Aim 1 we describe the brain’s global network changes following adversity, while in Aim 2 we describe amygdala’s BLA intracellular molecular cascade. In Aim 3, we focus on causation and chart the VTA-BLA neural circuit using optogenetics to manipulate neurons with a laser light and electrophysiology to record neural activity. This supplement builds on Aim 3 by using transgenic animals (genetic manipulation to permit laser light to manipulate dopamine neurons) that allow direct and specific modulation of dopamine neurons to permit us to precisely define the role of dopamine within the VTA-BLA circuit and used as a format to mentor a postdoctoral fellow. The significance of this research is that it explores network and circuit development, asking how a brain changes to accommodate behavioral transitions required during maturation. We use typical development, but also capitalize on rearing-induced atypical development when circuit transitions are compromised.

抽象的 婴儿依恋发生在需要父母护理生存的物种中，例如儿童和啮齿动物， 并允许使用动物模型来探索用于附着和附着功能障碍的机制。 在这里，我们建议使用婴儿大鼠了解依恋图的大脑机制，以减少恐惧 在婴儿中（即父母作为安全基础的工作）。使用涉及行为和大脑评估的方法 在网络级别（大脑区域之间的通信），电路水平（特定的神经元集）和分子 要问的级别（神经元内的事件），当婴儿独自一人或 和母亲？婴儿的大脑如何失去使用母亲随着年龄的增长或 病理？由于临床文献表明，当婴儿时，父母作为安全基础的功能有限 经历父母的粗暴对待，我们问大脑如何失去处理 父母是一个安全的基础？ 为了解决这些问题，我们使用气味恐惧调节，因为这是一种强大的神经行为 跨儿童和婴儿大鼠的系统已被证明是翻译价值，并且神经网络定义明确。 该奖项的前五年表明，在敏感时期，母体线索与威胁的接口 至少以两种方式学习电路。首先，母亲的存在改变了婴儿的网络处理 威胁通过添加节点（大脑区域），腹侧盖区域（VTA），它抑制了另一个节点， 基底外侧杏仁核（BLA）通过多巴胺释放（DA）。其次，母亲的存在压制了幼犬 细胞内信号分子（例如，ERK）的未成熟级联对于塑性学习至关重要 记忆。我们将有关典型养育的研究扩展到经历过小母子护理和的婴儿 在行为上，将母亲用作安全基地的行为显着降低。我们问这次冒险如何 婴儿的大脑与我们的行为与否分子的方法中的典型饲养婴儿区分开。目标 1我们描述了冒险之后大脑的全球网络变化，而在AIM 2我们描述了杏仁核的 BLA细胞内分子级联反应。在AIM 3中，我们专注于原因并绘制VTA-BLA神经电路 使用光遗传学用激光光和电生理来操纵神经元来记录神经元活性。这 补充通过使用转基因动物（遗传操纵以允许激光光的遗传操纵）建立补充 操纵多巴胺神经元），允许多巴胺神经元的直接调节和特定调节允许 我们精确地定义了多巴胺在VTA-BLA电路中的作用，并用作精神的格式 博士后研究员。 这项研究的意义在于它探索了网络和电路开发，询问大脑如何 更改以适应成熟过程中所需的行为转变。我们使用典型的发展，但是 当电路过渡受到损害时，还利用了饲养引起的非典型发展。