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，影响约0.4-1%的美国人口。来自药物研究、治疗性治疗和人类影像学研究的大量证据表明，精神分裂症中的精神病与皮质下多巴胺系统功能失调有关。精神分裂症的多巴胺假说有一个主要的警告，即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。两个这样的输入是内侧前额叶皮层（被认为主要与认知缺陷有关）和海马体，一个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尸检和神经影像学研究中得到了一致的证实。此外，越来越多的证据表明，人类精神分裂症患者的基线海马活动过度与精神病水平相关。与此一致，我们最近报道了在发育中断啮齿动物模型中腹侧海马的基线活动过度，即MAM G17，这似乎是该模型中多巴胺功能亢进背后的驱动力。因此，腹侧海马输出的衰减可能会使多巴胺传递正常化，并可能提供一种新的治疗靶点。 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腹侧海马的活动，具体目标如下：1）检查用于调节MAM和盐水大鼠中vHipp功能的潜在新方法，2）确定用于减弱vHipp活性的这些方法如何改变MAM和盐水大鼠中多巴胺系统功能，和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。检查这些系统之间的功能相互作用以及该电路内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.