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).

躁郁症（BD）的特征是深度情感失调。厌恶症状的时期（抑郁，焦虑，开胃菜的减少），与躁狂症的替代品（一种增强的食欲驱动力的状态奖励和快乐）。临床表现是异质的，具有主要的潜水模式症状，严重性和持续时间。值得注意的是，目前没有强大的神经电路模型来考虑这些模型临床表现。成像和事后研究指向杏仁核，杏仁核，一个嵌入在电路中的核参与威胁和奖励回应。我们小组和其他人的最新突破开始表征分子可识别的，功能多样的杏仁核神经元集，它们分别编码并调节厌恶和食欲的行为。具体而言，小鼠杏仁核中不同的神经元类型促进厌恶/恐惧反应（``恐惧''神经元），与食欲/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，类似的分子定义神经元人口在人杏仁核中呈现。我们的总体假设是神经元种群在BD中破坏了影响编码和动机行为的价值和动机行为（恐惧与APPT-ON神经元）导致抑郁症，焦虑和躁狂症。哪些因素可能会调节健康和疾病状态中恐惧和APPT-ON电路的功能？一个答案可能位于这些神经元的独特分子特征中，与它们的对立一致功能。首先，恐惧和appt-on神经元表达已知调节的不同分子因子杏仁核内的恐惧/威胁和奖励处理，包括焦虑激素[CRH]）和抗焦虑（例如神经素受体2 [NTSR2]）因子。第二，一个很好的经过验证的杏仁核恐惧和appt-on神经元的区分特征是它们独特的表达模式 Wnt/β链氨酸信号传导分子的。此特征表明Wnt/β链氨蛋白途径对调节差异恐惧和appt-on神经元。试验数据还显示了关键分子的表达改变，包括Wnt7a 和BD人的杏仁核中的CRH。我们的具体假设是细胞特定的恐惧和appt- 关于调节压力/焦虑和奖励/食欲行为的分子因素，BD发生了变化，并且 Wnt/β链氨蛋白途径的破坏会导致恐惧和appt-on神经元的不同异常。人类验尸研究结合了单细胞RNASEQ，多重mRNA/蛋白质细胞标记和定量 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”是预测恐惧和appt-on神经元中分子变化的不同模式（目标1和2）。因果小鼠遗传模型中的操纵将机械测试以下假设：Wnt信号的破坏有因果改变将深杏仁核与奖励和应力相关分子的表达伏隔核和核（AIM 3）。