Positive expectations contribute to the clinical benefits of the placebo effect. Such positive expectations are mediated by the brain's reward system; however, it remains unknown whether and how reward system activation affects the body's physiology and, specifically, immunity. Here we show that activation of the ventral tegmental area (VTA), a key component of the reward system, strengthens immunological host defense. We used 'designer receptors exclusively activated by designer drugs' (DREADDs) to directly activate dopaminergic neurons in the mouse VTA and characterized the subsequent immune response after exposure to bacteria (Escherichia coli), using time-of-flight mass cytometry (CyTOF) and functional assays. We found an increase in innate and adaptive immune responses that were manifested by enhanced antibacterial activity of monocytes and macrophages, reduced in vivo bacterial load and a heightened T cell response in the mouse model of delayed-type hypersensitivity. By chemically ablating the sympathetic nervous system (SNS), we showed that the reward system's effects on immunity are, at least partly, mediated by the SNS. Thus, our findings establish a causal relationship between the activity of the VTA and the immune response to bacterial infection.

Based on growing findings of brain volume loss and deleterious white matter alterations during the chronic stages of injury, researchers posit that moderate-severe traumatic brain injury (TBI) may act to “age” the brain by reducing reserve capacity and inducing neurodegeneration. Evidence that these changes correlate with poorer cognitive and functional outcomes corroborates this progressive characterization of chronic TBI. Borrowing from a framework developed to explain cognitive aging (Mahncke et al., Progress in Brain Research, 157, 81–109, 2006a; Mahncke et al., Proceedings of the National Academy of Sciences of the United States of America, 103(33), 12523–12528, 2006b), we suggest here that environmental factors (specifically environmental impoverishment and cognitive disuse) contribute to a downward spiral of negative neuroplastic change that may modulate the brain changes described above. In this context, we review new literature supporting the original aging framework, and its extrapolation to chronic TBI. We conclude that negative neuroplasticity may be one of the mechanisms underlying cognitive and neural decline in chronic TBI, but that there are a number of points of intervention that would permit mitigation of this decline and better long-term clinical outcomes.