Neural Mechanisms Controlling Infant-Directed Behavior

描述（由申请人提供）：保护和喂养幼小动物对其生存至关重要。亲代照顾通常落在母亲身上，而雌性往往自发地具有母性。相比之下，雄性表现出不同程度的亲代互动，从攻击或忽视到完全抚养后代。在老鼠身上，父权的照顾需要促进：未交配的雄性通常会攻击幼崽，只有在交配后才会成为父亲。雄性在交配后12-18天左右表现出亲代行为。雄性小鼠对幼崽的社会行为的这种转变为研究对幼崽的对立社会反应的细胞机制提供了一个独特的范例。虽然我们的实验室最近发现了内侧视前区表达丙氨酸的神经元在积极调节亲代行为中的关键作用，但涉及对幼崽的这些社会反应的大脑区域的研究很少。我的项目旨在定义参与父母对幼崽行为的负面调节的神经群，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，我将首先确定位于皮层周围区域的神经元的身份

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.