Dysregulation of Appetitive & Aversive Amygdala Circuits in Bipolar Disorder

食欲失调

基本信息

批准号：
10372144
负责人：
Sabina Berretta
金额：
$ 78.45万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
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/10372144
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 Felis catus Fingerprint Fright Gene Expression 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 base beta catenin cell type knock-down motivated behavior mouse genetics neural circuit neuronal circuitry novel novel therapeutic intervention optogenetics pleasure protein expression response reward processing single-cell RNA sequencing transcriptome sequencing

项目摘要

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）的特点是严重的情感失调。（抑郁、焦虑、食欲下降），与躁狂交替出现（一种食欲亢进的状态）奖励和快乐）的临床表现是异质的，具有不同的主要模式。值得注意的是，目前没有强大的神经回路模型来解释这些。临床表现和尸检研究指出杏仁核，一个嵌入电路的核。我们的团队和其他人最近在威胁和奖励反应方面取得了突破。表征分子可识别的、功能不同的杏仁核神经元组，这些神经元分别编码并调节小鼠杏仁核内的不同神经类型。促进厌恶/恐惧反应（“FEAR-ON”神经元），而不是食欲/奖励反应（“APPT-ON”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我们的首要假设是神经元群体存在于人类杏仁核中。影响价编码和动机行为（FEAR-ON 与 APPT-ON 神经元），在 BD 中被破坏，导致抑郁、焦虑和躁狂。在健康和疾病状态下，哪些因素可以调节 FEAR-ON 和 APPT-ON 电路的功能？答案可能在于这些神经元独特的分子特征，与其相反的一致首先，FEAR-ON 和 APPT-ON 神经元表达已知可调节的不同分子因子。杏仁核内的恐惧/威胁和奖励处理，包括致焦虑（例如促皮质激素释放）其次，分别是激素[CRH]）和抗焦虑（例如神经降压素受体2 [NTSR2]）因素。杏仁核 FEAR-ON 和 APPT-ON 神经元经过验证的显着特征是其独特的表达模式 Wnt/β 连环蛋白信号分子的这一特征表明 Wnt/β 连环蛋白通路的差异调节。 FEAR-ON 和 APPT-ON 神经元的试验数据还显示关键分子（包括 Wnt7a）的表达发生改变。我们的具体假设是细胞特异性的 FEAR-ON 和 APPT-。 BD 中调节压力/焦虑和奖赏/食欲行为的 ON 分子因素发生了改变，并且 Wnt/β 连环蛋白通路的破坏导致 FEAR-ON 和 APPT-ON 神经元的明显异常。结合单细胞 RNAseq、多重 mRNA/蛋白质细胞标记和定量的人类尸检研究 RDoC 临床领域的分析将检验以下假设：BD 中可量化的临床“指纹” 预测 FEAR-ON 和 APPT-ON 神经元分子变化的不同模式（目标 1 和 2）。小鼠遗传模型中的操作将在机制上检验 Wnt 信号传导中断的假设因果地改变连接深层杏仁核的回路中奖励和压力相关分子的表达 CE 和伏隔核（目标 3）。