Molecular and Cellular Basis of Cognitive Aging in Prefrontal Cortical Networks

描述（由申请人提供）：前额叶皮层（PFC）的工作记忆功能在衰老过程的早期下降。工作记忆依赖于前额叶皮层锥体细胞微回路之间的反复兴奋。随着年龄的增长，锥体树突棘的丢失，从而侵蚀了电路连接的解剖学基底。PFC电路也可能被改变网络连接功能状态的分子变化所削弱。NE（去甲肾上腺素）通过作用于突触后α 2 A肾上腺素受体（α 2 A-AR）来增强PFC认知功能，其抑制cAMP的产生。cAMP打开PFG树突棘上的HCN（超极化激活的环核苷酸门控）通道，降低膜电阻并削弱突触输入的功效。随着年龄的增长，PFC中的a2 A-ARs减少，cAMP被抑制，HCN通道增加。拟议的研究测试了这样一种假设，即过度的cAMP/HCN信号转导是老化过程早期PFC认知缺陷的基础，并通过减弱突触连接导致最终的脊柱丢失。本研究共涉及4个项目和3个核心。项目1将记录年轻与老年猴子执行工作记忆任务的PFC神经元集合，以检验PFC网络随年龄减弱的假设，以及通过离子电渗应用抑制cAMP或阻断HCN通道的药物可以加强连接。项目2将评估衰老大鼠和猴PFC中可能影响cAMP/HCN信号传导和脊柱丢失的分子变化。该项目还将使用大鼠PFC的腺病毒转染来测试HCN通道和其他信号蛋白的表达改变是否会减缓与年龄相关的工作记忆和脊柱密度下降。项目3将记录年轻和老年大鼠PFC神经元的集合，从而观察回路强度随时间的变化，以响应病毒（项目2）或药理学（项目4）操作。项目4将使用电子显微镜观察老化PFC中NE轴突、α 2A-AR和HCN通道的变化，并将测试用胍法辛慢性刺激α 2A-AR是否会减缓老化大鼠和猴子的工作记忆障碍和脊柱丢失。由于胍法辛可供人类使用，这项研究可以很容易地转化为治疗老年人PFC缺陷。

DESCRIPTION (provided by applicant): The working memory functions of the prefrontal cortex (PFC) decline early in the aging process. Working memory depends on recurrent excitation between PFC pyramidal cell microcircuits. With advancing age, there is a loss of pyramidal dendritic spines, thus eroding the anatomical substrate for circuit connectivity. PFC circuits may also be weakened by molecular changes that alter the functional status of network connectivity. NE (norepinephrine) strengthens PFC cognitive function through actions at post-synaptic a2A adrenoceptors (a2A-AR), which inhibit the production of cAMP. cAMP opens HCN (hyperpolarizationactivated cyclic nucleotide gated) channels on PFG dendritic spines, lowering membrane resistance and weakening the efficacy of synaptic inputs. With advancing age, there are fewer a2A-ARs, disinhibited cAMP and increased HCN channels in the PFC. The proposed research tests the hypothesis that excessive cAMP/HCN signaling underlies PFC cognitive deficits early in the aging process, and contributes to eventual spine loss through weakened synaptic connectivity. The research involves 4 Projects and 3 Cores. Project 1 will record from ensembles of PFC neurons in young vs aged monkeys performing working memory tasks to test the hypotheses that PFC networks are weakened with age, and that connectivity can be strengthened by iontophoretic application of agents that inhibit cAMP or block HCN channels. Project 2 will assess molecular changes in the aging rat and monkey PFC that may impact cAMP/HCN signaling and spine loss. This project will also use adenoviral transfection of rat PFC to test whether altered expression of HCN channels and other signaling proteins slow age-related decline in working memory and spine density. Project 3 will record from ensembles of PFC neurons in young and aged rats, and thus observe changes in circuit strength over time in response to viral (Project 2) or pharmacological (Project 4) manipulations. Project 4 will use electron microscopy to visualize changes in NE axons, a2A-AR, and HCN channels in the aging PFC, and will test whether chronic stimulation of a2A-AR with guanfacine will slow working memory impairment and spine loss in aging rats and monkeys. As guanfacine is available for human use, this research can readily translate to treating PFC deficits in the elderly.