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

cAMP 和 HCN 通道在应激诱发的前额功能障碍中的作用

• 批准号: 7408334
• 负责人: Nao Jennifer Gamo
• 金额: $ 4.1万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7408334
• 关键词: Acute; Animals; Behavioral; Biological Assay; Chronic stress; Cognitive; Cognitive deficits; Condition; Cyclic AMP; Dendritic Spines; Deterioration; Disinhibition; Elevation; Exposure to; Fire - disasters; Functional disorder; HCN1 channel; Image; Impaired cognition; Lead; Measures; Mental disorders; Monkeys; Neurobiology; Neurons; Neuropil; Patients; Physiological; Prefrontal Cortex; Psyche structure; Rattus; Research; Role; Schizophrenia; Short-Term Memory; Signal Transduction; Stress; Techniques; Testing; acute stress; base; biological adaptation to stress; cognitive function; cyclic nucleotide-gated cation channel; gray matter; loss of function mutation; neuroprotection; novel

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.

描述（由申请人提供）：前额叶皮层（PFC）的认知功能在精神疾病（如精神分裂症）中发生了深刻的改变，这种疾病因暴露于压力而恶化。神经病理学研究表明，精神分裂症患者的PFC中存在神经元的丢失，包括树突棘的丢失，并且成像研究表明，灰质的进行性丢失可能是精神状态恶化的关键。拟议的研究探讨了压力引起的PFC认知功能和结构完整性变化的可能神经生物学基础。在动物中的研究表明，PFC的认知功能受损暴露于急性或慢性应激，慢性应激导致树突棘的PFC的损失。拟议的研究将检查细胞内的信号机制，这些显着的变化，认知能力和树突的完整性。我们将检验cAMP-HCN信号传导（超极化激活的环核苷酸门控阳离子通道）的激活有助于在应激暴露期间PFC网络断开的假设。这种机制可能与精神分裂症特别相关，因为DISC 1（精神分裂症中断）中的功能缺失突变可能导致许多患有这种疾病的患者PFC中cAMP信号的去抑制。我们将具体研究急性应激是否通过cAMP打开HCN通道而在功能上断开PFC网络，导致PFC认知功能的快速丧失。我们将进一步研究慢性应激暴露是否通过持续升高cAMP-HCN信号传导导致更严重的认知障碍和树突棘的实际丧失。本研究将使用PFC完整性的生理、行为和解剖学分析来检验这些假设。目的1将采用单单位记录PFC神经元在猴子执行工作记忆任务，观察的作用，cAMP-HCN信号在生理措施的网络连接（持续放电期间的延迟期）的条件下，模仿应激反应。目的2：探讨急性应激诱导大鼠PFC认知功能障碍的机制。目的3将使用新的腺病毒技术来测试是否敲低大鼠PFC中的HCN 1通道将保护PFC免受慢性应激暴露所产生的认知和结构变化。积极的结果可能会带来新的治疗策略，用于精神疾病中前额叶灰质的神经保护。