Regulation of ventral hippocampal system function

描述（由申请人提供）：精神分裂症是一种毁灭性的精神疾病，影响了大约0.4-1%的美国人口。来自药物研究、治疗治疗和人类影像学研究的大量证据表明，精神分裂症患者的精神病与皮质下多巴胺系统功能失调有关。这种精神分裂症的多巴胺假说有一个主要的警告，即在中脑多巴胺系统本身似乎没有特定的病理。因此，很可能是多巴胺系统的传入调节在精神分裂症中功能失调。其中两个输入是内侧前额叶皮层（被认为与认知缺陷有很大关系）和海马体（主要与学习和记忆有关的颞叶结构）。精神分裂症患者海马结构和功能的改变在死后和神经影像学研究中得到了一致的证明。此外，有越来越多的证据表明，人类精神分裂症患者的基线海马过度活跃与精神病水平相关。与此一致的是，我们最近报道了一个发育中断的啮齿动物模型（即MAM G17）中腹侧海马体的基线过度活跃，这似乎是该模型中多巴胺过度功能背后的驱动力。因此，海马腹侧输出的衰减可能会使多巴胺传递正常化，并可能提供一个新的治疗靶点。我们计划利用不同的方法来研究这个模型，这些方法专门针对调节海马腹侧活动，目的如下：1)研究调节MAM和生理盐水大鼠vHipp功能的潜在新方法；2)确定这些减弱vHipp活性的方法如何改变MAM和生理盐水大鼠多巴胺系统功能；3)确定减弱vHipp系统功能是否可以逆转MAM模型中与精神分裂症相关的行为缺陷。研究这些系统之间的功能相互作用，以及该回路的中断如何影响信息处理、神经化学和行为，是我们确定新的和改进的治疗剂的最终目标的核心。

DESCRIPTION (provided by applicant): Schizophrenia is a devastating psychiatric condition that affects approximately 0.4-1% of the US population. Substantial convergent evidence from drug studies, therapeutic treatments, and human imaging studies demonstrate that psychosis in schizophrenia is associated with a dysregulation of subcortical dopamine system function. This dopamine hypothesis of schizophrenia has one major caveat in that there appears to be no specific pathology in the midbrain dopamine system itself. Thus it is likely that it is the afferent regulation of the dopamine system that is dysfunctional in schizophrenia. Two such inputs are the medial prefrontal cortex (thought to be largely associated with cognitive deficits) and the hippocampus, a temporal lobe structure principally associated with learning and memory. Alterations in hippocampal structure and function in schizophrenia are consistently demonstrated in postmortem and neuro-imaging studies. Furthermore, there is increasing evidence for baseline hippocampal hyperactivity in human schizophrenia patients that is correlated with levels of psychosis. Consistent with this, we have recently reported baseline hyperactivity in the ventral hippocampus in a developmental disruption rodent model, namely MAM G17, that appears to be the driving force behind the dopamine hyperfunction in this model. Thus, attenuation of ventral hippocampal output may act to normalize dopamine transmission and may provide a novel therapeutic target. We plan to examine this model utilizing distinct approaches aimed specifically at modulating ventral hippocampal activity along the following Specific Aims: 1) Examine potential novel methods for regulating vHipp function in MAM and saline rats, 2) Determine how these methods for attenuating vHipp activity alter dopamine system function in MAM and saline rats, and 3) Determine whether attenuating vHipp system function can reverse behavioral deficits associated with schizophrenia in the MAM model. Examining the functional interactions among these systems and how disruption within this circuit affects information processing, neurochemistry and behavior is central to our ultimate goal of identifying new and improved therapeutic agents.