Dysregulation of Appetitive & Aversive Amygdala Circuits in Bipolar Disorder

双相情感障碍(BD)的特点是严重的情感调节失调。反感症状的周期 (抑郁、焦虑、食欲下降)，与躁狂交替出现(一种增强的食欲状态 奖励和快乐)。临床表现是不同的，具有不同的优势模式 症状、严重程度和持续时间。值得注意的是，目前还没有健壮的神经回路模型来解释这些 临床表现。成像和尸检研究指向杏仁核，这是一个嵌入电路的核 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、功能不同的杏仁核神经元集，它们分别编码 并规范厌恶和食欲的行为。具体地说，小鼠杏仁核内的不同神经元类型 促进厌恶/恐惧反应(“恐惧”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元 人类杏仁核中存在种群。我们最重要的假设是神经元群体 冲击价编码和动机行为(恐惧-ON与APPT-ON神经元)在BD中被破坏， 会导致抑郁、焦虑和躁狂。 在健康和疾病状态下，哪些因素可能调节恐惧和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，与它们的对立面一致 功能。首先，恐惧-ON和APPT-ON神经元表达不同的已知调节分子因素 杏仁核内的恐惧/威胁和奖励处理，包括引起焦虑的(例如，促皮质激素释放) 激素[CRH])和抗焦虑因子(如神经降压素受体2[NTSR2])。第二，一口井- 杏仁核恐惧-ON和APPT-ON神经元的有效区别特征是其不同的表达模式 Wnt/β连环蛋白信号分子。这一特征表明，Wnt/β连环蛋白通路具有差异性调节作用 恐惧和APPT-ON神经元。试点数据还显示，包括Wnt7a在内的关键分子的表达发生了变化 和CRH在BD患者的杏仁核中。我们的具体假设是细胞特有的恐惧-ON和APPT- 调节应激/焦虑和奖赏/食欲行为的分子因素在BD中改变，并且 Wnt/β连环蛋白通路的破坏导致恐惧-ON和APPT-ON神经元的明显异常。 结合单细胞RNAseq、多重mRNA/蛋白细胞标记和定量 对RDoC临床领域的分析将检验BD中可量化的临床“指纹”的假设 预测恐惧-ON和APPT-ON神经元分子变化的不同模式(目标1和2)。因果关系 在小鼠遗传模型中的操作将从机械上检验Wnt信号中断的假设 因果改变奖赏和应激相关分子在连接杏仁核深部与 CE和伏隔核(目标3)。

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).