Molecular and Cellular Basis of Cognitive Aging in Prefrontal Cortical Networks

描述（由申请人提供）：在衰老过程中，前额叶皮层（PFC）的工作记忆功能下降较早。工作记忆依赖于PFC锥体细胞微电路之间的循环激发。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础。PFC电路也可能被改变网络连接功能状态的分子变化削弱。NE（去甲肾上腺素）通过突触后a2A肾上腺素受体（a2A- ar）增强PFC认知功能，从而抑制cAMP的产生。cAMP打开PFG树突棘上的HCN（超极化激活环核苷酸门控）通道，降低膜阻力并削弱突触输入的效力。随着年龄的增长，PFC中a2A-ARs减少，cAMP去抑制，HCN通道增加。本研究验证了cAMP/HCN信号过多是PFC在衰老早期认知缺陷的基础，并通过突触连接减弱导致最终脊柱丢失的假设。本研究涉及4个项目和3个核心。项目1将记录执行工作记忆任务的年轻猴子和老年猴子的PFC神经元集合，以测试PFC网络随着年龄的增长而减弱的假设，以及通过离子吸附应用抑制cAMP或阻断HCN通道的药物可以加强连接的假设。项目2将评估衰老大鼠和猴子PFC中可能影响cAMP/HCN信号和脊柱丢失的分子变化。该项目还将使用腺病毒转染大鼠PFC来测试HCN通道和其他信号蛋白表达的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将记录年轻和年老大鼠的PFC神经元群，从而观察回路强度随时间变化对病毒（项目2）或药物（项目4）操作的反应。项目4将使用电子显微镜观察衰老PFC中NE轴突、a2A-AR和HCN通道的变化，并将测试胍法辛慢性刺激a2A-AR是否会减缓衰老大鼠和猴子的工作记忆损伤和脊柱丧失。由于胍法辛可用于人类，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.