Developmental Programming of Neural Circuits Impacting Hypothalamic Integration

影响下丘脑整合的神经回路的发育编程

• 批准号: 10445646
• 负责人: RICHARD B SIMERLY
• 金额: $ 51.24万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-03 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445646
• 关键词: Address; Adult; Affect; Architecture; Behavioral; Body Weight; Brain; Brain region; Calcium; Cell Nucleus; Cerebral cortex; Cues; Data; Development; Endocrine; Ensure; Environmental Risk Factor; Esthesia; Exposure to; Feeding behaviors; Health; High Fat Diet; Hormones; Hypothalamic structure; Image; Individual; Label; Lactation; Lateral; Leptin; Life; Light; Maternal Exposure; Mediating; Metabolic; Modification; Mus; Neural Pathways; Neurons; Neurophysiology - biologic function; Nucleus solitarius; Obesity; Output; Pathway interactions; Play; Population; Predisposition; Process; Property; Prosencephalon; Regulation; Role; Sensory; Signal Transduction; Stimulus; Structure; Structure of nucleus infundibularis hypothalami; System; Testing; Text; Tissues; Vagus nerve structure; Viral; awake; base; cell type; developmental neurobiology; energy balance; feeding; fluorescence imaging; in vivo; in vivo imaging; insight; metabolic phenotype; microendoscopy; mother nutrition; neural circuit; neural network; neurobiological mechanism; nutrition; offspring; paraventricular nucleus; perinatal environment; postnatal; postsynaptic neurons; relating to nervous system; response

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Environmental perturbations that occur during early postnatal life, such as exposure to maternal high fat diet during lactation (MHFD), may alter how interosensory signals are centrally processed and transmitted in adulthood, leading to dysregulation of feeding behavior. Although MHFD is known to alter feeding behavior in offspring, the underlying neurobiological mechanisms remain largely unexplored. The overarching premise for the proposed studies is that, MHFD exposure causes significant changes in the organization and activity of neural pathways conveying convergent interoceptive information to key components of neural circuits known to regulate feeding behavior. Because the architecture of neural pathways transmitting interosensory information is a state defining feature of how the brain integrates interoceptive sensation, understanding how MHFD impacts quantitative changes in the input/output structure and activity of these circuits will provide mechanistic insight into developmental programming of metabolic phenotype. Viscerosensory information is transmitted centrally by the vagus nerve to the nucleus of the solitary tract (NTS), which contains neurons known to convey regulatory signals to the hypothalamus, as well as to other brain regions involved in the control of feeding. Similarly, circulating levels of leptin signal the state of systemic energy stores and regulate neurons in multiple brain regions. The arcuate nucleus of the hypothalamus (ARH) contains AgRP neurons, which play a key role in the regulation of feeding and distribute leptin and other metabolic signals to downstream components of feeding circuitry, such as the paraventricular hypothalamic nucleus (PVH). In contrast, the lateral hypothalamus (LHA) shares strong connections with cerebral cortex and plays a key role in consummatory aspects of feeding. For the proposed studies, tissue clearing and light sheet fluorescence imaging will be used to label, image and register the brain-wide distributions of neurons that provide inputs to the ARH, PVH and LHA in order to test the hypothesis that MHFD exposure causes permanent changes in the multiregional convergence of projections to distinct components of feeding circuitry. (Specific Aim 1). Calcium-based microendoscopy will be used to determine how MHFD impacts the ensemble activity of neurons in the PVH, and LHA, within the context of feeding behavior (Specific Aim 2). Together, the studies proposed in this 3-year project will identify neural substrates that integrate diverse metabolic signals required for coordinated control of feeding behavior, as well as contribute to our understanding of the developmental neurobiology of metabolic programming.

在此处输入文本，这是您应用程序的新摘要信息。本节必须不超过30行文本。 在产后早期生活期间发生的环境扰动，例如在泌乳期间暴露于母体高脂饮食（MHFD），可能会改变成年期间的感官间信号的中心处理和传播的方式，从而导致喂养行为失调。尽管已知MHFD会改变后代的喂养行为，但潜在的神经生物学机制在很大程度上尚未探索。拟议的研究的总体前提是，MHFD暴露会导致神经通路的组织和活动发生重大变化，将收敛性互感信息传达到已知可以调节进食行为的神经回路的关键组成部分。因为传输间隙信息的神经通路的结构是大脑如何整合跨感官感觉的状态特征，因此了解MHFD如何影响这些电路的输入/输出结构和活动的定量变化，将为代谢表型的开发计划提供机械洞察力。内脏感知信息是通过迷走神经向集中传播的，它包含已知的神经元的神经元的核（NTS），该神经元已知可将调节信号传达给下丘脑，以及其他参与喂养控制的大脑区域。同样，循环水平的瘦素水平向全身能量储存的状态发出了多个大脑区域的神经元的调节。下丘脑（ARH）的弧形核包含AGRP神经元，在调节喂食和分布瘦素和其他代谢信号的喂养电路下游成分（例如脑室下丘脑下丘脑核（PVH））中起关键作用。相比之下，下丘脑（LHA）与大脑皮层有着牢固的联系，并且在喂养的完整方面起着关键作用。对于拟议的研究，将使用组织清除和光片荧光成像来标记，图像和注册神经元的大脑范围分布，这些神经元为ARH，PVH和LHA提供输入，以测试MHFD暴露的假设，即MHFD暴露会导致预测电路不同组成部分的多个预测融合的永久变化。 （特定目标1）。基于钙的微镜检查将用于确定MHFD在喂养行为的背景下如何影响PVH和LHA中神经元的集合活性（特定目标2）。共同提出的3年项目中提出的研究将确定整合对喂养行为协调控制所需的多种代谢信号的神经底物，并有助于我们理解代谢程序的发展神经生物学。