Cytokine variations within brain structures in rats selected for differences in aggression

Significance 

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.

Cytokine variations within brain structures in rats selected for differences in aggression-Medicine Innovates

About the author

Dr. Elizaveta Alperina, is currently a Major Researcher in the Department of Experimantal and Clinical Neuroscience at the Institute of Physiology and Basic Medicine, Novosibirsk (Russia). After graduation from the State Medical Institute in Novosibirsk, she began working in the Laboratory of the Mechanisms of Neurochemical Modulation in the Institute of Physiology, Siberian Branch of the Russian Academy of Medical Sciences, where she received her Ph.D. (1983) and Doctoral (1999) Degrees.

Her early research interests included neurochemical mechanisms of immunomodulation, with a focus on the contribution of brain serotonin and dopamine neuromediator systems and their receptors in the immune response control in animal models of different psychoemotional states (anxiety, depression, aggression), and the search of immunoinflammatory markers implicated in the neurobiology of stress-induced or genetically defined forms of behavior.

Her current research, conducted in A1 Clinic of the Institute of Physiology and Basic Medicine, is focused on the role of neuroinflammatory processes in the pathogenesis of neuropsychiatric disorders, such as Parkinson’s disease and major depression, with the aim to reveal new strategies to target and prevent immunologic contributions to disease development. Dr. Alperina is author/coauthor of over 200 scientific peer reviewed publications, the majority of which in leading journals, such as “Brain Research”, “Brain, Behavior and Immunity”, “Neuroscience Letters”, “Immunopharmacology”.

About the author

Galina Idova, Doctor of Biological Sciences, Professor. She graduated from Novosibirsk State University in 1967 and started working as a postgraduate student in the Laboratory of the Mechanisms of Neurochemical Modulation in the Institute of Physiology, Siberian Branch of the Russian Academy of Medical Sciences, Novosibirsk (Russia). In this Institute, she received a Ph.D. (1973) and doctoral (1994) degrees. For more than 20 years Galina Idova headed the Laboratory of the Mechanisms of Neurochemical Modulation. One of her main research areas involved studding the roles of brain neurotransmitter systems (serotonin-, dopamine- and GABAergic) in the immune response control, central receptor and cellular mechanisms of their action on immunity; the analysis of neuroimmune interactions in stress-induced and genetic models of depressive and aggressive behaviors.

Dr. Idova is currently a Major Researcher in the Laboratory of affective, and translational neuroscience sector of psychoneuroimmunology (sector of psychoneuroimmunology), Institute of Physiology and Basic Medicine (Novosibirsk) and a Professor of the Department of Physiology in Novosibirsk State University, where she reads lectures on psychoneuroimmunology.

Her current experimental and clinical research aims to elucidate the most informative peripheral immune markers of T- and B-cell subpopulations, monocytes, Toll-like receptor expression on these cells, production of pro-inflammatory and anti- inflammatory cytokines, which can determine a risk of the development of Parkinson’s disease. This investigation is supported from Russian Foundation of Basic Research. Dr. Idova is the author/coauthor of more than 300 scientific works and books.

About the author

Elena Zhukova, Ph.D., is currently a senior researcher at the Institute of Physiology and Basic Medicine, Novosibirsk (Russia). After graduation  from  Novosibirsk State University she started her postgraduate courses in the Laboratory of the Mechanisms of Neurochemical Modulation in the Institute of Physiology, Siberian Branch of the Russian Academy of Medical Sciences, where she received her Ph.D. in 2003. She explored the role of central serotonin (5-HT1A) and dopamine (D1, D2) receptors in neuroimmunomodulation using animal models of social conflict stress and immune reactivity analysis approach.

Her recent studies uncovered a link between altered immune function, including peripheral and brain cytokine variations and genetic differences in aggression, as well as differential contribution of 5-HT2A receptors in immunomodulation in animals demonstrating defensive or offensive types of aggressive behavior. Dr. Zhukova is author/coauthor of over 40 scientific peer reviewed publications.

About the author

Svetlana Zhanaeva, PhD., is currently a leading researcher in the Laboratory of affective, and translational neuroscience (sector of psychoneuroimmunology), Institute of Physiology and Basic Medicine (Novosibirsk, Russia). She graduated from Novosibirsk State University and took postgraduate courses in the Institute of Clinical and Experimental Lymphology, Siberian Branch of the Russian Academy of Medical Sciences, where she received her Ph.D. in 2000. After few years, she joined Institute of Physiology and Basic Medicine, and worked on the involvement of lysosomal proteases in cancer malignancy and progression, tumor sensitivity for chemotherapy and efficiency of treatment. Her current interest concerns neuroimunological and neurochemical processes in neurodegenerative and physic disorders. Dr. Zhanaeva is author/coauthor of over 70 scientific peer reviewed publications.

About the author

Rimma Kozhemyakina is currently a junior researcher in the Laboratory of Evolutionary Genetics, Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Medical Sciences (Novosibirsk, Russia). She took an active part in breeding rats that have been selected to either reduced aggressiveness or increased social tolerance to both humans and members of their own species or increased aggressiveness.

Her scientific research aims to get better insight in the genetic basis underlying the phenotypic changes, neurochemical and neuroendocrinal mechanisms responsible for the manifestation of aggression and tameness. Her recent study has shown a significant role of oxytocinergic system in contrasting behaviors formed in the process of selection by reaction to humans. She is a coauthor of over 30 scientific peer reviewed publications in leading journals.

Reference

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.

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