Dysregulation of Appetitive & Aversive Amygdala Circuits in Bipolar Disorder

食欲失调

• 批准号: 10579190
• 负责人: Sabina Berretta
• 金额: $ 77.36万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-20 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579190
• 关键词: Affect; Affective; Algorithms; Amygdaloid structure; Anhedonia; Anti-Anxiety Agents; Anxiety; Appetitive Behavior; Arousal; Autopsy; Behavior; Bipolar Disorder; Cell Nucleus; Cells; Clinical; Data; Desire for food; Dimensions; Disease; Electronic Health Record; Emotional; Fingerprint; Fright; Gene Expression; Genetic; Genetic Models; Goals; Health; Hormones; Human; Image; Impulsive Behavior; Intercalated Cell; Intervention; Knock-out; Label; Lateral; Link; Lithium; Manic; Mental Depression; Mental disorders; Messenger RNA; Modeling; Molecular; Molecular Abnormality; Molecular Profiling; Mus; National Institute of Mental Health; Neurons; Neurotensin Receptors; Nucleus Accumbens; Pathway interactions; Pattern; Persons; Phenotype; Population; Proteins; RNA; Research Domain Criteria; Resolution; Rewards; Rodent; Role; Severities; Signal Transduction; Signaling Molecule; Stress; Symptoms; System; Testing; Therapeutic; WNT Signaling Pathway; beta catenin; cell type; knock-down; motivated behavior; mouse genetics; neural circuit; neuronal circuitry; novel; optogenetics; pleasure; protein expression; response; reward processing; segregation; single-cell RNA sequencing; transcriptome sequencing

Bipolar disorder (BD) is characterized by profound affective dysregulation. Periods of aversive symptoms (depression, anxiety, decreased appetitive drive), alternate with mania (a state of enhanced appetitive drive for reward and pleasure). The clinical manifestation is heterogeneous, with diverse patterns of predominant symptoms, severity and duration. Notably, there are no current robust neurocircuit models to account for these clinical manifestations. Imaging and postmortem studies point to the amygdala, a nucleus embedded in circuits involved in threat and reward responses. Recent breakthroughs from our group and others are beginning to characterize molecularly identifiable, functionally divergent sets of amygdala neurons, which separately encode and regulate aversive and appetitive behaviors. Specifically, distinct neuronal types within the mouse amygdala promote aversive/fear responses (`FEAR-ON' neurons), vs. appetitive/reward responses (`APPT-ON' neurons). Our preliminary data using single-cell RNA sequencing show that analogous molecularly defined neuronal populations are present in human amygdala. Our overarching hypothesis is that neuronal populations impacting valence encoding and motivated behavior (FEAR-ON vs. APPT-ON neurons), are disrupted in BD, contributing to depression, anxiety and mania. What factors may regulate the functions of FEAR-ON and APPT-ON circuitry in health and disease states? An answer may lie within the distinctive molecular signatures of these neurons, consistent with their opposing functions. First, FEAR-ON and APPT-ON neurons express distinct molecular factors known to regulate fear/threat and reward processing within the amygdala, including anxiogenic (e.g. corticotropic releasing hormone [CRH]) and anxiolytic (e.g. neurotensin receptor 2 [NTSR2]) factors, respectively. Second, a well- validated distinguishing feature of amygdala FEAR-ON and APPT-ON neurons is their distinct expression pattern of Wnt/β catenin signaling molecules. This feature indicates that Wnt/β catenin pathways differentially regulate FEAR-ON and APPT-ON neurons. Pilot data also show altered expression of key molecules, including Wnt7a and CRH in the amygdala of people with BD. Our specific hypothesis is that cell-specific FEAR-ON and APPT- ON molecular factors modulating stress/anxiety and reward/appetitive behaviors are altered in BD, and that disruption of Wnt/β catenin pathways contributes to distinct abnormalities FEAR-ON and APPT-ON neurons. Human postmortem studies combining single-cell RNAseq, multiplex mRNA/protein cell labeling and quantitative analyses of RDoC clinical domains will test the hypothesis that quantifiable clinical `fingerprints' in BD are predictive of distinct patterns of molecular changes in FEAR-ON and APPT-ON neurons (Aims 1 and 2). Causal manipulation in mouse genetic models will mechanistically test the hypothesis that a disruption of Wnt signaling causally alters expression of reward- and stress- related molecules in circuits linking deep amygdala nuclei to the CE and nucleus accumbens (Aim 3).

双相情感障碍（BD）的特征是严重的情感失调。厌恶症状的时期 （抑郁，焦虑，食欲下降），与躁狂交替（一种增强食欲的状态， 奖励和快乐）。临床表现多样，以多种类型为主， 症状、严重程度和持续时间。值得注意的是，目前还没有可靠的神经回路模型来解释这些问题。 临床表现成像和死后研究指向杏仁核，一个嵌入电路的核团 参与威胁和奖励反应。我们小组和其他人最近的突破开始 表征分子上可识别的，功能上不同的杏仁核神经元组，它们分别编码 并调节厌恶和食欲行为。具体来说，小鼠杏仁核内不同的神经元类型 促进厌恶/恐惧反应（“恐惧-开启”神经元），相对于食欲/奖赏反应（“APPT-开启”神经元）。 我们使用单细胞RNA测序的初步数据表明，类似的分子定义的神经元 在人类杏仁核中存在。我们的总体假设是， 影响效价编码和动机行为（FEAR-ON与APPT-ON神经元），在BD中被破坏， 导致抑郁焦虑和狂躁 在健康和疾病状态下，哪些因素可以调节FEAR-ON和APPT-ON回路的功能？一个 答案可能在于这些神经元独特的分子特征，与它们的相反方向一致。 功能协调发展的首先，FEAR-ON和APPT-ON神经元表达不同的分子因子，已知它们调节 杏仁核内的恐惧/威胁和奖励处理，包括焦虑（例如促皮质激素释放 激素[CRH]）和抗焦虑（例如神经降压素受体2 [NTSR 2]）因子。第二，一个很好的- 验证杏仁核FEAR-ON和APPT-ON神经元的区别特征是它们不同的表达模式 Wnt/β catenin信号分子。这一特征表明Wnt/β-catenin通路在不同的细胞内调节细胞凋亡。 FEAR-ON和APPT-ON神经元。试验数据还显示，包括Wnt 7a在内的关键分子的表达发生了改变。 以及杏仁核中的CRH。我们的具体假设是，细胞特异性FEAR-ON和APPT- 调节压力/焦虑和奖励/食欲行为的分子因素在BD中改变， Wnt/β连环蛋白通路的破坏导致FEAR-ON和APPT-ON神经元的不同异常。 结合单细胞RNAseq、多重mRNA/蛋白质细胞标记和定量的人死后研究 RDoC临床领域的分析将检验BD中可量化的临床“指纹”是 预测FEAR-ON和APPT-ON神经元中不同的分子变化模式（目标1和2）。因果 在小鼠遗传模型中的操纵将从机制上检验Wnt信号传导的破坏 因果性地改变了连接杏仁核深部的回路中与奖励和压力相关的分子的表达， CE和延髓核（Aim 3）。