Noradrenergic Signaling and Neuroinflammation Crosstalk Regulate Toxoplasma gondii-Induced Behavioral Changes

In the central nervous system (CNS), neuroimmune crosstalk is mediated by neural-cell-derived neurotransmitters and immune cytokines.

CNS infections can induce cognitive alterations with neurotransmitter changes and neuroinflammation. The contribution and interplay of these two pathways are weakly defined. Upon infection, Toxoplasma gondii persists in the CNS, induces behavioral changes, neuroinflammation, and downregulates the neurotransmitter norepinephrine.

Norepinephrine activates noradrenergic signaling in brain glial cells and peripherally recruited immune cells, thereby modulating neuroinflammation.

During chronic T. gondii infection in rodents, we propose that the parasite-induced reduction in norepinephrine results in reduced noradrenergic signaling in CNS immune cells, in turn unleashing proinflammatory mechanisms, which may finally alter cognitive functions.

Infections of the nervous system elicit neuroimmune responses and alter neurotransmission, affecting host neurological functions. Chronic infection with the apicomplexan parasite Toxoplasma correlates with certain neurological disorders in humans and alters behavior in rodents. Here, we propose that the crosstalk between neurotransmission and neuroinflammation may underlie some of these cognitive changes. We discuss how T. gondii infection suppresses noradrenergic signaling and how the restoration of this pathway improves behavioral aberrations, suggesting that altered neurotransmission and neuroimmune responses may act in concert to perturb behavior. This interaction might apply to other infectious agents, such as viruses, that elicit cognitive changes. We hypothesize that neurotransmitter signaling in immune cells can contribute to behavioral changes associated with brain infection, offering opportunities for potential therapeutic targeting.