The Role of Early Life Stress in Feeding Behaviors

早期生活压力在喂养行为中的作用

• 批准号: 10974200
• 负责人: Estefania Pereira Cardoso Azevedo
• 金额: $ 13.21万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10974200
• 关键词: Role; Early; Life; Stress; Feeding

Neurodevelopmental disorders (NDD) affect the development of the nervous system, leading to abnormal brain function which may affect emotion and self-control. Obesity is an important co-morbidity of NDDs and are thought to arise from the impairment of important feeding-relevant circuits. Early life stress (ELS) can remodel feeding relevant circuits and contribute to obesity, yet the underlying mechanisms driving these changes are unknown. The current project aims to provide a link between early life stress and obesity. Our preliminary data show that in adult rodents, chemogenetic inhibition of neurotensin-expressing neurons in the lateral septum (LSNTS) increases standard chow intake. When exposed to HFD, silencing of LSNTS neurons increase HFD intake and accelerates obesity. Interestingly, LSNTS neurons respond to stressful but also to rewarding stimuli (i.e. HFD) and are key to the brain circuitry regulating feeding behavior. Additionally, ELS has been shown to alter neuronal activity in the LS and affect motivated behaviors, such as social interaction. We will extend these preliminary data to test the hypothesis that ELS reprograms LSNTS neurons activity downregulating important molecular pathways, ultimately impacting feeding behavior. In Aim 1, we will employ in vivo calcium imaging to monitor changes in the activity of LSNTS neurons to better understand how ELS alters LSNTS neuronal encoding of rewarding information and how these changes impact binge eating behavior and HFD consumption. In Aim 2, we will use cell type-specific molecular profiling (viralTRAP) and next-generation sequencing to molecularly profile LSNTS neurons in ELS and control mice to assess which specific gene transcripts are altered by ELS. Together, our study will clarify how ELS contributes to obesity by affecting feeding-relevant specific circuits in the brain. The project will benefit from the CNDD cores for behavioral assays, in vivo imaging, bioinformatics approaches, and advanced biostatistical consulting. The career development and mentorship will help the PI obtain future NIH R01 funding to facilitate the transition to an established investigator in the field of neurodevelopment and its disorders.

神经发育障碍（NDD）影响神经系统的发育，导致异常的 影响情绪和自我控制的大脑功能。肥胖是NDD的重要共病， 被认为是由重要的进食相关回路的损伤引起的。早期生活压力（ELS） 重塑进食相关回路并导致肥胖，但驱动这些的潜在机制 变化未知。目前的项目旨在提供早期生活压力和肥胖之间的联系。我们 初步数据显示，在成年啮齿类动物中， 外侧隔（LSNTS）增加标准食物摄入。当暴露于HFD时，LSNTS的沉默 神经元增加HFD摄入并加速肥胖。有趣的是，LSNTS神经元对压力有反应， 也是奖励刺激（即HFD）的关键，是大脑回路调节进食行为的关键。 此外，ELS已被证明可以改变LS中的神经元活动并影响动机行为，例如 as social社会interaction互动.我们将扩展这些初步数据来检验ELS重编程的假设， LSNTS神经元活动下调重要的分子通路，最终影响进食 行为在目标1中，我们将采用体内钙成像来监测LSNTS活性的变化 更好地理解ELS如何改变LSNTS神经元对奖励信息的编码，以及 这些变化影响暴食行为和HFD消耗。在目标2中，我们将使用特定于细胞类型的 分子分析（viralTRAP）和下一代测序，以分子分析ELS中的LSNTS神经元 和对照小鼠以评估哪些特定基因转录物被ELS改变。我们的研究将 阐明ELS如何通过影响大脑中与进食相关的特定回路而导致肥胖。项目 将受益于CNDD核心的行为测定，体内成像，生物信息学方法， 高级生物统计咨询职业发展和指导将帮助PI获得未来 NIH R01资助，以促进过渡到一个既定的研究领域， 神经发育及其障碍。