Determining the unique and dynamic neural constellation belonging to acute and chronic stress states

项目总结：本次“创新型新科学家生物行为研究奖”的目标 建议确定CRF(促肾上腺皮质激素释放因子)系统对编码和 具有不同应激源暴露生活史的个体对环境中显著刺激的反应。 CRF是一种神经肽神经调节剂，在几个大脑区域表达，并在下列情况下释放 既有积极的，也有消极的，都会引起环境刺激。目前还不清楚CRF是如何作为一个全脑神经系统的 对不同价态的刺激做出不同的反应，以激发适当的接近或回避行为。 此外，有证据表明，CRF系统是高度可塑性的，可以在 对应激源暴露的反应。此外，有研究认为，在超负荷的病理状态下，这些 CRF系统中的适应以次优的方式持续存在。然而，目前尚不清楚CRF的活动模式是如何 大脑中丰富的核团在应激诱导的稳态超负荷状态下发生变化，这一点也不清楚 不同CRF基因座的变化如何结合起来促进不良适应行为反应。这项提议旨在 通过检验以下假设来解决这些悬而未决的问题：积极或消极的显著环境 刺激刺激独特的含CRF核团的活动，以驱动适当的情感 行为反应。此外，慢性应激使CRF网络的反应性向更大程度的激活转变 对消极刺激和对积极刺激的抑制激活，从而增强了对这些刺激的回避 显著的环境刺激。为了检验这一假设，我提出了两个具体目标。 目的1.生成CRF神经元在反应中的活动模式的全脑功能图 对急性环境刺激的对照组和慢性应激的雄性和雌性小鼠。这一目标使用 三维功能神经解剖学和活体钙成像技术确定活性 CRF对带有不同价态的显著环境刺激的核表达模式。我们 将在对照组和长期应激的雄性和雌性小鼠中评估这一点。总而言之，这些实验将 通过将CRF视为全脑神经来提供CRF对显著刺激的反应(S)的整体视角 而不是专注于单一的区域或途径。 目的2.确定定位抑制含CRF神经元或缺失CRF的影响 提供给对照组和应激暴露小鼠的对急性显著刺激行为反应的多肽。 本研究的目的是评估CRF在调节途径中对不同脑核的相对贡献。 以及利用尖端的转基因和光遗传技术的回避行为。 Brains计划的目的是通过促进对 雄心勃勃而重要的问题。这项提议响应了这一号召，并准备改变我们的思维方式 关于大脑中的慢性肾功能衰竭。

Project Summary: The objective of this “Biobehavioral Research Awards for Innovative New Scientists” proposal is to determine the contributions of the CRF (corticotropin releasing factor) system to encoding and responding to salient stimuli in the environment in individuals with different life histories of stressor exposure. CRF is a neuropeptide neuromodulator that is expressed in several brain regions and is released in response to both positive and negative arousing environmental stimuli. It is unclear how CRF as a brain wide neural system differentially responds to stimuli with different valences to motivate appropriate approach or avoidance behaviors. In addition, there is evidence that the CRF system is highly plastic and can undergo allostatic adaptations in response to stressor exposure. Moreover, it is thought that in pathological states of allostatic overload, these adaptations in the CRF system persist in suboptimal ways. Yet, it is unclear how the activity patterns of CRF enriched nuclei across the brain are altered in a stress-induced state of allostatic overload, nor is it understood how changes at different CRF loci combine to promote maladaptive behavioral responses. This proposal seeks to resolve these unanswered questions by testing the hypothesis that positive or negative salient environmental stimuli stimulate the activity of unique ensembles of CRF-containing nuclei to drive the appropriate affective behavioral responses. Furthermore, that chronic stress shifts CRF network responsivity toward greater activation to negative stimuli and depressed activation toward positive stimuli which leads to enhanced avoidance of these salient environment stimuli. To test this hypothesis, I propose two specific aims. Aim 1. Generate a whole brain functional map of activity patterns of CRF-containing neurons in response to acute environmental stimuli in control and chronically stressed male and female mice. This aim uses three-dimensional functional neuroanatomy and in vivo calcium imaging techniques to determine the activity patterns of CRF expressing nuclei in response to salient environmental stimuli that carry different valences. We will assess this in control and chronically stressed male and female mice. Collectively, these experiments will offer a holistic perspective on the response(s) of CRF to salient stimuli by viewing it as a whole-brain neural system rather than focusing on a single region or pathway. Aim 2. Determine the effects of site-specific suppression of CRF-containing neurons or deletion of CRF peptide on behavioral responses to acute salient stimuli presented to control and stress-exposed mice. This aim assesses the relative contributions of CRF localized to different brain nuclei in modulating approach and avoidance behavior by utilizing cutting-edge transgenic and optogenetic techniques. The purpose of the BRAINS program is to nurture innovative new investigators by promoting investigation of ambitious and important questions. This proposal answers that call and is poised to transform the way we think about CRF in the brain.