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Konsman Immune-brain circuits and behavior

response to infection, one may wonder how come then temperature is regulated by the preoptic hypothalamus,
that the infected organism refrains from taking in more this gave rise to the question how the immune system
energy? In fact, reducing food intake upon infection may signals the brain to bring about fever when animals are
be an adaptive response as well since force-feeding infected with bacteria.
mice during acute bacterial infection, it was indeed
found to increase mortality. [5] The view of sickness behavior as being due to a
motivation also implies immune-to-brain signaling.
Sickness behavior as motivated behavior Indeed, even though the brain circuits underlying every
Benjamin Hart stated that in a “sickness behavior” single postulated motivational system are not known
[4]
perspective “the sleepy or depressed or inactive animal is in full detail, motivations are mediated by brain circuits
less motivated to move about using energy that could fuel comprising the hypothalamus and limbic system.
metabolic increases associated with fever”. To consider Thus, the occurrence of sickness behavior in response
sickness a motivation, like fear, hunger, thirst and other to exposure of animals to bacteria also begged the
motivational states, implies that its expression is flexible question as to how such events are signaled to the
depending on other motivations. Thus, it is important brain. In what follows the actions of the pro-inflammatory
to show that its occurrence does indeed depend on cytokine interleukin-1 (IL-1) on peripheral nerves, brain
environmental conditions. Interestingly, rats that depend circumventricular organs and the blood-brain barrier
entirely on hoarded food for their consumption, when (BBB), IL-1 transport across the BBB and IL-1 synthesis
rendered sick by bacterial lipopolysaccharide (LPS) in the brain will be discussed as immune-to-brain
endotoxins, continued to hoard more food, even though signaling pathways.
they did not consume it, than did animals injected with
LPS that had the possibility to hoard, but also received FROM IMMUNE-TO-BRAIN SIGNALING TO
food in their cage. Thus, the expression of sickness NEUROINFLAMMATION?
[6]
behavior depends on the external conditions and, in this
case, likely on the motivation to hoard food. Based on Intereukin-1 as a mediator of immune-to-brain
these and other observations, sickness behavior is now signaling that cannot passively cross the BBB
considered as the expression of a motivational system Once bacteria or their components have entered host
that reorganizes the organism’s perception and action. tissues, they activate innate immune cells, including
monocytes-macrophages and neutrophils, to generate
Sepsis-associated encephalopathy and an inflammatory response mediated by cytokines, such
delirium an interleukin-1β (IL-1β). [12,13] Peripheral injection of IL-
Septic encephalopathy or brain dysfunction occurs in 1β mimics the symptoms of sickness and the signs of
up to 70% of sepsis patients. Encephalopathy was disease normally seen after infection. Conversely,
[7]
[14]
replaced by delirium due to a general medical condition systemic administration of the naturally occurring
in Diagnostic and Statistical Manual of Mental Disorders- IL-1 receptor antagonist (IL-1ra) alleviates or blocks
IV and described as a disturbance in consciousness systemic bacterial LPS-induced fever in rats. [15,16]
or perception or change in cognition characterized In addition, peripheral IL-1ra also attenuates the
by reduced ability to focus or sustain attention and reduction in locomotor activity and social interactions
fluctuating changes in mental status, ranging from after systemic LPS injection. Thus, IL-1 mediates, at
[17]
confusion to coma. However, functioning of the entire least in part, fever and sickness behavior when these
neuraxis and peripheral nerves can be disturbed occur in response to the administration of bacterial
during sepsis. Indeed, abnormal or slowed postural or LPS. However, the fact that IL-1 is a hydrophilic large
protective reflexes have often been reported to occur peptide of 17 kDa means that it cannot passively cross
during sepsis. [8-10] Therefore, and notwithstanding the the BBB separating the brain parenchyma from blood.
fact that sickness behavior can clearly be adaptive in Consequently, proposing and testing IL-1-mediated
response to an acute infection, it should also be clear immune-to-brain signaling pathways became a topic of
that during severe sepsis important cerebral dysfunction intense research activity from the 1990s onwards.
can occur.
Circulating IL-1 acting in brain circumventricular
Why immune-to-brain signaling? organs lacking a BBB
Fever can be defined as “a state of elevated core In the early 1980s, antipyretics were already known to
temperature” that is “due to an elevation of the set-point inhibit the synthesis of prostaglandins, a family of small
of body temperature, according to which the higher lipophilic mediators. IL-1 was subsequently found to
temperature is actively established by the operation induce the formation of prostaglandin E2 (PGE2) by
of thermo-effectors”. Since the set-point of body stimulating the synthesis of the rate-limiting enzyme
[11]
208 Neuroimmunology and Neuroinflammation ¦ Volume 3 ¦ September 26, 2016