Cytokines and Brain Signaling

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Table of Contents

Cytokine Signals access in the brain
The Dantzer’s Motivational Model of Sickness Behavior
The Motivational Competition between Motivational States for Behavioral Output
References

Sickness behavior refers to non-specific adaptive response of the innate immune system and is an expression of a central motivational state (Dantzer and Kelly, 2007; Aubert at al., 1997). Thus, cytokine induced sickness behavior refers to a motivational state that belongs to the realm of physiology, similar to other motivational states, such as fear or hunger (Dantzer and Kelly, 2007).

Withdrawing from the environment to seek rest and care for the body is as normal in response to infectious agents as being able to shift to a state of increased arousal and readiness for action when confronted with a potential external threat. Sickness behavior refers to an adaptive response of the host to infectious microorganisms. In theory, cytokines released in response to infection or inflammation alert the brain of any real or potential threats and initiate behaviors that are important for survival (Frink et al, 2009).

The result of a hyperactive proinflammatory state marked by excess production of proinflammatory cytokines may contribute to the pathogenesis of various human diseases such as allergy, autoimmunity, obesity, depression and atherosclerosis (Sternberg, 2006). Some even refer to the ability of the immune system to alert or communicate with the brain as a “sixth sense” (Blalock & Smith, 2007). Sickness behavior is adaptive in that it forces an individual to rest and withdraw from activities so that physiological processes can effectively produce healing (Blalock & Smith, 2007; Kelley, Dantzer, Zhou, Shen, Jhonson & Broussard, 2003).

However, sickness behavior is no longer adaptive if it goes beyond the organism’s resources and/or out of proportion with the triggering contributory factors that initiated the adaptive response. This is prevalent during a variety of chronic inflammatory diseases (Dantzer and Kelly, 2007).

Proinflammatory cytokines released during infection, inflammation, injury and even psychological stress can signal the brain to initiate behavioral changes that facilitate adaptation to these threats. Cytokine-to-brain signaling leads to mood disorders, particularly depression that accompanies the illness (Dantzer, 2009: Dantzer et al, 2008). Cytokines signal the brain to induce sickness behaviors through neural, hormonal, and cellular pathways (Capuron and Miller, 2011).

Therefore, the purpose of this paper is to describe how cytokines signal access the brain, then describe the key evidence that supports the concept that cytokines signal the brain to induce sickness behaviors through shedding the light on the two crucial models; the Dantzer’s Motivational Model of Sickness Behavior and The Two Hit Model of Cytokine-induced-Depression. Finally, the paper will derive clinical implications.

Cytokine Signals access in the brain

Cytokines are relatively large molecules prohibited from passing through the blood brain barrier. However, evidence reveals that cytokines signal the brain through hormonal, neural and cellular pathways (Capuron and Miller, 2011).

Data has shown that activation of the specific mechanisms differentially mediates cytokine effects on the central nervous system. Within the brain, there is a cytokine network consisting of cells. The neural pathway of immune signals underlies the potent effects of peripheral proinflammatory cytokines on pathways involved in the pathophysiology of neuropsychiatric disorders, including the activation of the HPA axis and corticotrophin-releasing hormone and the alteration of the metabolism of key neurotransmitter, such as serotonin (Dantzer et al., 1999)

Cytokine signals the brain through humoral, neural and cellular pathways. Hormonal pathways refer to the activation of monocytes and macrophages, which release the proinflammatory cytokine and enter the brain through the choroid plexus region and circumventricular organs of the blood-brain barrier. However, in the brain, the activation of endothelial cells is responsible for the subsequent release of second messengers that act on specific brain targets (Capuron and Miller, 2011).

While the neural pathways refer to the activation of monocytes, macrophages stimulate primary afferent nerve fibers in the vagus nerve, which result in the release of proinflammatory cytokines. Then, this information gets to the brain by sensory afferents of the vagus nerve to specific brain regions through the activation of the nucleus of the tractus solitarius and postrema area (Capuron and Miller, 2011).

Lastly, D’Mello & Swain (2009) identified another new immune-to-central nervous system communication pathway in the setting of organ-centered peripheral inflammation. According to D’Mello & Swain (2009), evidence shows that there is a significant infiltration of activated monocytes into the brain in mice with hepatic inflammation (D’Mello & Swain, 2009). This cellular pathway refers to the stimulation of microglia by proinflammatory cytokines to produce monocyte chemoattractant protein-1, which in turn is responsible for the recruitment of monocytes into the brain (D’Mello & Swain, 2009).

The Dantzer’s Motivational Model of Sickness Behavior

The Origin of Motivational Model of Sickness Behavior

Dantzer’s proposition of sickness as a motivational state built on Bolles’ definition of motivations as central states that reorganize perception and action (Bolles and Fanselow, 1980). Bolles (1974) emphasized that a motivational state enables the individual to detach perception from action, which results in a selective appropriate strategy depending on the encountered state. In order for the body to deal with the invading infectious organism efficiently, sickness takes precedence over other behavioral activities as the infected organism is at the death stage (Dantzer & Kelley, 2007).

Bolles and Fanselow (1980) presented a fear motivation system, which by assumption, activates a unique class defensive behavior, such as freezing and flight from a frightening situation. This activation aims at defending the animal against predation of natural danger while reorganizing the perception of environmental events to facilitate the perception of danger and safety (Bolles and Fanselow, 1980). The following example illustrates the expression of sickness behavior as a motivational state:

First, Neal Miller (1964) conducted the first series of experimental investigation that demonstrated a differential effect of bacterial endotoxin on behavior. Endotoxin administration decreased bar pressing when it resulted in an appetitive stimulus like food or water, but endotoxin did not decrease when it resulted in the termination of an aversive event. Rats given an endotoxin injection increased bar pressing to stop the rotation of a drum, an aversive stimulus (Miller, 1964). Interestingly, these results revealed that the consequence of the behavior which, does not necessarily decrease following exposure to sickness-inducing agents, influences the effect of the sickness-inducing agent.

Second, Aubert, Goodall, and Dantzer (1995) compared the effects of cold and cytokines on spontaneous dietary self-selection of rats. First, they habituated rats to free access to carbohydrate, protein and fat diets for 4 hours a day for 10 days. Then they randomly received physiological saline, IL-1 beta injection or lipopolysaccharide (LPS), or exposed to cold (5 degrees C). Results revealed that LPS- and IL-1 beta-treated rats ate less, but ingested relatively more carbohydrates and less proteins whereas relative fat intake remained unchanged. The rats exposed to cold slightly increased their food intake, but in a non-significant manner.

They also increased their relative intake of fat but did not change their relative intake of carbohydrate and protein. These results reveal interesting pyrogenic and metabolic effects of cytokines, which provides a clear-cut example or behavioral reorganization in response to sickness (Aubert, Goodal, and Dnatzer, 1995). In a subsequent study, Aubert, Goodall, Dantzer, & Gheusi (1997) investigated the sensitivity to LPS injection in lactating mice. They found that nest building significantly decreased in LPS-treated mothers compared to saline-treated animals at an ambient temperature of 22 degrees C. Furthermore, they found that LPS-treated mice exposed to cold temperature (6 degrees C) expressed not only pup-retrieving but also nest-building activity. Therefore, these activities are a result of a motivational state to due to the cooler environment.

These differential results indicate that the maternal behavioral expressions of LPS-induced sickness are dependent on the comparative priority of the behavior under consideration (different components of maternal care under consideration). Apparently, sickness prevents mice from displaying motor activities (pup retrieving or nest building) and from evaluating the situation under consideration efficiently (Aubert, Goodall, Dantzer, & Gheusi, 1997).

Finally, Aubert Kelley, & Dantzer (1997) compared the effects of LPS on food intake and food hoarding. Rats underwent tests under different motivational levels for food hoarding (receiving food supplement to maintain stable body weight or did not receive such a supplement). Interestingly, they found that LPS-injection significantly decreased total food intake in rats in general whereas food hoarding suffered less in LPS-treated rats from those who did not receive a supplement.

The expression of a still salient secondary motivation in LPS-treated rats, which did not receive any food supplement, suggested the expression of an anticipatory feeding behavior along with a reduced immediate appetite. Their results demonstrated that LPS treatment disrupted food hoarding in a minor way when rats received all of their food from hoarding, compared to rats that had supplemental food in their home cages (Aubert, Kelley, & Dantzer, 1997). LPS-treated animals still appear able to adjust their defensive behavioral strategies with regard to their needs and capacities. These findings support the adaptive value of the behavioral changes displayed by LPS-treated animals (Aubert, Kelley, & Dantzer, 1997).

These evidences confirm the hypothesis that sickness behaviors reflect the expression of motivational changes and reorganizations of behavioral priorities (Dantzer, 2007). Additionally, Aubert, Kelley, & Dantzer (1997) confirm that environmental conditions can be determinants of the behavioral change induced by illness or cytokines, in other words, when there are possible adverse effects of behavioral depression, behavior is less likely to suffer disruptions by infections and cytokines.

Motivational aspect of sickness behavior

From the previous discussion of historical origin of the motivational model, it was clear that sickness has motivational properties that reorganize the function on the organism at subjective, behavioral, and visceral levels in order to cope with the threat encountered (Dantzer, 2009). The Motivational aspect of sickness behavior is a vital perspective in pathophysiology; it entails that the neural pathways underlie the expression of sickness behavior, activated by immune stimuli but could possibly receive activations from non-Immune stimuli (Dantzer, 1997).

Therefore, cytokines signal the brain by inducing sickness behavior as result expression of a motivational state triggered by activation of the peripheral innate immune system (Danzter, 2009). As mentioned earlier it is an adaptive normal response to the exposure to a threat of a predator rather than being pathologic. In theory, cytokines released in response to infection or inflammation alert the brain to any real or potential threats and initiate behaviors that are important for survival (Frink et al, 2009). Some even refer to the ability of the immune system to alert or communicate with the brain as a “sixth sense” (Blalock & Smith, 2007).

Sickness behavior is adaptive in that it forces an individual to rest and withdraw from activities so that physiological processes can more effectively produce healing (Blalock & Smith, 2007; Kelley, Dantzer, Zhou, Shen, Jhonson & Broussard, 2003). Proinflammatory cytokines released during infection, inflammation, injury and even psychological stress can signal the brain to initiate behavioral changes that facilitate adaptation to these threats.

However, similar to other responses, sickness behavior can become anomalous or pathologic outside its original context and in the absence of inflammatory stimulus which, when it happens over longer period of time (Dantzer, 2009). This pathologic state derives from several factors:

The hyperactive proinflammatory state marked by persistent excess production of proinflammatory cytokines like IL-1, IL-6 and TNF and IFN gamma (Dantzer, 2009), which may also contribute to the pathogenesis of various human diseases in addition to sickness behaviors, such as allergy, autoimmunity, obesity, depression and atherosclerosis (Sternberg, 2006).
The predominance of proinflammatory cytokines over anti-inflammatory cytokines (which normally down-regulate the activation of the proinflammatory cytokines of the sickness response), this mismatch result in the exaggerated sickness response due to the peripheral immune system or direct activation of the brain cytokine system (Dantzer, 2009).
The sensitization of the neuronal circuits: Activation of afferent nerve fibers by peripherally released cytokines represents the fast pathway of transmission of immune signals from the periphery to the brain. This neural pathway certainly sensitizes the brain target areas of inflammatory mediators to the action of brain-produced cytokines that relay and amplify the action of peripheral cytokines (Dantzer, 2001).

The Motivational Competition between Motivational States for Behavioral Output

Normally, hierarchal organization of motivational states is required for the expression of behaviors, along with continuous evaluation of the encountered internal context and external events occurrences (Dantzer, 2001). For example, if an individual is sick with a flu have generalized muscle weakness that result in bed rest for the whole day, this individual is more likely to overcome this illness in the case of an alarming emergency immediately in order to escape a threat/predator.

The effect of cytokines on maternal behavior provides more representative example of the competition of motivational states, in the sense that maternal behaviors are critical for the survival of the offspring. In the previously mentioned study by Aubert, Goodall, Dantzer, & Gheusi (1997) LPS-treated mice exposed to ambient temperature of 22 degrees C, compared to saline-treated mice, demonstrated pup retrieving but nest building was significantly decreased.

However, LPS-treated mice exposed to ambient cold temperature, compared to saline-treated mice, demonstrated pup-retrieving and nest-building activity. Interestingly, their results signify that the behavioral expression of LPS-induced sickness depends on the priority of the behavior under consideration (Aubert, Goodall, Dantzer, & Gheusi, 1997). In motivational terms, maternal behaviors compete with sickness, and maternal-motivated behavior takes superiority over sickness behavior. This observation provides a valuable example of the motivational competition between behaviors.

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