Nicotinic modulation of brain physiology and cognition in human aging

• Applicant: Min-Fang Kuo, Ph.D.
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 416397042

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.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Michael A. Nitsche