Serotonin, Maternal Behavior and Postpartum Depression

描述(申请人提供)：老鼠的母性行为是一种动机很强、组织良好的社会行为。它是研究情绪、动机、奖励、学习记忆和社会互动等基本心理过程的生态有效的动物模型，最近已被用于模拟产后抑郁症和精神病。大鼠母性行为背后的核心神经回路已经被很好地阐明。最近的工作也确认了中脑边缘多巴胺系统在这种行为中的作用。然而，关于5-羟色胺(5-羟色胺)在产妇保健中的作用，人们知之甚少。鉴于5-羟色胺在情绪、动机、社交行为和严重抑郁中的重要性，以及它与多巴胺的已知相互作用，5-羟色胺系统的功能障碍很可能会改变产妇护理的质量，并可能导致产后抑郁。剩下的一个关键问题是确定特定的神经受体和潜在的心理过程，血清素通过这些过程影响母亲的行为。首席调查员的长期目标是了解母亲行为的行为机制和神经生物学基础。建议的R01项目的目的是描述5-HT2A和5-HT2C受体在大鼠母性行为中的各自作用，并确定它们相关的心理过程。在前期研究和文献回顾的基础上，主要研究者假设伏隔核壳核(Nas)和内侧前额叶皮质(MPFC)相关神经网络中5-HT2A和5-HT2C受体介导的神经传递障碍扰乱了母亲的行为。由于5-HT2A和5-HT2C受体在激励动机、厌恶加工和执行控制中扮演着重要而对立的角色，因此进一步假设，仅激活或阻断每个5-HT2受体就会扰乱母亲的行为。然而，由于两者之间的拮抗作用，同时激活或阻断这两种受体将不会或不会造成较少的干扰。5-HT2A和5-HT2C受体的紊乱会降低母体的动机，增加对幼崽的负面情绪反应(如恐惧、回避)，和/或使幼崽的反应碎片化，从而导致母体行为缺陷。在拟议的研究中，目标1将确定全身注射选择性5-HT2A和5-HT2C激动剂、拮抗剂及其组合对母亲行为的影响。此外，还将研究5-HT2A和5-HT2C操作可能影响的心理过程(如激励动机、恐惧反应、行为碎片化)。目标2将确定中枢单独和联合向NAS、mPFC和背外侧纹状体注入这些药物对母体行为的影响。这个项目涉及母性行为中一个研究不足的领域。它的创新之处在于，将行为、全身和颅内药理学方法结合起来，全面研究正常大鼠母体行为中涉及的5-羟色胺受体机制。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.