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的因素方面取得了很大进展，并且有大量的脑成像数据可以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有很长的路要走。前额叶皮层、颞叶、杏仁核和基底神经节都参与其中。此外，包括多巴胺、谷氨酸和GABA在内的几个传递系统也有牵连。事实上，动物模型依赖于许多发育操作，包括海马体损伤。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。我们计划遵循最近的研究表明，多巴胺在前额叶皮层的作用，特别是在中间神经元，在青春期成熟。我们将探索可能导致幼稚动物这种延迟成熟的细胞和突触机制，并将这些研究扩展到精神分裂症的发育动物模型。新生儿海马腹侧病变的大鼠表现出与精神分裂症相似的异常行为和认知缺陷。我们还发现，这些动物对多巴胺激活的电生理反应是不正常的。尽管在早期就有病变，但所有这些变化都在青春期出现；因此，该模型非常适合研究生理异常的延迟出现。我们将评估在病变和症状出现之间的前额皮质中间神经元的成熟，以及青春期出现的对多巴胺的异常反应的机制。我们还将测试是否药理学模型（阻断NMDA受体）通过选择性靶向中间神经元发挥其作用。本文提出的实验可能为思考精神分裂症的病理生理和脑成熟开辟新的途径。例如，这些研究可能会产生治疗方法的新想法。公共卫生相关性：该项目旨在确定前额皮质中间神经元的改变是否是精神分裂症不同动物模型中的共同因素。由于中间神经元在死后研究中多次被认为是异常的，因此确定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，可以提供信息，从而形成对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的多巴胺调节的青春期周围成熟可能在这些模型中受到影响；如果这项应用的整体假设是正确的，那么研究这种晚成熟可以为设计针对GABA和谷氨酸在前额皮质中的传递的新型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.