The long-term goal of our laboratory is to identify the neural circuitry and neurochemical and neurophysiological mechanisms that underlie the expression and control of rage and aggressive behavior. The primary focus of the present grant application, which represents a major new direction in our research program, is to identify and characterize the roles of serotonin and cytokines in the medial hypothalamus in regulating these forms of aggression. This rationale for this application is based upon our most recent preliminary studies. They provide evidence that, in the medial hypothalamus, 5-HT1A and 5-HT2 receptors and cytokines, IL-lbeta and IL-2, powerfully modulate defensive rage behavior in the cat. The overarching hypothesis is that differential cytokine effects upon defensive rage and predatory attack are mediated principally through distinct neurotransmitter receptors of which serotonin and possibly GABA are primary candidates. Five experiments are proposed to test this hypothesis. The first will utilize immunocytochemical and neuroanatomical methods to characterize the pathway from the PAG to the medial hypothalamus mediating defensive rage and its relationship to serotonin axons and pre-terminals in this region. The second experiment will determine the effects of 5-HT1A and 5-HT2 receptors in the medial hypothalamus upon defensive rage. The third experiment will determine: the role of IL-1beta in the medial hypothalamus upon defensive rage, its relationship to 5-HT2 receptors, the distribution of IL-1R in this region and its relationship to serotonin axons and pre-terminals as well as to c-Fos labeled neurons following the expression of defensive rage. The fourth experiment will seek to determine the role of IL-2 in the medial hypothalamus upon defensive rage and their underlying neurotransmitter-receptor mechanism. The fifth experiment will identify the effects of activation of 5-HT and the above cytokines upon predatory attack behavior. The discovery that cytokines in the brain play a significant role in defensive rage represents a most significant observation. It has provided an entirely new direction of research - a direction in which the focus will address how cytokines and related substances in the brain may play critical roles in the expression and control of aggression and rage. By identifying the mechanisms underlying these effects, the proposed studies are of further significance because the strategies utilized here can now be applied for the study of how cytokines in the brain may regulate other behavioral processes.
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| Bhatt, Suresh; Bhatt, Rekha; Zalcman, Steven S et al. (2008) Role of IL-1 beta and 5-HT2 receptors in midbrain periaqueductal gray (PAG) in potentiating defensive rage behavior in cat. Brain Behav Immun 22:224-33 |
