Serotonin, Maternal Behavior and Postpartum Depression

描述（由申请人提供）：大鼠的母性行为是一种高度动机和组织良好的社会行为。它是一种生态有效的动物模型，用于研究基本的心理过程，如情绪，动机，奖励，学习和记忆以及社会互动，最近已被用于建模产后抑郁症和精神病。大鼠母性行为的核心神经回路已经得到很好的阐明。最近的工作也确定了中脑边缘多巴胺系统在这种行为中的作用。然而，对5-羟色胺（5-HT）在孕产妇保健中的作用知之甚少。鉴于5-羟色胺在情绪、动机、社会行为和重度抑郁症中的重要性及其与多巴胺的已知相互作用，5-羟色胺系统的功能紊乱可能会改变孕产妇护理质量，并可能导致产后抑郁症。剩下的一个关键问题是要确定特定的神经受体和潜在的心理过程，通过血清素的作用，影响母亲的行为。主要研究者的长期目标是了解母性行为的行为机制和神经生物学基础。R 01项目的目的是描述5-HT 2A和5-HT 2C受体在大鼠母性行为中的各自作用，并确定其相关的心理过程。基于初步研究和文献综述，主要研究者假设，5-HT 2A和5-HT 2C受体介导的神经传递在丘脑核壳（NAs）和内侧前额叶皮层（mPFC）相关神经网络中的紊乱会破坏母性行为。由于5 -HT 2A和5-HT 2C受体在激励动机、厌恶处理和执行控制中发挥重要但相反的作用，因此进一步假设单独激活或阻断每种5-HT 2受体会破坏母体行为。然而，由于两者之间的拮抗作用，同时激活或阻断两种受体将不引起或引起较少的破坏。5-HT 2A和5-HT 2C受体的紊乱通过降低母体动机、增加对幼崽的负面情绪反应（例如恐惧、回避）和/或使幼崽定向反应片段化而引起母体行为缺陷。在拟议的研究中，目的1将是确定全身注射选择性5-HT 2A和5-HT 2C激动剂、拮抗剂及其组合对母体行为的影响。此外，可能的心理过程（如激励动机，恐惧反应，行为分裂）的影响5-HT 2A和5-HT 2C操纵将进行调查。目的2将确定这些药物单独和联合中枢输注至NA、mPFC和背外侧纹状体对母体行为的影响。这个项目解决了母性行为中一个研究不足的领域。本研究的创新之处在于将行为药理学、全身药理学和颅内药理学方法相结合，全面研究了正常大鼠母性行为中5-HT受体的作用机制。这将有助于识别与母亲行为改变有关的行为过程 和产后抑郁症

DESCRIPTION (provided by applicant): Maternal behavior in rats is a highly motivated and well-organized social behavior. It is an ecologically valid animal model for the study of basic psychological processes such as emotion, motivation, reward, learning and memory and social interaction, and has recently been used in modeling postpartum depression and psychosis. The core neural circuits underlying rat maternal behavior have been well elucidated. Recent work has also identified a role of the mesolimbic dopamine system in this behavior. However, considerably less is known about the role of serotonin (5-HT) in maternal care. Given the importance of serotonin in emotion, motivation, social behavior and major depression and its known interaction with dopamine, it is likely that functional disturbances of 5-HT systems would alter the quality of maternal care and may contribute to postpartum depression. One key issue remaining is to identify specific neuroreceptors and the underlying psychological processes through which serotonin act to affect maternal behavior. The Principal Investigator's long-term goal is to understand the behavioral mechanisms and neurobiological basis of maternal behavior. The objective of the proposed R01 project is to delineate the respective roles of 5-HT2A and 5-HT2C receptors in rat maternal behavior and identify their associated psychological processes. Based on preliminary studies and literature review, the Principal Investigator hypothesizes that disturbances of 5-HT2A and 5-HT2C receptor-mediated neurotransmission in the nucleus accumbens shell (NAs) and medial prefrontal cortex (mPFC)-related neural network disrupt maternal behavior. Because 5 -HT2A and 5-HT2C receptors play important yet opposing roles in incentive motivation, aversive processing, and executive controls, it is further hypothesized that activation or blockade of each 5-HT2 receptor alone disrupts maternal behavior. However, activation or blockade of both receptors concurrently will cause no or less disruption due to the antagonistic action between the two. Disturbances of 5-HT2A and 5-HT2C receptors cause maternal behavior deficits by decreasing maternal motivation, increasing negative emotional responses (e.g. fear, avoidance) toward pups, and/or fragmenting pup- directed responses. In the proposed study, Aim 1 will be to determine the effects of systemic injections of selective 5-HT2A and 5-HT2C agonists, antagonists, and their combinations on maternal behavior. Furthermore, the possible psychological processes (e.g. incentive motivation, fear responses, behavioral fragmentation) affected by 5-HT2A and 5-HT2C manipulations will be investigated. Aim 2 will be to determine the effects on maternal behavior of central infusions of these drugs - alone and in combination - into the NAs, mPFC and dorsolateral striatum. This project addresses an understudied area in maternal behavior. It is innovative in that behavioral, systemic and intracranial pharmacology approaches will be combined to comprehensively investigate the 5-HT receptor mechanisms involved in normal rat maternal behavior. It will help identify the behavioral processes linking altered maternal behavior and postpartum depression.