Electrophysiology of the Prefrontal Cortex

描述（由申请人提供）：尽管在揭示赋予精神分裂症遗传易感性的因素方面取得了很大进展，并且大量的脑成像数据已经允许识别在这种疾病中受影响的关键脑区域，但我们仍然远远没有对其病理生理机制的明确看法。前额叶皮层、颞叶、杏仁核和基底神经节都与此有关。此外，包括多巴胺、谷氨酸和GABA在内的几种递质系统也与此有关。事实上，动物模型依赖于许多发育操作，包括海马体中的损伤。一个尚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后期或成年早期出现。我们计划遵循最近的研究表明，多巴胺在前额叶皮层，特别是中间神经元，在青春期成熟的行动。我们将探索可能导致幼年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动物模型。新生大鼠腹侧海马损伤表现出异常的行为和认知缺陷，类似于精神分裂症中观察到的现象。我们还表明，多巴胺激活的电生理反应在这些动物中是异常的。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，该模型非常适合研究生理异常的延迟出现。我们将评估病变和症状发作之间的前额叶皮质中间神经元的成熟，以及青春期出现的多巴胺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）是否通过选择性靶向中间神经元发挥其作用。这里提出的实验可能会开辟新的途径来思考精神分裂症的病理生理学和大脑成熟。例如，治疗方法的新想法可能会从这些研究中出现。公共卫生相关性：该项目旨在确定前额叶皮层中间神经元的改变是否是不同精神分裂症动物模型中的共同元素。由于中间神经元在死后研究中一再被认为是异常的，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，从而形成对这种破坏性疾病的病理生理机制的新观点。我们最近报道的这个细胞群的多巴胺调节的青春期成熟可能会受到这些模型的影响;如果在这个应用程序中的整体假设是正确的，研究这种晚期成熟可以提供独特的机会，设计新的治疗方法，靶向GABA和谷氨酸在前额叶皮层的传输。

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.