The role of noradrenaline receptors in working memory processes of the prefrontal cortex

工作记忆是一种用于临时存储和操作信息的大脑系统，对各种认知操作（如推理、计划和解决问题）至关重要。众所周知，前额叶皮层背外侧区域与工作记忆有关，但其神经化学基础尚不清楚。最近，去甲肾上腺素及其在PFC背外侧的α _2-肾上腺素能受体与工作记忆有关，但缺乏直接或重要的证据支持这一假设。为了解决这个问题，我们在猴子身上进行了一系列的研究；1)脑内显微注射去甲肾上腺素拮抗剂与动眼肌延迟反应（ODR）任务相结合的研究；2)去甲肾上腺素离子电泳分析与ODR任务中单神经元记录相结合的研究。ODR任务对工作记忆很敏感，PFC神经元的一个子集表现出定向延迟期活动，这代表了视觉空间工作记忆过程的“记忆……更多领域”。在本研究中，我们发现1)局部注射育亨宾（一种α _2-肾上腺素受体拮抗剂）到左外侧PFC可引起特异性的ODR功能缺陷，而α _1-肾上腺素受体拮抗剂普拉唑嗪或β -肾上腺素受体拮抗剂普萘洛尔没有明显的作用；2)使用育亨宾，而不是哌唑嗪或心得安，可以显著减弱PFC神经元在ODR表现中的定向延迟期活性。这些发现首次提供了重要而直接的证据，证明了alpha_2-肾上腺素能受体参与了背外侧PFC介导的工作记忆过程。研究表明，维持/促进工作记忆过程中的神经元活动需要充分激活背外侧PFC中的alpha_2-肾上腺素能受体；如果没有这样的激活，工作记忆就会减弱或丢失，需要这种认知功能的行为任务就会表现不佳。由于PFC中alpha_2-肾上腺素能受体的功能障碍在伴随精神障碍（如精神分裂症和Korsakoff失忆症）以及衰老的工作记忆缺陷中是明显的，因此目前的数据可能有助于在细胞水平上理解与此类精神障碍和衰老相关的认知缺陷/下降。少

Working memory is a brain system for the temporary storage and manipulation of information, and is critical for various cognitive operations, such as reasoning, planning and problem-solving. Whereas it is well known that dorsolateral regions of the prefrontal cortex (PFC) are involved in working memory, its neurochemical basis is poorly understood yet. Recently, noradrenaline and its alpha_2-adrenergic receptors in the dorsolateral PFC have been implicated in working memory, but direct or significant evidence on this hypothesis is lacking.To address this problem, we have performed a series of study in monkeys ; 1) studies combining intracerebral microinjections of noradrenaline antagonists with an oculomotor delayd-response (ODR) task, and 2) studies combining iontophoretic analysis of noradrenaline with single-neuron recording during the ODR task. The ODR task is sensitive to working memory, and a subset of PFC neurons show directional delay-period activity which represents a "memory … More filed" for visuospatial working memory processes.In the present studies, we found that 1) local injections of yohimbine, an alpha_2-adrenergic receptor antagonist, into the dor S olateral PFC induced a specific deficit on ODR performance, whereas alpha_1-adrenergic receptor anatagonist prazosin or beta-adrenergic receptor anatagonist propranolol did not have any clear effect ; and 2) iontophoretic applications of yohimbine, but not prazosin or propranolol, attenuated significantly and preferentially directional delay-period activity in PFC neurons during ODR performance.These findings are first to provide significant and direct evidence on the involvement of alpha_2-adrenergic receptors in working memory processes mediated by the dorsolateral PFC.Sufficient/adequate activation of alpha_2-adrenergic receptors in the dorsolateral PFC are suggested to be required for maintaining/facilitating neuronal activities for working memory processes ; without such an activation, working memory is attenuated or lost and behavioral tasks requiring this cognitive function are poorly performed. Since dysfunction of alpha_2-adrenergic receptors in the PFC is evident in working memory deficits which accompany some mental disorders, such as schizophrenia and Korsakoff's amnesia, as well as aging, the present data may be useful for understanding, at the cellular level, cognitive deficits/declines associated with such mental disorders and aging. Less