Electrophysiology of the Prefrontal Cortex

描述(由申请人提供)：尽管在揭示精神分裂症遗传易感性方面取得了巨大进展，以及丰富的脑成像数据使我们能够识别受这种疾病影响的关键大脑区域，但我们对其病理生理机制仍远未有一个清晰的认识。已知受累的是前额叶皮质、颞叶、杏仁核和基底节。此外，包括多巴胺、谷氨酸和GABA在内的几个递质系统也被牵连。事实上，动物模型依赖于许多发育操作，包括海马体的损伤。一个有待解决的重要问题是，为什么(以及如何)早期发育/遗传因素会导致症状在青春期晚期或成年早期出现。我们计划跟踪最近的研究表明，多巴胺在前额叶皮质的作用，特别是对中间神经元的作用，在青春期成熟。我们将探索可能导致NAOVE动物成熟延迟的细胞和突触机制，并将这些研究扩展到精神分裂症的发育性动物模型。患有新生大鼠腹侧海马区损伤的大鼠表现出异常行为和认知缺陷，类似于精神分裂症中观察到的现象。我们还表明，在这些动物中，对多巴胺激活的电生理反应是异常的。尽管在早期就有病变，但所有这些变化都出现在青春期；因此，这个模型非常适合于研究延迟出现的生理异常。我们将评估从病变到症状出现期间前额叶皮质中间神经元的成熟情况，以及青春期出现的对多巴胺的异常反应所涉及的机制。我们还将测试药理学模型(阻断NMDA受体)是否通过选择性地靶向中间神经元来发挥作用。这里提出的实验可能会为研究精神分裂症的病理生理学和大脑成熟开辟新的途径。例如，从这些研究中可能会出现治疗方法的新想法。公共卫生相关性：该项目旨在确定前额叶皮质中间神经元的改变是否是不同的精神分裂症动物模型的共同因素。由于中间神经元在尸检研究中一再被认为是异常的，识别a)它们在动物模型中是否异常，以及b)这些异常的性质，具有很大的潜力提供信息，可能形成关于这种毁灭性疾病的病理生理机制的新观点。我们最近报道的这种细胞群体的多巴胺调制的青春期周围成熟可能会在这些模型中受到影响；如果这一应用中的总体假设是正确的，研究这种晚成熟可能为设计针对前额叶皮质中GABA和谷氨酸传递的新的治疗方法提供独特的机会。

DESCRIPTION (provided by applicant): Despite strong progress in unveiling the elements that confer genetic predisposition for schizophrenia and a wealth of brain imaging data that has allowed identifying critical brain regions that are affected in this disorder, we are still far from a clear view on its pathophysiological mechanisms. The prefrontal cortex, the temporal lobe, amygdala and basal ganglia are known to be involved. Also, several transmitter systems, including dopamine, glutamate and GABA, have been implicated. Indeed, animal models have relied on a number of developmental manipulations, including a lesion in the hippocampus. An important question that remains to be solved is why (and how) early developmental/genetic factors can yield a condition in which symptoms emerge late in adolescence or in early adulthood. We plan to follow recent studies indicating that the actions of dopamine in the prefrontal cortex, in particular on interneurons, mature during adolescence. We will explore the cellular and synaptic mechanisms that may be responsible for this delayed maturation in naove animals, and we will extend those studies to a developmental animal model of schizophrenia. Rats with a neonatal lesion of the ventral hippocampus exhibit abnormal behaviors and cognitive deficits that resemble phenomena observed in schizophrenia. We have also shown that the electrophysiological response to dopamine activation is abnormal in those animals. Despite having the lesion at early ages, all these changes emerge during adolescence; thus, this model is well suited to study delayed emergence of physiological anomalies. We will assess the maturation of prefrontal cortical interneurons in the period between the lesion and the onset of symptoms, and the mechanisms involved in the abnormal responses to dopamine that emerge during adolescence. We will also test whether a pharmacological model (blocking NMDA receptors) exerts its actions by selectively targeting interneurons. The experiments proposed here may open new avenues to think about schizophrenia pathophysiology and brain maturation. New ideas for therapeutic approaches, for example, may emerge from these studies. PUBLIC HEALTH RELEVANCE: This project is aimed at determining whether alterations in prefrontal cortical interneurons are a common element in different animal models of schizophrenia. As interneurons have been repeatedly suggested to be abnormal in post-mortem studies, identifying a) whether they are abnormal in animal models, and b) the nature of those anomalies, has a great potential to provide information that could shape new views on pathophysiological mechanisms in this devastating disorder. The periadolescent maturation of the dopamine modulation of this cell population we reported recently is likely to be affected in these models; if the overall hypothesis in this application is correct, studying this late maturation could provide unique opportunities to design novel therapeutic approaches that target GABA and glutamate transmission in the prefrontal cortex.