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）是一种应力和外伤疾病，影响数百万美国人，面对PTSD诊断的妇女的男性率几乎是男性的两倍。 PTSD的特征是持续的焦虑，一种失调的自主神经系统，避免行为，通常与主要的抑郁症和药物滥用。内侧前额叶皮层的参与度减少与过度活跃的基底外侧杏仁核（BLA）伴随着强烈的情绪失调与PTSD相关的响应。在灭绝学习过程中，内侧前额叶皮层被认为会抑制 BLA活动，从而减少了防御性响应不威胁性线索的响应，这一过程被破坏 PTSD。有很多证据支持直接前额外输入会影响BLA的可塑性的想法，并且将杏仁核中的兴奋性抑制平衡转移到抑制作用。但是，这种机制电路级相互作用尚不清楚。值得注意的是，内侧前额叶皮层不是单片结构，及其连续的子区域（在指定为前比（PL）和ifralimbic（IL）的啮齿动物中，防守响应的增加和减少。尽管已经提出了一些想法到目前为止功能性二分法。知识的差距阻止了更有针对性的治疗治疗的发展对于PTSD。一种可能性是PL和IL通过间接对杏仁核功能产生差异影响途径。先前的工作表明，PL和IL与基础前脑有差异化，这是一个关键调节杏仁核中恐惧和灭绝学习的区域。基础前脑提供强大向杏仁核，皮质地幔和海马的胆碱能，谷氨酸能和GABA能输入，使其成为下游中灭绝学习前偏缘调制的有趣的集中位置结构。提出的实验的目的是揭示PL和IL -BASAL的结构和功能前脑-Amygdala灭绝期间的通信。为此，在特定目的中，我将使用病毒追踪和免疫组织化学可揭示PL和IL连通性与杏仁核细胞的详细电路在腹侧粒细胞/底膜中，以及基底前脑的对角线带的水平肢。然后，在特定的目标2和3中，我将使用光遗传学操纵IL和PL输入到基础前脑，然后多站点内记录以记录IL/PL-BASAL前脑bla电路的神经生理学恐惧条件，灭绝训练和召回。神经活动的其他免疫组织化学分析将指示在消灭期间哪个细胞类型的PL和IL驱动器中的基础前脑驱动。所有实验将是在两个性别中进行的表演以评估该电路是否有助于提高PTSD诊断率女性。这种方法是专门设计的，以提高我们对灭绝基础电路的理解学习，并旨在寻找新型的治疗方法，以改善PTSD的治疗结果。