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Fig. 9 | Journal of Neuroinflammation

Fig. 9

From: Peripheral and central compensatory mechanisms for impaired vagus nerve function during peripheral immune activation

Fig. 9

CNS (central nervous system), NTS (nucleus tractus solitarii), HPT (hypothalamus), PTG (pituitary gland), ADC (adrenal cortex), BBB (blood-brain barrier), CVO (circumventricular organs), GLU (glutamate), GABA (gamma-aminobutric acid), PGE2 (prostaglandin E2), Ach (acetylcholine), GCs (corticosteroids), IL-1β (interleukin 1β), IL-6 (interleukin 6), TNF-α (tumor necrosis factor α), upwards arrow (increase/green), downwards arrow (decrease/red), solid lines (afferent signaling), dotted lines (efferent signaling), gray lines (inactive pathways), black lines (active pathways). At physiological conditions (a), afferent vagal signaling provides an appropriate level of stimulating GLU within the NTS [81]. In the case of peripheral inflammation (b), the afferent of the vagus nerve is stimulated among others by IL-1β, that activating COX-2 and PGE2 synthesis in the presynaptic terminals of this fibers in within the NTS [5, 64]. PGE2 secreted by the vagus nerve stimulates other neurons in the NTS to secrete additional portions of GLU. This mechanism permits quick “detection” of peripheral inflammation and rapid “launching” of the HPA axis. This signal is also transmitted to the other CNS structures, resulting in specific changes in activity of neurotransmission systems, which, while remaining physiologically balanced, allows for a correct central reaction to the inflammation development. When inflammatory mediators reach the brain via the bloodstream (c), they stimulate vascular endothelial cells, tissue macrophages, and glial cells in the brain to release PGE2, which stimulates NTS cells to release GLU [84]. Glutamatergic information from the vagus nerve becomes unnecessary and could threaten to overstimulate (glutamate excitotoxicity, [97]), which is why it is limited by PGE2 acting on the EP3 receptors on the presynaptic membrane of the afferent endings of the vagus nerve [83]. It is possible that when afferent vagal signaling is absent (d), GLU concentration in the NTS may be chronically decreased. This could lead to disturbances in the functioning of major neurotransmitter systems. As demonstrated in our experiment, in some brain areas, serotonergic activity decreased. There was also a strong increase in extracellular dopamine metabolism likely secondary to a lack of glutamatergic stimulation of inhibitory GABAergic neurons. It is also possible that brain releases additional portions of the neurotransmitter (dopamine) into the synaptic cleft, to maintain the neural activity at an appropriate, physiological level, thus compensating for the insufficient level of GLU in NTS. Under such conditions, when infection appears in the periphery (e), limited sensory and immunosuppressive functions of the vagus nerve renders delayed detection of the infection. This may lead to the aforementioned significant increase in PGE2 in blood plasma. The inflammatory signal is transferred to the brain through the BBB and CVO (f) causing an increase in the GLU content in NTS, and then an apparent “normalization” of the neurotransmitter activity of the limbic system areas. The HPA axis is also activated. This model is supported by fact that PGE2 is necessary to cholinergic anti-inflammatory pathway functioning [98]

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