Developmental Programming of Neural Circuits Impacting Hypothalamic Integration

在此输入文本，它是应用程序的新摘要信息。此部分不得超过30行文本。 出生后早期发生的环境扰动，如哺乳期暴露于母体高脂肪饮食（MHFD），可能会改变成年期内感觉信号的中枢处理和传递方式，导致摄食行为失调。虽然已知MHFD会改变后代的摄食行为，但其潜在的神经生物学机制仍在很大程度上未被探索。拟议研究的首要前提是，MHFD暴露导致神经通路的组织和活动发生显著变化，这些神经通路将会聚内感受信息传递给已知调节进食行为的神经回路的关键组成部分。因为传递内感觉信息的神经通路的结构是大脑如何整合内感受感觉的状态定义特征，所以理解MHFD如何影响这些回路的输入/输出结构和活性的定量变化将提供对代谢表型的发育编程的机械见解。内脏感觉信息由迷走神经集中传递到孤束核（NTS），孤束核包含已知将调节信号传递到下丘脑以及参与控制进食的其他脑区域的神经元。类似地，瘦素的循环水平发出全身能量储存状态的信号，并调节多个大脑区域的神经元。下丘脑弓状核（ARH）含有AgRP神经元，其在摄食调节中起关键作用，并将瘦素和其他代谢信号分配到摄食回路的下游组件，如下丘脑室旁核（PVH）。与此相反，外侧下丘脑（LHA）与大脑皮层有着密切的联系，在进食的完成方面起着关键作用。对于拟议的研究，将使用组织清除和光片荧光成像来标记、成像和配准向ARH、PVH和LHA提供输入的神经元的全脑分布，以检验MHFD暴露导致投射到进食回路不同组件的多区域会聚永久性变化的假设。（具体目标1）。钙基显微内窥镜将用于确定MHFD如何影响进食行为背景下PVH和LHA中神经元的整体活动（具体目标2）。总之，在这个为期3年的项目中提出的研究将确定神经基质，这些神经基质整合了协调控制进食行为所需的各种代谢信号，并有助于我们理解代谢编程的发育神经生物学。

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.