Early Life Stress Effects on Ventral Hippocampal Microcircuitry during Emotional Behaviors

情绪行为过程中早期生活压力对腹侧海马微电路的影响

• 批准号: 10431805
• 负责人: Wei-li Chang
• 金额: $ 19.51万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10431805
• 关键词: 3-Dimensional; Academic Medical Centers; Address; Adult; Affect; Anhedonia; Animal Model; Anxiety; Area; Bathing; Behavior; Behavioral; Biological Assay; Brain; Calcium; Caring; Cell Count; Cell Density; Cell physiology; Cells; Chronic stress; Computational Technique; Computer Analysis; Development; Dorsal; Emotional; Environment; Environmental Risk Factor; Equilibrium; Exposure to; FOS gene; Foundations; Fright; Functional disorder; Future; Goals; Hippocampus (Brain); Image; Immediate-Early Genes; Institutes; Interneurons; K-Series Research Career Programs; Life; Light; Measures; Mediating; Mental disorders; Mentorship; Microscopy; Modeling; Mus; Neurons; New York; Noise; Opsin; Output; Parvalbumins; Pattern; Phase; Physicians; Physiology; Population; Psychiatry; Pyramidal Cells; Research; Research Personnel; Resolution; Rewards; Risk; Risk Factors; Rodent; Rodent Model; Scientist; Signal Transduction; Stimulus; Synapses; Testing; Time; Tissues; Training; Transgenic Mice; Universities; Work; anxiety-like behavior; behavior test; brain tissue; calcium indicator; career; cell type; conditioned fear; density; early life stress; emotional behavior; exposed human population; gene product; improved; in vivo; in vivo calcium imaging; insight; microendoscopy; microscopic imaging; mouse model; neural circuit; neurodevelopment; optogenetics; postnatal period; relating to nervous system; resilience; response; reward processing; therapeutic target

I am a physician-scientist in psychiatry studying neural circuits involved in psychiatric illness using animal models that enable us to record and manipulate real-time neuronal activity with single-cell resolution. My career goal is to become an expert on developmental risk factors, microcircuit physiology, and emotional processing. This career development award will support my work to determine the impact of early life stress on ventral hippocampal microcircuitry and how this influences anxiety- and anhedonia-related behaviors in adulthood. Early life stress (ELS) increases the risk of adult psychiatric illnesses, so understanding how ELS affects the neural circuits controlling emotional behaviors would provide a mechanism for this increased vulnerability and point towards therapeutic targets. We can model ELS in rodents by inducing fragmented maternal care in the early postnatal period and then examine neural activity during anxiety-like and reward- seeking behaviors in adulthood. The ventral portion of the hippocampus is directly connected to both fear and reward circuits, and heavily involved in emotional processing. The balance between excitatory pyramidal cells and inhibitory interneurons in the hippocampus is important for controlling the flow of information to and from other regions of these circuits. ELS alters the development of interneurons and decreases excitatory and inhibitory synaptic density in the hippocampus. We do not yet know how ELS affects hippocampal excitatory and inhibitory cell activity in vivo and how these changes relate to observed behavioral differences. This proposal will address these questions through three Specific Aims. In Aim 1, I will test the hypothesis that altered anxiety-like behavior and decreased reward-seeking in adult mice after ELS are correlated with increased pyramidal cell activity in the CA1 output region of the ventral hippocampus (vCA1). In Aim 2, I will determine the effects of ELS on PV neurons in the vCA1 during development and adulthood. First, I will test the hypothesis that ELS decreases vCA1 PV cell activity during anxiety-like and reward behaviors. Then, I will test the hypothesis that precocious expression of PV in the hippocampus after ELS is associated with changes in global hippocampal neural activity in response to positive and negative stimuli. In Aim 3, I will test the hypothesis that inhibition of vCA1 PV cell activity in normally-reared adult mice can alter anxiety- and anhedonia-like behaviors. I will conduct this work within the New York State Psychiatric Institute and Columbia University under the mentorship of Drs. René Hen and Kevin Bath. The training objectives of this K08 are to become an expert in in vivo calcium imaging and optogenetic manipulations in freely moving mice, animal models for ELS and neurodevelopment, computational techniques for examining task-related representations in neural firing, and volume microscopy imaging with immunostaining. Upon completing these scientific aims and training objectives, I will be prepared to transition to the next phase of my career as an independent investigator directing a research group at an academic medical center.

我是精神病学的内科科学家，研究涉及精神疾病的神经回路。 动物模型，使我们能够记录和操纵单细胞分辨率的实时神经元活动。 我的职业目标是成为发育风险因素、微电路生理学和情感方面的专家 正在处理。这个职业发展奖将支持我的工作，以确定早期生活压力的影响 腹侧海马区微电路及其对焦虑和快感缺乏相关行为的影响 成人期。早期生活压力(ELS)会增加成人精神疾病的风险，因此了解ELS是如何 影响控制情绪行为的神经回路将为这种增加提供一种机制 易受攻击，并指向治疗目标。我们可以通过诱导片段化的方法在啮齿类动物中建立ELs模型 产后早期的产妇护理，然后检查焦虑和奖赏期间的神经活动- 成年后的寻找行为。海马体的腹侧部分与这两种恐惧直接相连 和奖赏回路，并在很大程度上参与情绪处理。兴奋性锥体之间的平衡 海马区的细胞和抑制性中间神经元对于控制信息流向和 来自这些环路的其他区域。ELS改变中间神经元的发育，降低兴奋性 以及海马区的抑制性突触密度。我们还不知道ELS如何影响海马区 体内兴奋性和抑制性细胞活性以及这些变化与观察到的行为的关系 不同之处。该提案将通过三个具体目标解决这些问题。在目标1中，我将测试 ELS后改变成年小鼠焦虑样行为和减少奖赏寻求的假说 与腹侧海马区(VCA1)CA1输出区锥体细胞活动增加有关。 在目标2中，我将确定ELS在发育和成年期对vCA1区PV神经元的影响。 首先，我将测试ELS在焦虑和奖励期间降低vCA1光伏细胞活性的假设 行为。然后，我将检验ELS后海马区PV早熟表达的假设 与整体海马神经活动对积极和消极刺激的反应的变化有关。在……里面 目的3，我将验证这样一种假设，即抑制正常饲养的成年小鼠的vCA1光伏细胞活性可以改变 焦虑和快感缺乏症的行为。我将在纽约州精神病研究所内进行这项工作 和哥伦比亚大学，在勒内·亨和凯文·巴斯博士的指导下。的培训目标 这款K08将成为体内钙成像和自由移动光遗传操作方面的专家 小鼠，ELS和神经发育的动物模型，检查任务相关的计算技术 神经放电的表现和免疫染色的体积显微镜成像。在完成后 这些科学目标和培养目标，我将准备过渡到我职业生涯的下一个阶段 在学术医学中心领导研究小组的独立调查员。