Stress, the Autonomic Nervous System, and the Immune-kynurenine Pathway in the Etiology of Depression

Abstract

The autonomic nervous system is one of the major neural pathways activated by stress. In situations that are often associated with chronic stress, such as major depressive disorder, the sympathetic nervous system can be continuously activated without the normal counteraction of the parasympathetic nervous system. As a result, the immune system can be activated with increased levels of proinflammatory cytokines. These inflammatory conditions have been repeatedly observed in depression. In the search for the mechanism by which the immune system might contribute to depression, the enhanced activity of indoleamine 2,3- dioxygenase by pro-inflammatory cytokines has been suggested to play an important role. Indoleamine 2,3-dioxygenase is the first enzyme in the kynurenine pathway that converts tryptophan to kynurenine. Elevated activity of this enzyme can cause imbalances in downstream kynurenine metabolites. This imbalance can induce neurotoxic changes in the brain and create a vulnerable glial-neuronal network, which may render the brain susceptible to depression. This review focuses on the interaction between stress, the autonomic nervous system and the immune system which can cause imbalances in the kynurenine pathway, which may ultimately lead to major depressive disorder.

Fig. (1)

The interaction between stress, the autonomic nervous system, the immune system and the kynurenine pathway in the etiology of depression. The hypothalamus secretes CRH in response to stress, and from the paraventricular nucleus of the hypothalamus, CRH-containing neurons have projections to the locus coeruleus. The locus coeruleus sends direct projections to the sympathetic and parasympathetic preganglionic neurons, increasing sympathetic activity and decreasing parasympathetic activity through the activation of adrenoceptors. In turn, the activation of the sympathetic nervous system stimulates the release of CRH. When stress is prolonged, as in major depressive disorder, the sympathetic nervous system continues to be activated, with a lack of parasympathetic counter activity. As a result, NE and E levels are increased and ACh levels are decreased, which lead to an increased release of pro-inflammatory cytokines from immune cells. Pro-inflammatory cytokines, such as TNF, IL-1, IL-6 and interferons can induce IDO activity, which increases the KYN/tryptophan ratio. As a result, downstream metabolites, such as 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid are increased, which all have neurotoxic effects on the brain. 3-hydroxykynurenine generates free-radicals and causes neuronal apoptosis. 3-hydroxyanthranilic acid generates highly reactive hydrogen peroxide and hydroxyl radicals. Quinolinic acid selectively activates N-methyl-d-aspartate (NMDA) receptors, and high concentrations of extracellular glutamate and persistent activation of excitatory neurons cause excitotoxicity. Therefore, the accumulation of quinolinic acid can result in neuronal excitotoxicity and the selective apoptosis of astrocytes. This can ultimately lead to neurodegenerative changes, which may render the brain susceptible to depression.

Fig. (2)

IDO and kynurenine monooxygenase activity are enhanced by pro-inflammatory cytokines, and as a result the balance between the formation of 3-hydroxykynurenine and of kynurenic acid is shifted to the side of 3-hydroxykynurenine, which forms 3-hydroxyanthranilic acid and finally quinolinic acid. As KYN synthesized in the periphery can also penetrate the brain, KYN pathway metabolism in the brain is also initiated by KYN that crosses the blood brain barrier. KYN and 3-hydroxykynurenine easily cross the BBB, whereas quinolinic acid and kynurenic acid crosses the BBB poorly. The 3-hydroxykynurenine arm of the pathway leading to quinolinic acid production takes place in microglia, and kynurenic acid production takes place in astrocytes. The KYN pathway in the microglia can be enhanced in inflammatory conditions, as kynurenine monooxygenase activity is enhanced by pro-inflammatory cytokines. Immune responses can also activate microglia and cause an influx of macrophages into the brain, which causes a significant increase in quinolinic acid synthesis.