Molecular and Cellular Basis of Cognitive Aging in Prefrontal Cortical Networks

描述(申请人提供)：前额叶皮质(PFC)的工作记忆功能在衰老过程中早期下降。工作记忆依赖于PFC锥体细胞微电路之间的反复兴奋。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础。PFC电路也可能被分子变化削弱，从而改变网络连接的功能状态。去甲肾上腺素通过作用于突触后A2A型肾上腺素受体(A2AAR)，抑制cAMP的产生，从而增强PFC的认知功能。CAMP开放PFG树突棘上的超极化激活环核苷酸门控(HCN)通道，降低膜电阻，削弱突触传入的作用。随着年龄的增长，PFC内A2AARs减少，cAMP去抑制，HCN通道增多。这项拟议的研究验证了这一假说，即过度的cAMP/HCN信号是PFC认知缺陷的早期衰老过程的基础，并通过削弱突触连接最终导致脊椎丧失。本次研究涉及4个项目、3个核心。项目1将从执行工作记忆任务的年轻猴子和老年猴子身上记录PFC神经元的集合，以测试PFC网络随着年龄的增长而减弱的假设，以及通过离子导入应用抑制cAMP或阻断HCN通道的药物可以增强连接性。项目2将评估衰老大鼠和猴子PFC中可能影响cAMP/HCN信号转导和脊椎丢失的分子变化。该项目还将使用腺病毒转染鼠PFC来测试HCN通道和其他信号蛋白的表达改变是否减缓了与年龄相关的工作记忆和脊柱密度的下降。项目3将从年轻和老年大鼠的PFC神经元集合中进行记录，从而观察电路强度随时间的变化，以响应病毒(项目2)或药物(项目4)操作。项目4将使用电子显微镜观察老化的PFC中NE轴突、A2A-AR和HCN通道的变化，并将测试长期刺激A2A-AR是否会减缓衰老大鼠和猴子的工作记忆损害和脊柱丢失。由于鸟嘌呤可供人类使用，这项研究可以很容易地转化为治疗老年人的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.