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: 10579986
• 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/10579986
• 关键词: 3-Dimensional; Acute; Affective; Anxiety; Award; Behavior; Brain; Brain region; Cell Nucleus; Cells; Central Nervous System; 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; 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; 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; neural; neurochemistry; neuropsychiatric disorder; novel; optogenetics; particle; programs; 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：这个“创新新科学家的生物行为研究奖”的目的 建议是确定CRF（皮质激素释放因子）系统对编码和 在有压力源暴露寿命不同的个体中，对环境中的显着刺激做出了反应。 CRF是一种神经肽神经调节剂，在几个大脑区域表达，并释放 正面和负面的唤醒环境刺激。目前尚不清楚CRF如何作为大脑的神经系统 对刺激的响应不同，以不同的速度融合适当的方法或回避行为。 此外，有证据表明，CRF系统是高度塑料的，可以在 对压力源的反应。而且，人们认为在同级超负荷的病理状态中 CRF系统中的适应性以次优的方式持续存在。但是，目前尚不清楚CRF的活动模式如何 在压力引起的同种异体超负荷状态下，富含大脑的核能变化，也不理解 不同CRF基因座的变化如何结合起来促进适应不良的行为反应。该建议寻求 通过检验正面或负面环境的假设来解决这些未解决的问题 刺激刺激含有CRF的核的独特合奏的活性，以推动适当的情感 行为反应。此外，慢性应力将CRF网络响应转移到更大的激活 负面刺激和向阳性刺激的激活抑郁，从而增强了这些刺激 显着的环境刺激。为了检验这一假设，我提出了两个具体目标。 目标1。生成全脑功能图，以响应含有CRF的神经元的活动模式 在对照和长期压力的雄性和雌性小鼠中进行急性环境刺激。这个目的使用 三维功能神经解剖学和体内钙成像技术以确定活性 CRF表达核的模式，以响应带有不同价值的显着环境刺激。我们 将在对照和长期压力的雄性和雌性小鼠中评估这一点。总的来说，这些实验将 通过将其视为全脑神经元，就CRF对显着刺激的反应提供了整体观点 系统而不是专注于单个区域或途径。 目标2。确定位点特异性抑制含有CRF的神经元或CRF缺失的影响 肽对对控制和应激暴露小鼠的急性显着性刺激的行为反应。 该目标评估了CRF在调节方法中定位于不同脑核的相对贡献 通过利用尖端的转基因和光遗传技术来回避行为。 大脑计划的目的是通过促进调查来护理创新的新调查人员 雄心勃勃的重要问题。该提议回答了该调用，并被毒死以改变我们的想法 关于大脑中的CRF。