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Konsman Immune-brain circuits and behavior

24 h after systemic injection of LPS suggests that unaffected by this procedure. [61-68] Furthermore, selective
neutrophil infiltration into brain provides an important chemical lesions of C-fiber afferents after intraperitoneal
source of IL-1β at later time points. Hence, brain IL-1 injection of capsaicin in adult rodents were found to
[47]
production and action sustains sickness behavior after also attenuate the first phase of the fever response in
systemic LPS administration, but not necessarily fever. response to systemic administration of LPS. This
[69]
suggests that LPS-induced rapid fever responses may
Circulating IL-1 inducing prostaglandin synthesis at involve vagally-mediated immune-to-brain signaling
the BBB with later fever peaks or prolonged fever depending on
In the early 1990s, a second form of the rate-limiting prostaglandin synthesis at blood-brain interfaces.
prostaglandin synthesizing enzyme cyclooxygenase
(COX) was identified and found to be induced along Soon after the first vagotomy studies, intravenous IL-1β
brain blood vessels after peripheral administration of administration was found to increase afferent discharge
bacterial LPS or IL-1β. [48-50] Concurrently, it was shown activity of the hepatic and gastric branches of the
that most IL-1 receptors in the rodent brain were vagus nerve in a prostaglandin-dependent way. [70-72]
expressed along blood vessels making up the BBB Subsequently, vagal paraganglia and the nodose
[Figure 1B-4]. [31-34] This led to the hypothesis according ganglion containing the neuronal cell bodies of the vagus
to which circulating IL-1 acts on its signaling receptor nerve were observed to bind IL-1ra and to express the
expressed by brain endothelial cells to induce COX- signaling IL-1 receptor. [72,73] In addition, spinal sensory
2-mediated prostaglandin production, which, given afferent cell bodies in dorsal root ganglia also express
their lipophilic profile, can diffuse across the BBB and mRNA coding the signaling IL-1 receptor and their
activate prostaglandin receptors on neurons to bring peripheral fibers respond to local administration of IL-
about sickness symptoms. [48,49] Testing of this hypothesis 1β by increasing their activity as well as their sensitivity
using mice in which endothelial cells were deficient in to heat in vitro. [74,75] Interestingly, ganglia of both vagal
COX-2 or PGE synthase showed that although the fever and spinal sensory nerves express TLRs and some
response to an intraperitoneal injection of IL-1β was bacteria have been shown to directly activate sensory
abolished in these animals, the reduction in locomotor neurons. [76-78] Taken together, these findings suggest
activity was not affected. [51,52] So, in accordance with a that low doses of IL-1β or bacterial fragments may act
hypothesis put forward in 2002, BBB prostaglandin on sensory nerve fibers to signal the central nervous
[53]
synthesis underlies IL-1β-induced fever, but not system to give rise to early fever, hyperalgesia and
necessarily sickness behavior. sickness behavior [Figure 1C-6].

IL-1 action on peripheral nerves ACTIVATION OF NEURAL SUBSTRATES
At least two of the classical symptoms of local OR INITIATION OF NEURODEGENERATION
inflammation, heat and pain, correspond to sensory DURING SYSTEMIC INFLAMMATION?
modalities and thus involve neural activation.
Interestingly, local IL-1β application under the skin of a Neural substrates of acute sickness behavior
rat paw was shown in 1994 to increase the sensitivity Possible neural substrates of bacterial LPS-induced
to mechanical and heat stimuli and to augment electric hypophagia
activity of sensory nerve fibers. Based on these The basomedial hypothalamus plays an important
[54]
considerations, IL-1 was proposed to act on neural role in the long-term regulation of food intake.
sensory afferents to signal the brain and bring about Interestingly, lesions of the arcuate nucleus of the
symptoms of sickness [Figure 1C-5]. In accordance hypothalamus [Figure 1D] exacerbated the anorectic
with this hypothesis, subdiaphragmatic vagotomy effect of peripheral IL-1β administration. However;
[79]
was shown to attenuate the reduction in social antagonizing the action of α-melanocyte stimulating
exploration and food-motivated behavior, conditioned hormone, which is produced by neurons of the arcuate
taste aversion, increased sleep and hyperalgesia as nucleus of the hypothalamus, on central melanocortin
early as 2 h after intraperitoneal administration of IL- receptors has been found to alleviate hypophagia after
1β or bacterial LPS. [55-59] Reversible inactivation of the peripheral administration of either IL-1β or LPS
the dorsal vagal complex, which contains the central from 8 h onwards. [80,81] These findings indicate that the
terminals of vagal sensory fibers, by local anesthesia overall role of the arcuate hypothalamus is to counter
also restored social exploration after intraperitoneal reduced food intake, even though activation of some
LPS administration. Moreover, the febrile responses of its composing neurons does seem to play a role in
[60]
to systemic administration of low doses of IL-1β or sustained inflammation-associated hypophagia.
LPS were also attenuated by prior subdiaphragmatic
vagotomy, whereas fevers after higher doses were The brainstem mediates short-term regulation of food
210 Neuroimmunology and Neuroinflammation ¦ Volume 3 ¦ September 26, 2016