Integrative Role For Brain Cytokines

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During an acute bout of stress, signs of behavioral activation are frequently displayed that presumably allow the organism to identify and escape the impending threat. However, after the acute threat has passed, it is common to observe delayed and sustained disruptions in normal behavior and reactivity. As a result, there has been the suggestion that behavioral alterations that occur during stressor exposure may be mediated by wholly separate neurobiological entities than the delayed and sustained behavioral alterations (Hennessy et al., 2001). Many of the immediate behavioral consequences of stressor exposure are mediated by the interaction of the sympathetic nervous system (including catecholaminergic cell groups in the brainstem) and extrahypothalamic CRH systems. In contrast, recent data suggest that long-term changes in behavior that are produced by stressor exposure (decreased food and water intake, decreased social and sexual interaction, reduced exploration of novel environments, etc.) may be mediated by factors that are more traditionally associated with the immune system (Maier and Watkins, 1998).

These immune factors are referred to as proinflammatory cytokines and are more commonly acknowledged for their role in coordinating the immune response during times of infection. Activation of the immune system also leads to a characteristic set of behavioral responses that are typically referred to as sickness behaviors (Hart, 1988). For example, immune activation can reduce food and water consumption, decrease sexual behavior, increase slow-wave sleep, decrease locomotor activity, reduce aggressive behavior, and decrease social interaction (see Kent et al., 1992). Interestingly, many of these same behavioral changes are also observed following stressor exposure (Short and Maier, 1993; Milligan et al., 1998). These similarities have led some investigators to postulate that the neural circuitry underlying the behavioral effects of stressor exposure and immune challenge may also be similar.

Many of these behavioral changes observed following immune stimulation are mediated by central production of the proinflammatory cytokine interleukin-1 (IL-1). Central administration of IL-1 produces fever, hyperalgesia (Watkins et al., 1994), induces slow-wave sleep (Opp and Krueger, 1991), reduces food and water intake (Kent et al., 1996), alters peripheral immune function (Sullivan et al., 1997), increases plasma ACTH and glucocorticoids (Dunn, 1995), reduces social interaction (Kent et al., 1992), and decreases some measures of anxiety (Montkowski et al., 1997). Many of the behavioral changes produced by icv administration of IL-1 can be blocked or attenuated by prior icv administration of IL-1 receptor antagonist (IL-1ra) (Opp and Krueger, 1991; Kent et al., 1996). Thus, central production of IL-1 appears to be a critical component of host defense against peripheral infection and subsequent recovery.

In addition to its role in mediating sickness behaviors, central production of IL-1 has also emerged as an important mediator of behavioral and neuroendocrine responses to stress. Shintani et al. (1995) have shown that central injection of IL-1 produced a robust activation of the HPA axis and increased hypothalamic monoamine turnover. These changes are typically considered the hallmarks of stressor exposure. Importantly, IL-1ra has been shown to block the HPA and monoamine response to immobilization stress (Shintani et al., 1995). Central IL-1 has also been implicated in mediating the behavioral consequences of inescapable tail shock since the enhancement of fear conditioning and interference with escape learning produced by this shock experience can also be blocked by icv administration of IL-1ra (Maier and Watkins, 1995). Likewise, a-MSH administered icv blocked all of the acute phaselike changes that have been observed following inescapable tail shock exposure (Milligan et al., 1998). When coupled with the demonstration that exposure to psychological stressors can increase IL-1 production in specific brain regions (Nguyen et al., 2000), it can be concluded that stress-induced production of IL-1 may be critically involved in long-term behavioral and physiological adjustments that are produced by stressor exposure.

This is not to say that all stressors induce central production of IL-1, or that IL-1 mediates all effects of stressors. Indeed, there are some stressors, such as exposure to predators, that do not affect brain cytokine levels at all (e.g., Plata-Salaman et al., 2000). As a result, the critical determinant(s) for the observation of stress-induced increases in brain IL-1 remains elusive and demands further study. These efforts must begin by determination of which stressors cause increases in central cytokine production, and the role that these cytokines play in mediating subsequent behavioral and physiological consequences of stressor exposure.

Implications for Biological Psychiatry. Traditionally, psychological stress and major depression have both been associated with impaired immune function and increased susceptibility to disease. In recent years, however, it has been recognized that exposure to psychological stressors and major depressive episodes are also associated with signs of immune activation [for an excellent review see Connor and Leonard (1998)]. One particularly interesting facet of this immune activation is that circulating levels of proinflammatory cytokines are elevated during times of stress and in clinically depressed populations. Since proinflammatory cytokines normally produce the behavioral and physiological adjustments that occur during sickness, it has been suggested that their release may mitigate some consequences of exposure to psychological stressors and major depressive episodes (Maier and Watkins, 1998). For instance, psychological stressors, depression, and sickness due to infection all produce disturbances in appetite, alterations in normal sleep patterns, reduced social interaction, impaired cognitive function, and psychomotor agitation or impairment (Connor and Leonard, 1998). Moreover, similarities have also been observed between the physiological responses to stressors and major depression. These physiological symptoms include changes in circulating lymphocytes, alterations in plasma levels of acute-phase proteins, persistent fever, elevated plasma cytokines, and hypercortisolemia (Deak et al., 1997; Maes, 1999). As a result of these findings, it has been suggested that activation of the immune system may be etiologically related to depressive illness in certain prone individuals.

The key element we are emphasizing here is that in some cases, exposure to psychological stressors alone (i.e., in the absence of any apparent tissue damage or pathogenic insult) is capable of inducing proinflammatory cytokine production. Furthermore, cytokine production in response to stress appears to be important for at least some of the long-term changes in behavior that are normally produced by that stressor, especially those that resemble depressive or despairlike behaviors (Hennessy et al., 2001). Thus, stressor-induced proinflammatory cytokine production may represent a novel mechanism underlying certain human psychiatric illnesses. This new conceptualization raises a whole host of empirical questions regarding the possible role of infection as a precipitating event in the onset of major psychiatric illness, especially if such a challenge were to occur during critical developmental periods.

In summary, while we have tried to emphasize the preeminent role of stress and its far-reaching implications for biological psychiatry, we have also tried to emphasize stress responsive systems are not restricted to a single neural pathway, a single neuro-chemical system, or even to the central nervous system itself. Rather, stress responsive systems—upon activation—have the ability to alter molecular, cellular, and systemic processes across the entire organism. Indeed, stress affects everything an organism does. In the following two sections, we will briefly focus on two systems that are especially stress responsive, sexuality and sleep. However, our aim is not simply to focus on the fact that both are greatly impaired by stress (that is true of all motivational systems) but to briefly discuss key aspects of the physiology of these systems.

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