Role of cAMP and HCN channels in stress-induced prefrontal dysfunction

描述(申请人提供)：前额叶皮质(PFC)的认知功能在精神疾病(如精神分裂症)中会发生深刻的变化，这些疾病会因暴露在压力下而恶化。神经病理学研究表明，精神分裂症患者的PFC中神经纤维丢失，包括树突棘的丢失，成像研究表明灰质的进行性丢失可能是精神状态恶化的关键。这项拟议的研究考察了压力导致PFC认知功能和结构完整性变化的可能神经生物学基础。在动物身上的研究表明，无论是急性还是慢性应激都会损害PFC的认知功能，而慢性应激会导致PFC内树突棘的丢失。这项拟议的研究将检查导致认知能力和树突完整性这些显着变化的细胞内信号机制。我们将测试cAMP-HCN信号的激活(超极化激活的环核苷酸门控阳离子通道)在应激暴露中导致PFC网络断开的假设。这一机制可能与精神分裂症特别相关，因为DISC1功能丧失突变(在精神分裂症中中断)可能导致许多这种疾病患者PFC中cAMP信号的解除抑制。我们将具体研究急性应激是否通过cAMP开放HCN通道来功能性地切断PFC网络，导致PFC认知功能的迅速丧失。我们将进一步研究慢性应激暴露是否通过cAMP-HCN信号的持续升高而导致更严重的认知损害和树突棘的实际丧失。这项研究将使用PFC完整性的生理、行为和解剖学分析来检验这些假说。目标1将使用执行工作记忆任务的猴子的PFC神经元的单个单位记录来观察cAMP-HCN信号在模拟应激反应的条件下网络连通性的生理测量中的作用(延迟期内的持续放电)。目的2确定PFC内cAMP-HCN信号是否参与急性应激大鼠的PFC认知功能障碍。目的3将使用新腺病毒技术来测试敲除大鼠PFC中的HN1通道是否会保护PFC免受慢性应激所产生的认知和结构变化的影响。积极的结果可能导致精神疾病患者前额叶灰质神经保护的新治疗策略。

DESCRIPTION (provided by applicant): The cognitive functions of the prefrontal cortex (PFC) are profoundly altered in mental illnesses such as schizophrenia, which are worsened by exposure to stress. Neuropathological studies have demonstrated loss of neuropil, including loss of dendritic spines, in the PFC of patients with schizophrenia, and imaging studies suggest that progressive loss of gray matter may be key to the deterioration in mental state. The proposed research examines a possible neurobiological basis for stress-induced changes in PFC cognitive function and structural integrity. Studies in animals have shown that the cognitive functioning of the PFC is impaired by exposure to either acute or chronic stress, and that chronic stress leads to dendritic spine loss in the PFC. The proposed research will examine the intracellular signaling mechanisms contributing to these marked changes in cognitive ability and dendritic integrity. We will test the hypothesis that activation of cAMP-HCN signaling (Hyperpolarization-activated Cyclic Nucleotide-gated cation channels) contributes to disconnections of PFC networks during stress exposure. This mechanism may have particular relevance to schizophrenia, as a loss-of-function mutation in DISC1 (Disrupted In Schizophrenia) likely leads to a disinhibition of cAMP signaling in PFC in many patients with this illness. We will specifically examine whether acute stress functionally disconnects PFC networks through cAMP opening of HCN channels, leading to rapid loss of PFC cognitive function. We will further examine whether chronic stress exposure leads to more profound cognitive impairment and actual loss of dendritic spines through sustained elevations in cAMP-HCN signaling. The research will examine these hypotheses using physiological, behavioral and anatomical assays of PFC integrity. Aim 1 will employ single-unit recordings of PFC neurons in monkeys performing a working memory task to observe the role of cAMP-HCN signaling in physiological measures of network connectivity (persistent firing during the delay period) under conditions that mimic the stress response. Aim 2 will determine whether cAMP-HCN signaling in PFC contributes to PFC cognitive deficits induced by acute stress exposure in rats. Aim 3 will use novel adenoviral techniques to test whether knockdown of HCN1 channels in rat PFC will protect PFC from the cognitive and architectural changes produced by chronic stress exposure. Positive results may lead to novel treatment strategies for neuroprotection of PFC grey matter in mental illness.