טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentBen-Shaanan Tamar
SubjectReward System Regulation of Immunity
DepartmentDepartment of Medicine
Supervisor Professor Asya Rolls
Full Thesis textFull thesis text - English Version


Abstract

Psychological and emotional factors, such as stress, have been shown to modulate the activity of the immune system. However, it remains largely unknown whether and how positive emotions can also affect immunity. In this study, we tested whether reward system activation, a neuronal network associated with positive emotions and expectations, can affect the activity of the immune system. To test this, we designed a new experimental platform that combines targeted neuronal manipulation with analysis of peripheral immunological responses.

We used ‘designer receptors exclusively activated by designer drugs’ (DREADDs) in mice to directly activate the dopaminergic neurons in the ventral tegmental area (VTA). The VTA is a key component of the brain’s reward system, associated mostly with reward, positive expectation and motivation. DREADDs-induced VTA activation strengthens the immunological host defense against bacterial infection, revealing a causal relationship between the activity of the reward system and enhanced antibacterial immunity. Specifically, we found an increase in the antibacterial activity of monocytes and macrophages, and a heightened immune response in the mouse model of delayed-type hypersensitivity (DTH). The findings describing the effects of reward system activation on anti-bacterial immunity were published in Nature Medicine on July 2016.

Emotional and psychological factors have been shown to affect cancer survival. Thus, we hypothesized that activation of mood-regulating neuronal circuits, such as the reward system, would not only enhance antibacterial immunity but could also affect cancer progression. We found that daily activation of the reward system in tumor-bearing mice (Louis Lung carcinoma; LLC), resulted in a 52% ± 15.1% reduction in tumor weight. In addition, we found functional changes in myeloid-derived suppressor cells (MDSCs), specifically, elevated levels of TNF expression and reduced ability to suppress T cell proliferation. Finally, using an adoptive transfer experiment we demonstrated the sufficiency of MDSCs to recapitulate the effects of reward system activation on tumor growth. The manuscript describing these findings currently is under review (Ben-Shaanan TL & Schiller M et al, Nature Communication).

The effects of the reward system on peripheral immunity must be mediated by descending neuro-immune pathways, as dopamine from the VTA does not cross the blood-brain barrier (BBB). The sympathetic nervous system (SNS) anatomically connects the CNS with all major internal organs, including lymphoid organs, and is known to be affected by activation of the reward system. We found that the effects of reward system activation on antibacterial and anticancer immunity were dependent on the sympathetic nervous system (SNS). Chemical sympathetic ablation blocked the effects of reward system activation on both antibacterial and anticancer immunity. In addition, we show that repeated reward system activation in tumor-bearing mice reduced noradrenergic input to the bone marrow, and that MDSCs can be functionally manipulated by adrenergic stimulation. 

Taken together, this project establishes, for the first time, a causal relationship between the activity of the reward system and regulation of the immune system. Given the central role the reward system has in emotional processes, our findings provide evidence of a mechanism enabling mental and emotional states to regulate peripheral immunity.