Increased parasympathetic tone slows cognitive decline: defining the pathway

Abstract

By 2050 life spans in both the UK and Brazil are predicted to reach 85-90 years. This brings challenges of increased burden of age-related ill-health, especially from neurodegenerative conditions which require long-term care. A sedentary(lifestyle impairs cognitive development in early life(and is associated with cognitive(decline in later life. By contrast, maintenance of(physical activity confers long-term, neuro-protective benefits. The autonomic nervous system is responsible for unconscious regulation of the body's internal environment by modulating the activities of its sympathetic and parasympathetic branches. The presence of autonomic dysfunction in all common sub-types of dementia is well established. We are currently conducting a long-term study aimed to establish a link between autonomic (parasympathetic) function, longevity and cognition in an animal model. Recently, we have shown that ability to exercise is critically dependent on the activity of the parasympathetic outflow. This is mediated by preganglionic cholinergic neurons located within the dorsal motor nucleus of the vagus nerve (DMNX). We hypothesize that the benefit is derived from the ability to maintain exercise capacity, which confers benefits including suppression of pro-inflammatory mechanisms, increased autophagy and/or improved cerebral perfusion. Two research groups, one from the University College of London, UCL (Center for Cardiovascular and Metabolic Neuroscience - Patrick Hosford) and other from the University of São Paulo, USP (Laboratory of Neural Control of Circulation - Vagner R. Antunes) are running a collaborative project investigating the effect of DMNX function on longevity. In 2017 a FAPESP Research Mobility Award enabled us to expand the current scope of the originally designed study. By the time, mice have been transduced at 4-6 weeks of age with 2 viral constructs in order to control DMNX group of cells that generate vagal tone, using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) technology to increase DMNX neuronal activity for 12 months before exercise capacity and cognitive testing was performed. This approach allows chronic activation of central parasympathetic outflow, which was tested on exercise capacity and cognition during aging experiments by performing cognitive assessment test, and exercise capacity. At the next step of the proposed project we are going to perform a series of experiments to directly test the hypothesis that exercise is enabled to increase parasympathetic tone leading to suppression of pro-inflammatory mechanisms, increased autophagy and/or improved cerebral perfusion. The following series of experiments will be tested: 1) To determine whether, the effects described above caused by increasing parasympathetic tone are maintained over the entire life-span of the animal; 2) To determine the effects of parasympathetic tone and aging on brain blood flow; 3) To determine the effects of parasympathetic tone and aging on inflammatory and autophagy markers. The experimental approach to be conduct will be: i) Exercise capacity and cognition: forced exercise capacity and cognition will be re-assessed as in all animals; ii) Brain blood flow, which will be assessed using brain tissue PO2 to be monitored by fluorescence method (Oxylite); iii) Markers of inflammation and autophagy: tissues will be collected from all groups of mice and preserved for shipment back to the UK for assessment of inflammatory markers HMGB-1 and NLRP3 by western blot analysis. Autophagy will be assessed by measurement of LC3 protein as it is the most widely monitored autophagy-related protein. This series of experiments will generate data adding further support to the concept that autonomic mechanisms confer joint benefits of cardiovascular and cognitive health in ageing. (AU)