Neural Mechanisms Controlling Infant-Directed Behavior

控制婴儿定向行为的神经机制

• 批准号: 8831244
• 负责人: Anita Autry
• 金额: $ 4.86万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8831244
• 关键词: Aggressive behavior; Agonistic Behavior; Animals; Apoptotic; Area; Behavior; Behavioral; Birth; Brain; Caring; Cell Count; Cells; Cellular Stress; Child Rearing; Chloride Ion; Chlorides; Chronic; Clozapine; Corticosterone; Data; Designer Drugs; Diagnosis; Discipline of Nursing; Environmental Risk Factor; Estrogens; FOS gene; Female; Galanin; Gene Expression; Gene Expression Regulation; Glycine Receptors; Goals; Hormones; Hypothalamic structure; Immediate-Early Genes; In Situ Hybridization; Infant; Injection of therapeutic agent; Lasers; Lead; Ligands; Link; Literature; Major Depressive Disorder; Mammals; Medial; Mediating; Mediator of activation protein; Mental disorders; Methods; Microarray Analysis; Microscopy; Molecular; Mothers; Mus; Muscarinic Acetylcholine Receptor; Mutate; Neurons; Neuropeptides; Oxides; Partner in relationship; Personal Satisfaction; Physiological; Population; Postpartum Depression; Preoptic Areas; Progesterone; Prolactin; Protocols documentation; Psyche structure; Regulation; Role; Signal Transduction; Social Behavior; Specificity; Stress; Techniques; Testing; Tissues; Transgenic Mice; Variant; Viral; Virus; anxiety-related behavior; base; behavior influence; candidate marker; caspase-3; disturbance in affect; experience; falls; feeding; functional gain; gain of function; juvenile animal; loss of function; male; neglect; neuromechanism; novel; offspring; promoter; public health relevance; pup; receptor; recombinase; relating to nervous system; research study; response; sex; social; social stress; stress reactivity; urocortin

DESCRIPTION (provided by applicant): Protection and feeding of young animals is essential for survival. Parental care typically falls to the mother and females are often spontaneously maternal. In contrast, males show varying levels of parental interactions ranging from attack or neglect to full parenting of offspring. In mice, paternal care requires facilitation: virgin males typically attack pups, becoming paternal only after mating. Males display parental behavior around 12-18 days after mating. This switch in the social behavior of male mice toward pups provides a unique paradigm to study cellular mechanisms underlying opposing social responses to pups. The brain areas involved in these social responses toward pups are poorly studied, though our lab has recently uncovered the critical role of galanin-expressing neurons of the medial preoptic area in the positive regulation of parental behavior. My project aims to define neural populations involved in the negative regulation of parental behavior toward pups and to understand physiological and environmental factors influencing this behavior. To accomplish this goal, I will first determine the identity of neurons located in the perifornical area that are activated during pup-directed agonistic behavior (Aim 1). I will isolate populations of active neurons by combining in situ hybridization against immediate early gene c-fos with laser capture microscopy techniques (Aim 1a). This experiment will provide potential candidate markers specific to behaviorally relevant neuron populations. Preliminary studies indicate that urocortin 3 (ucn3) is a promising candidate with specific expression in the perifornical area and a documented role in social and stress-related behaviors. I will study the sex- and experience-dependent modulation of perifornical ucn3 cell number and gene expression level in virgin and mated males and females (Aim 1b). Furthermore, I will uncover the behavioral specificity of perifornical ucn3 cells by comparing their activity in males and females during a variety of social behaviors (Aim 1c). To functionally test the role of perifornical ucn3 neurons, I will perform loss and gain-of-function experiments (Aim 2). I have resuscitated a mouse line expressing Cre recombinase under a ucn3 promoter in the lab to facilitate use of conditional viral techniques for neuron-specific manipulation. I will specifically ablate neurons using a Cre-dependent capase 3 virus (Aim 2a) or activate them using a Cre-dependent excitatory designer receptor exclusively activated by designer drug approach (Aim 2b) to determine their role in pup- directed behavior. Lastly, I will uncover the role of perifornical ucn3 cells as a mediator of stress-induced disruptions in parental behavior (Aim 3). First, I will correlate perifornical ucn3 cell activationwith stress- induced parental behavior deficits (Aim 3a) and then attempt to abrogate these behavioral effects of stress by inhibiting ucn3 neurons using a Cre-dependent virus expressing a mutated glycine receptor activated by a pharmacologically selective actuator molecule (Aim 3b). The overall goal of these experiments is to functionally assess the role of perifornical ucn3 neurons in the negative regulation of parental behavior. In addition, I aim to understand the role of these neurons as a mediator of stress-induced parental behavior modulation. These studies will illuminate brain circuits involved in essential social behaviors and provide new entry-points to inform the diagnosis and treatment of mental disorders associated with stress-induced mood alterations.

描述（由申请人提供）：保护和喂养年幼的动物是生存所必需的。父母的照顾通常由母亲福尔斯承担，而女性往往是自发的母性。相反，男性表现出不同程度的父母互动，从攻击或忽视到完全养育后代。在小鼠中，父亲的照顾需要促进：处女雄性通常攻击幼崽，只有在交配后才成为父亲。雄性在交配后约12-18天表现出亲性行为。雄性小鼠对幼崽的社会行为的这种转变提供了一个独特的范式来研究对幼崽的相反社会反应的细胞机制。虽然我们的实验室最近发现了内侧视前区的甘丙肽表达神经元在父母行为的积极调节中的关键作用，但对这些对幼崽的社会反应所涉及的大脑区域的研究很少。我的项目旨在定义参与父母对幼犬行为的负面调节的神经群体，并了解影响这种行为的生理和环境因素。 为了实现这一目标，我将首先确定位于穹窿周围区域的神经元的身份， 在幼鼠定向激动行为期间激活（Aim 1）。我将结合原位杂交对即刻早期基因c-fos与激光捕获显微镜技术（目的1a）的活性神经元的人口。该实验将提供特异于行为相关神经元群体的潜在候选标记。初步研究表明尿皮质素3 （ucn 3）是一个有希望的候选者，其在穹窿周围区域中具有特异性表达，并且在社会和压力相关行为中具有记录的作用。我将研究性和经验依赖性调制穹窿周围ucn 3细胞数量和基因表达水平在处女和交配的男性和女性（目的1b）。此外，我将通过比较它们在各种社交活动中在男性和女性中的活性，揭示穹窿周围ucn 3细胞的行为特异性。 行为（目标1c）。为了在功能上测试穹窿周围ucn 3神经元的作用，我将进行功能丧失和获得实验（目的2）。我在实验室中复苏了一个表达Cre重组酶的小鼠品系，该小鼠品系在ucn 3启动子下表达Cre重组酶，以便于使用条件病毒技术进行神经元特异性操作。本人将使用Cre依赖性衣壳蛋白酶3病毒（Aim 2a）特异性地消融神经元，或使用通过设计者药物方法（Aim 2b）专门激活的Cre依赖性兴奋性设计者受体来激活它们，以确定它们在幼仔定向行为中的作用。最后，我将揭示穹窿周围ucn 3细胞作为应激诱导的父母行为中断的介质的作用（目的3）。首先，我将穹窿周围ucn 3细胞激活与应激诱导的亲代行为缺陷相关联（Aim 3a），然后尝试通过使用表达突变甘氨酸受体的Cre依赖性病毒抑制ucn 3神经元来消除应激的这些行为效应，所述突变甘氨酸受体被选择性激活分子激活（Aim 3b）。 这些实验的总体目标是从功能上评估穹窿周围ucn 3的作用。 神经元对父母行为的负调控。此外，我的目标是了解这些神经元的压力诱导的父母的行为调制的介质的作用。这些研究将阐明参与基本社会行为的大脑回路，并提供新的切入点，以告知与压力诱导的情绪改变相关的精神障碍的诊断和治疗。