Regulation of ventral hippocampal system function

腹侧海马系统功能的调节

• 批准号: 8073091
• 负责人: Daniel Lodge
• 金额: $ 33.08万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8073091
• 关键词: Ablation; Affect; Agonist; Animal Model; Attention; Attenuated; Autopsy; Behavior; Behavioral; Brain region; Chemicals; Cognitive; Cognitive deficits; Complex; Data; Deep Brain Stimulation; Development; Disease; Dopamine; Frequencies; Functional disorder; Glutamates; Goals; Hippocampus (Brain); Human; Hyperactive behavior; Image; Interneurons; Learning; Medial; Mediating; Memory; Mental disorders; Methods; Midbrain structure; Modeling; Neurobiology; Neurons; Nucleus Accumbens; Operative Surgical Procedures; Output; Parvalbumins; Pathology; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Population; Prefrontal Cortex; Principal Investigator; Property; Psychotic Disorders; Rattus; Recruitment Activity; Regulation; Reporting; Rest; Rodent Model; Role; Saline; Schizophrenia; Secondary to; Signal Transduction; Structure; Symptoms; System; Temporal Lobe; Temporal Lobe Epilepsy; Therapeutic; Therapeutic Agents; Therapeutic Studies; Toxic effect; Work; attenuation; base; brain pathway; dopamine system; driving force; gamma-Aminobutyric Acid; human data; improved; information processing; memory recall; mesolimbic system; neurochemistry; neuron development; neurophysiology; neuropsychiatry; neurotransmission; new therapeutic target; novel; programs; psychostimulant; receptor; response; transmission process

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.

描述（由申请人提供）：精神分裂症是一种毁灭性的精神病疾病，影响约0.4-1％的美国人口。来自药物研究，治疗治疗和人类成像研究的大量收敛证据表明，精神分裂症的精神病与皮质下多巴胺系统功能的失调有关。这种精神分裂症的多巴胺假说有一个主要的警告，因为中脑多巴胺系统本身似乎没有特定的病理。因此，精神分裂症中功能失调的多巴胺系统的传入调节很可能。两个这样的输入是内侧前额叶皮层（被认为与认知缺陷很大程度上相关）和海马，这是一种颞叶结构，主要与学习和记忆有关。在验尸和神经成像研究中，始终证明了海马结构和精神分裂症功能的改变。此外，与精神病水平相关的人类精神分裂症患者的基线海马过度活动有越来越多的证据。与此一致，我们最近报道了在发育破坏啮齿动物模型（即MAM G17）中，腹侧海马中的基线多动症，这似乎是该模型中多巴胺过度功能背后的驱动力。因此，腹侧海马输出的衰减可能起作用以使多巴胺传播正常化，并可能提供新颖的治疗靶标。 我们计划检查该模型采用旨在专门用于调节沿以下特定目的调节腹侧海马活动的不同方法：1）检查调节MAM和盐碱大鼠VHIPP功能的潜在新方法，2）确定这些方法如何减弱VHIPP活性在MAM和盐水中的延伸，并确定vhipp的行为是否能够改善vhipt的功能，并确定vhipt的功能，并确定nipt vhipt的功能，3） MAM模型中的精神分裂症。检查这些系统之间的功能相互作用以及该电路中的破坏如何影响信息处理，神经化学和行为对于我们确定新的和改进的治疗剂的最终目标至关重要。