In aggression neuroimmune responses get altered due to a variety of pro- and anti-inflammatory cytokines production where levels of IL-2, interleukin (IL)-1β, C-reactive protein, interferon (IFN) γ, IL-6 are increased with higher human’s aggressive traits and anger levels. Therefore, increased production of cytokines and immune responsiveness is correlated with aggressive behavior.
Animal studies also showed brain area changes and variations in peripheral cytokine levels lead to stress-induced aggression. Indeed, in rodents different behavior towards aggression and pro-inflammatory cytokines production can be observed. For example, aggressive behavior was abrogated in knockout of both TNFα-receptor-1 and TNFα-receptor-2, whereas shorter attack was observed in IL-6 knockout mice but frequency of aggressive behaviors increased.
The direct link between cytokines and aggression is now well established, but still different regional brain cytokine changes are still unknown. Scientists at Federal State Budgetary Scientific Institution “Scientific Research Institute of Physiology and Basic Medicine: Dr. Elizaveta Alperina, Dr. Galina Idova, Dr. Elena Zhukova, Dr. Svetlana Zhanaeva, and Rimma Kozhemyakina analyzed brain structure cytokine variations in rats who have genetic predisposition to fear-induced aggression or its absence. The research work is now published in journal, Neuroscience Letters.
The authors observed higher levels of IL1-β and IL-6 in frontal cortex in aggressive than non-aggressive rats, whereas in hippocampous aggressive rats showed decreased levels of IL-1β, IL-6, as well as IL-2. In striatum and frontal cortex level of IL-2 was increased then non-aggressive rats. By LPS stimulation cytokine level increased above baseline levels in both aggressive and nonaggressive rats, but the time pattern, cytokine changes were observed. IL-1β and IL-6 was in the hypothalamus of aggressive rats at 4 h compared to the low-aggressive rats. Hypothalamic levels of IL-2 difference were not noticeable in highly aggressive and nonaggressive rats, observed after 24 h after LPS administration.
The authors observed that LPS stimulation increased cytokine activity above baseline levels in both aggressive and nonaggressive rats, but the pattern, time course of cytokine changes, and their regional characteristics varied according to the animal aggressiveness. After LPS administration, aggressive rats showed increased levels of IL-1β in the hypothalamus at 2 and 4 h and in the frontal cortex at 4 and 24 h compared to LPS-treated nonaggressive line. IL-2 was increased in the frontal cortex and striatum of aggressive rats within 24 h, while IL-6 elevation in the hypothalamus was found at 4 h and in the frontal cortex at 2 and 4 h. In the hippocampus, the levels of IL-1β, IL-2, and IL-6 were lower in LPS-treated aggressive rats than in nonaggressive animals.
The levels of anti-inflammatory cytokine IL- 10 were also decreased in all brain structures of aggressive rats receiving LPS. The effects of proinflammatory cytokines are moderated by anti-inflammatory factors, such as IL-10, which is involved in the regulation of immune responses and suppression of inflammation in the peripheral immune system and in the brain cytokine network.
Collectively, their study showed that in rodents cytokine variations depends on brain area with genetic predisposition to high aggressiveness, and location of cytokines and differ over time. Aggressive rats after LPS administration, hypothalamus levels of IL-1β increased at 2 and 4 h and in the frontal cortex at 4 and 24 h compared to LPS-treated nonaggressive line. Levels of IL-2, IL-1β, and IL-6 were decreased in LPS-treated aggressive rats than in nonaggressive animals in the hippocampus, the anti-inflammatory cytokine IL-10 level was also reduced in aggressive rats brain structure who were administered LPS.
Time dependent changes in LPS have been induced in BBI transport of some chemokines and cytokines including MCP-1.
LPS effects are mediated through binding to toll-like receptors 4 (TLR4), a family of important pattern-recognition receptors in the innate immune system. TLR4 receptors are highly expressed in brain microglia, and are also known to be implicated in affective and motivational behaviors. The dysfunction of TLR genes (TLR-2, TLR-3, or TLR-4) in knock-out mice may contribute to the development of abnormal and aggressive behaviors.
Highly aggressive rats showed decreased anti-inflammatory response and decreased levels of IL-10 in nonaggressive animals. By contrast, long-term experience in social confrontations increased
The authors concluded that genetic predisposition is associated with increased aggression related to time and region-dependent changes in the pro- and anti-inflammatory cytokines levels.
The authors concluded that genetic predisposition to increased aggressiveness is associated with time- and region- dependent changes in the pro- and anti-inflammatory cytokines levels.
It will be interesting to find if similar pattern of cytokines levels and regional changes occur in larger animals (non-human primates) and humans. The study also may help in understanding better the pathology of aggression in patients.
Alperina, E., Idova, G., Zhukova, E., Zhanaeva, S., & Kozhemyakina, R. (2019). Cytokine variations within brain structures in rats selected for differences in aggression. Neuroscience Letters. Volume 692, Pages 193-198.Go To Neuroscience Letters