Electrophysiology of the Prefrontal Cortex

描述（由申请人提供）：前额叶皮质的多巴胺能神经支配是目前关于精神分裂症病理生理学假说的重要组成部分。不幸的是，多巴胺在大脑皮层中的作用还没有得到很好的理解，所以我们无法想象一个清晰的画面，多巴胺紊乱如何导致症状。这一领域有大量不一致的，往往是相互矛盾的报告，多巴胺的作用经常被描述为抑制，兴奋或简单的调节。我们计划检验这样一个假设，即前额叶皮层中的多巴胺维持了突触活动被门控的去极化（上升状态）时期。实验将涉及：1）多巴胺细胞活性是否与前额叶皮质的上升状态相关，以及是否使多巴胺的来源（腹侧被盖区）失活，消除或减少了上升状态; 2）在已知驱动多巴胺能投射的条件下，多巴胺细胞和前额叶皮质在清醒动物中是否增强了它们的同步性; 3）多巴胺是否可以调节脑切片制备中类似于上升状态的高原去极化; 4）中皮层投射的激活是否增强了前额叶皮层的代谢活动;以及5）从具有新生儿腹侧海马损伤的动物获得的前额叶皮层切片中的多巴胺-谷氨酸相互作用。

DESCRIPTION (provided by applicant): The dopaminergic innervation of the prefrontal cortex is an important component of current hypotheses on the pathophysiology of schizophrenia. Unfortunately, the actions of dopamine in the cortex are not well understood, so we cannot envision a clear picture of how dopamine disturbances can result in symptoms. This field has a large number of inconsistent and often contradictory reports, with the actions of dopamine frequently characterized as inhibitory, excitatory or simply modulatory. We plan to test the hypothesis that dopamine in the prefrontal cortex sustains periods of depolarization (up states) during which synaptic activity is gated. The experiments will address: 1) whether dopamine cell activity is correlated with prefrontal cortical up states and whether inactivating the source of dopamine, the ventral tegmental area, eliminates or reduces up states; 2) whether dopamine cells and the prefrontal cortex enhance their synchrony in awake animals during conditions known to drive the dopaminergic projection; 3) whether dopamine can modulate plateau depolarizations resembling up states in a brain slice preparation; 4) whether activation of the mesocortical projection enhances metabolic activity in the prefrontal cortex; and 5) dopamine-glutamate interactions in prefrontal cortical slices obtained from animals with a neonatal ventral hippocampal lesion.