Nicotinic modulation of brain physiology and cognition in human aging

胆碱能系统调节神经可塑性和广泛的认知行为功能，包括感知，注意力，学习和记忆，最有可能通过增强神经元网络中的信噪比。胆碱能神经传递的中断导致认知性能恶化，这在尼古丁成瘾、与神经变性相关的痴呆以及正常衰老中观察到。特别是烟碱受体亚型在认知相关的脑生理学中发挥相关作用。因此，烟碱剂已显示在烟碱受体低活化的情况下，例如在尼古丁戒断的吸烟者中，恢复可塑性和认知障碍。尼古丁还显示了老年受试者的认知益处。然而，关于烟碱受体对这些功能的贡献以及各自的生理机制的详细知识很少。我们将研究烟碱受体激活对年轻/老年和吸烟者/非吸烟者的神经可塑性和认知功能的具体影响，并探讨假设的状态依赖性效应差异的神经生理学机制，包括假设的保护/恢复影响。将在年轻和老年健康人中诱导神经可塑性，包括吸烟和非吸烟受试者。由于尼古丁对可塑性和认知功能的影响似乎主要是由具有钙通道特性的尼古丁受体驱动的，因此伐尼克兰（一种尼古丁α4β2和α7激动剂）将用于研究尼古丁对神经可塑性的调节。我们将进一步阐明生理可塑性和行为表现之间的关联，特别关注网络连接，建议反映在神经生理水平上的学习和记忆过程的动态。运动学习任务将通过监测和修改与任务相关的脑振荡和连接来实现。烟碱能对皮层可塑性、网络连接和认知的影响将被关联起来，以获得关于烟碱调节对认知的神经生理学基础的系统知识。更好地理解年龄相关的烟碱对人脑认知和神经生理的调节机制将有助于开发更有效的策略来预防或恢复衰老引起的功能衰退。

The cholinergic system regulates neuroplasticity and a broad range of cognitive-behavioural functions including perception, attention, learning, and memory, most probably via enhancing the signal-to-noise ration in neuronal networks. Disruption to cholinergic neurotransmission results in cognitive performance deterioration, which is observed in nicotine addiction, dementia related to neurodegeneration, but also in normal aging. Especially nicotinic receptor subtypes play a relevant role in cognition-relevant brain physiology. Accordingly, nicotinic agents have been shown to restore plasticity and cognitive impairment in case of nicotininc receptor hypo-activation, such as in smokers under nicotine withdrawal. Nicotine also revealed cognitive benefits in old subjects. Detailed knowledge however about the contribution of nicotinic receptors to these functions, and respective physiological mechanisms is scarce. We will investigate the specific impact of nicotinic receptor activation on neuroplasticity and cognitive functions in young/old age and smokers/non-smokers, and to explore the neurophysiological mechanism underlying hypothesized state-dependent differences of effects, including a presumed protective/restituting impact. Neuroplasticity will be induced in young and old healthy humans including both, smoking and non-smoking subjects. Since the impact of nicotine on plasticity and cognitive functions seems to be largely driven by nicotinic receptors with calcium channel properties, varenicline, a nicotinic α4β2 and α7 agonist will be applied to study nicotinergic modulation of neuroplasticity. We will further elucidate the association between physiological plasticity and behavioral performance, with particular focus on network connectivity which is suggested to reflect the dynamics of learning and memory processes at the neurophysiological level. Motor learning task will be implemented with monitoring and modifying task-related brain oscillations and connectivities. The nicotinergic effect on cortical plasticity, network connectivity, and cognition will be correlated to obtain systemic knowledge about the neueophysiological basis of nicotinic modulation on cognition. A better understanding of the mechanisms underlying age-related nicotinic modulation on both cognition and neurophysiology of human brain will help to develop more effective strategy for the prevention or restitution of functional decline caused by senescence.