Developmental Trajectories of Negative Symptoms in Schizophrenia

描述(申请人提供)：孔特中心的目标是探索人类和小鼠精神分裂症核心负面症状的大脑回路，精神分裂症的情感表达能力和社交动力减弱。该中心将加强和扩大宾夕法尼亚精神分裂症研究中心，这是联合发现和基础设施的核心，旨在了解精神分裂症的神经基础。它利用该领域的新合作和进展，通过多层次的互补方法追求翻译目标，专注于解剖具有临床重要性但鲜为人知的精神分裂症的主要表型特征。主要目的包括：1.将青春期的阴性症状和社会功能障碍与厌恶学习期间杏仁核回路功能障碍的神经行为和神经生理学措施联系起来。2.确定杏仁核回路NMDAR1信号在发育过程中的社会情绪行为中的作用。3.确定NMDAR1信号在杏仁核生理和社会行为中的作用。4.研究患者死后杏仁核NMDA受体功能障碍与突触连接调节的关系。5.研究NMDAR功能低下的基因组基础及其与发育过程中情感和社会功能受损的表型之间的关系。该中心将有五个项目：1.青少年厌恶学习和社交功能障碍的神经生理学；2.小鼠社会和情绪行为及杏仁核功能的早期发展；3.社会功能的电生理标记物；4.杏仁核中NMDA受体功能低下；V.精神分裂症中NMDA受体途径的综合基因组分析。两个核心将支持这些项目：核心A行政和核心B数据和生物统计。该中心利用宾夕法尼亚大学研究人员的协作专业知识和资源进行这项具有挑战性的跨学科翻译研究。除了推进其科学议程外，该中心还将成为教职员工、研究员、住院医生、研究生和本科生的教育资源。这也将是一次临床和教育。 公共卫生相关性：阴性症状是精神分裂症的核心特征，也是限制功能恢复的严重的未得到满足的治疗需求。该中心培养了一种跨学科的方法，应用多层次的分析，跨越行为、人体电路和基因以及模型系统，以促进对重大科学差距的理解。这一努力可能有助于早期识别、开发生物标记物和新的治疗方法。

DESCRIPTION (provided by applicant): The goal of the Conte Center is to probe brain circuitry that underlies the core negative symptoms of schizophrenia, diminished emotional expressivity and social drive, in humans and mice. The Center will enhance and expand the Penn Schizophrenia Research Center, a nucleus of joint discovery and infrastructure directed at understanding neural substrates of schizophrenia. It capitalizes on new collaborations and advances in the field, pursuing translational aims with multi-level complementary approaches focused on dissecting major phenotypic features of schizophrenia that are of clinical importance yet poorly understood. Major aims include: 1. Relate negative symptoms and social dysfunction in adolescence to neurobehavioral and neurophysiological measures of amygdala circuit dysfunction during aversive learning. 2. Determine the role of amygdala circuit NMDAR1 signaling in social-emotional behavior during development. 3. Determine the role of NMDAR1 signaling in amygdala physiology and social behavior in vivo. 4. Delineate NMDA receptor dysfunction in the postmortem amygdala of patients in relation to modulation of synaptic connectivity. 5. Investigate genomic underpinnings for NMDAR hypofunction and its association with phenotypes of impaired affective and social functioning during development. The Center will have five Projects: I. Neurophysiology of aversive learning and social dysfunction in youths; II. Early development of social and emotional behaviors and amygdala function in mice; III. Electrophysiological markers of social function; IV. NMDA receptor hypofunction in the amygdala; V. Integrative genomic analyses of NMDA receptor pathway in schizophrenia. Two Cores will support the Projects: Core A Administration and Core B Data and Biostatistics. The Center capitalizes on the collaborative expertise of investigators and resources at Penn for conducting this challenging interdisciplinary translational research. In addition to advancing its scientific agenda, the Center will be an educational resource for faculty, fellows, residents, graduate and undergraduate students. It will also be a clinical and educational. PUBLIC HEALTH RELEVANCE: Negative symptoms are core features of schizophrenia and a critical unmet treatment need that limits functional recovery. The Center fosters an interdisciplinary approach, applying multiple levels of analysis, spanning behavior, circuits and genes in humans and model systems toward advancing the understanding of a significant scientific gap. This effort may contribute to early identification, development of biomarkers and novel therapeutics.