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

确定属于急性和慢性应激状态的独特且动态的神经星座

• 批准号: 10365980
• 负责人: Julia C Lemos
• 金额: $ 49.13万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10365980
• 关键词: 3-Dimensional; Acute; Affective; Anxiety; Award; Behavior; Brain; Brain region; Cell Nucleus; Cells; Chronic stress; Corpus striatum structure; Corticotropin-Releasing Hormone; Depressed mood; Disease; Environment; Female; Fiber; Genetic; Genetic Recombination; Glutamates; Imaging Techniques; In Situ Hybridization; Individual; Investigation; Knock-out; Lead; Light; Link; Maps; Mediating; Mental Depression; Microscopy; Mus; National Institute of Mental Health; Nature; Negative Valence; Neuroanatomy; Neuromodulator; Neurons; Neuropeptides; Neurotransmitters; Pathologic; Pathway interactions; Pattern; Peptides; Peripheral Nervous System; Photometry; Population; Positive Valence; Process; Regulation; Reporter; Research; Research Personnel; Research Project Grants; Scientist; Site; Stimulus; Stress; System; Techniques; Technology; Testing; Therapeutic; Transgenic Organisms; Viral; Vision; Withdrawal; Work; acute stress; anxiety-related disorders; approach avoidance behavior; approach behavior; avoidance behavior; base; behavioral outcome; behavioral response; biobehavior; biological adaptation to stress; brain pathway; calcium indicator; cell type; dopaminergic neuron; dorsal raphe nucleus; experience; experimental study; high risk; hypothalamic-pituitary-adrenal axis; in vivo calcium imaging; innovation; life history; male; mind control; neurochemistry; neuropsychiatric disorder; novel; optogenetics; particle; programs; relating to nervous system; release factor; response; stress state; stressor; success; tool; wireless

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.

项目摘要：本届“创新新科学家生物行为研究奖”的目标 建议是确定CRF（促肾上腺皮质激素释放因子）系统对编码的贡献， 对环境中显著刺激的反应，在个体与不同的生活史的压力暴露。 CRF是一种神经肽神经调质，在几个脑区表达，并响应于 积极和消极的环境刺激。目前还不清楚CRF作为一个脑神经系统， 对不同效价的刺激有不同的反应，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，可以经历适应性适应， 对压力暴露的反应。此外，据认为，在非稳态超负荷的病理状态下， 通用报告格式系统中的适应性调整以次优的方式持续存在。然而，目前尚不清楚CRF的活动模式如何 在应激诱导的变静态超负荷状态下，大脑中富集的核团发生了改变， 不同CRF位点的变化如何结合联合收割机促进适应不良的行为反应。该提案寻求 为了解决这些未回答的问题，通过测试假设，积极或消极的显着环境， 刺激刺激含有CRF的核团的独特集合的活动，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的激活方向转变， 对消极刺激和对积极刺激的抑制激活，这导致对这些刺激的增强回避。 突出的环境刺激。为了验证这一假设，我提出了两个具体目标。 目标1.生成包含CRF的神经元在响应时的活动模式的全脑功能图 急性环境刺激在控制和慢性应激雄性和雌性小鼠。这一目标使用 三维功能神经解剖学和体内钙成像技术来确定活性 CRF表达细胞核对携带不同效价的显著环境刺激的反应模式。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。总的来说，这些实验 通过将CRF视为全脑神经元， 系统，而不是专注于一个单一的区域或路径。 目标2.确定含CRF神经元的位点特异性抑制或CRF缺失的影响 肽对呈现给对照和应激暴露小鼠的急性显著刺激的行为反应的影响。 本研究的目的是评估定位于不同脑核团的CRF在调节途径中的相对贡献 和回避行为。 BRAINS计划的目的是通过促进以下方面的研究来培养创新的新研究人员： 雄心勃勃的重要问题。这项提案响应了这一呼吁，并准备改变我们的思维方式 关于脑中的CRF。