Emotion regulation in the prefrontal - basal forebrain-amygdala circuit

前额叶 - 基底前脑 - 杏仁核回路的情绪调节

基本信息

批准号：
10381622
负责人：
Ekaterina Likhtik
金额：
$ 39万
依托单位：
HUNTER COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-20 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10381622
关键词：
Address Affect American Amygdaloid structure Anatomy Anxiety Attention Automobile Driving Autonomic nervous system Basal Cell Behavior Behavioral Brain Cell Nucleus Cells Cognition Collection Communication Complex Cues Development Diagnosis Disease Emotional Emotions Equilibrium Extinction (Psychology)Failure Female Freezing Fright Functional disorder Globus Pallidus Glutamates Goals Hippocampus (Brain)Hyperactivity Immunohistochemistry Impairment Intercalated Cell Interneurons Knowledge Learning Limb structure Location Major Depressive Disorder Medial Mediating Memory Mental disorders Midbrain structure Modeling Mus Neurobiology Neurons Noise Output Pathway interactions Pattern Physiology Play Post-Traumatic Stress Disorders Prefrontal Cortex Process Pyramidal Cells Rodent Role Signal Transduction Site Specificity Stress Structure Substance abuse problem Substantia Innominata Therapeutic Intervention Tracer Training Trauma Treatment outcome Viral Woman Work avoidance behavior basal forebrain cell type cholinergic comorbidity conditioned fear design emotion regulation experimental study generalized anxiety hippocampal pyramidal neuron improved in vivo learning extinction male men nerve supply neurophysiology novel therapeutic intervention optogenetics prevent relating to nervous system response sex targeted treatment

项目摘要

Abstract Post-traumatic stress disorder (PTSD) is a stress- and trauma- induced condition that affects millions of Americans, with women facing PTSD diagnoses at almost twice the rate of men. PTSD is characterized by persistent anxiety, a dysregulated autonomic nervous system, avoidance behaviors, and is often co-morbid with major depressive disorder and substance abuse. Diminished engagement of the medial prefrontal cortex concomitant with a hyperactive basolateral amygdala (BLA) strongly contribute to the dysregulated emotional responses associated with PTSD. During extinction learning, the medial prefrontal cortex is thought to suppress BLA activity, thereby decreasing defensive responding to non-threatening cues, a process that is disrupted in PTSD. There is much evidence to support the idea that direct prefrontal input affects plasticity in the BLA, and shifts the excitatory-inhibitory balance in the amygdala towards inhibition. However, the mechanisms of this circuit-level interaction are not well understood. Notably, the medial prefrontal cortex is not a monolithic structure, and its contiguous subregions, in rodents designated as the prelimbic (PL) and infralimbic (IL), are associated with increased and decreased defensive responding, respectively. Although some ideas have been proposed, thus far no differences have been found in direct PL vs. IL interactions with the BLA that can account for their functional dichotomy. This gap in knowledge prevents the development of more targeted therapeutic treatments for PTSD. One possibility is that the PL and IL may have differential effects upon amygdala function via indirect pathways. Previous work shows that the PL and IL are differentially connected with the basal forebrain, a critical region for modulating fear and extinction learning in the amygdala. The basal forebrain provides strong cholinergic, glutamatergic, and GABAergic inputs to the amygdala, the cortical mantle, and the hippocampus, making it an intriguing centralized location for prefrontal modulation of extinction learning in downstream structures. The goal of the proposed experiments is to uncover the structure and function of PL and IL -basal forebrain -amygdala communication during extinction. To this end, in Specific Aim I will use viral tracing and immunohistochemistry to uncover the detailed circuitry of PL and IL connectivity with amygdala-projecting cells in the ventral pallidum/substantia innominata, and horizontal limb of the diagonal band of the basal forebrain. Then, in Specific Aims 2 and 3, I will use optogenetics to manipulate IL and PL inputs to the basal forebrain, and multi-site in-vivo recordings to record the neurophysiology across the IL/PL-basal forebrain-BLA circuit during fear conditioning, extinction training and recall. Additional immunohistochemical analyses of neural activity will indicate which cell types the PL and IL drive in the basal forebrain during extinction. All experiments will be performed in both sexes to assess whether this circuit contributes to increased rates of PTSD diagnosis in women. This approach is specifically designed to improve our understanding of the circuitry underlying extinction learning, and is geared toward finding novel therapeutic approaches for improving treatment outcomes in PTSD.

抽象的创伤后应激障碍 (PTSD) 是一种由压力和创伤引起的疾病，影响数百万人在美国人中，女性患创伤后应激障碍 (PTSD) 的比例几乎是男性的两倍。创伤后应激障碍的特点是持续的焦虑、自主神经系统失调、回避行为，并且通常与重度抑郁症和药物滥用。内侧前额叶皮层的参与度减少伴随基底外侧杏仁核（BLA）过度活跃，强烈导致情绪失调与 PTSD 相关的反应。在消退学习过程中，内侧前额叶皮层被认为会抑制 BLA 活动，从而减少对非威胁性线索的防御反应，这一过程在创伤后应激障碍。有大量证据支持直接前额叶输入影响 BLA 的可塑性这一观点，并且将杏仁核的兴奋-抑制平衡转向抑制。然而，这种机制的电路级交互还没有被很好地理解。值得注意的是，内侧前额叶皮层不是一个整体结构，及其邻近的子区域，在啮齿动物中被指定为前边缘（PL）和下边缘（IL），是相关的分别增加和减少防御反应。尽管已经提出了一些想法，迄今为止，尚未发现 PL 与 IL 与 BLA 的直接相互作用存在差异，这可以解释它们的差异功能二分法。这种知识差距阻碍了更有针对性的治疗方法的开发对于创伤后应激障碍。一种可能性是 PL 和 IL 可能通过间接方式对杏仁核功能产生不同的影响。途径。先前的研究表明 PL 和 IL 与基底前脑有不同的连接，基底前脑是一个关键的区域。杏仁核中调节恐惧和灭绝学习的区域。基底前脑提供强大的胆碱能、谷氨酸能和 GABA 能输入至杏仁核、皮质套和海马体，使其成为下游灭绝学习的前额叶调节的一个有趣的集中位置结构。所提出的实验的目的是揭示 PL 和 IL -basal 的结构和功能灭绝期间前脑-杏仁核的通讯。为此，在特定目标中，我将使用病毒追踪和免疫组织化学揭示 PL 和 IL 与杏仁核投射细胞连接的详细电路位于腹侧苍白球/无名质，以及基底前脑对角带的水平肢。然后，在具体目标 2 和 3 中，我将使用光遗传学来操纵基底前脑的 IL 和 PL 输入，并且多部位体内记录，记录 IL/PL-基底前脑-BLA 回路的神经生理学恐惧调节、消退训练和回忆。神经活动的额外免疫组织化学分析将表明在灭绝过程中 PL 和 IL 在基底前脑中驱动哪些细胞类型。所有实验都将在男女中进行，以评估该回路是否有助于增加 PTSD 诊断率女性。这种方法是专门为提高我们对灭绝背后的电路的理解而设计的学习，并致力于寻找新的治疗方法来改善 PTSD 的治疗结果。