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Konsman Immune-brain circuits and behavior

intake and glutamatergic projections from the nucleus to infectious microorganisms or their components. [88,89]
of the solitary tract [Figure 1D] to the parabrachial However, the findings of Chaskiel et al. show that
[83]
nuclei reduce food intake. Interestingly, brainstem selective lesioning of IL-1 receptor-expressing cells in
[82]
metabotropic glutamate receptor antagonism was found the hippocampus does not alter the reduction in social
to attenuate hypophagia and to increase food intake exploration after intracerebroventricular administration
during the first 6 h after peripheral LPS to a greater of IL-1β in mice. Thus, IL-1 receptors in the hippocampus
extent than in vehicle-treated animal. In parallel, do not seem to mediate the component of sickness
[83]
intra fourth ventricle administration of this metabotropic behavior that involves reduced exploration.
glutamate receptor antagonist also reduced expression
of the cellular transcription activation marker c-Fos in Severe sepsis may lead to neurodegeneration
the nucleus of the solitary tract and lateral parabrachial Magnetic resonance imaging of septic patients with brain
nuclei. These findings suggest that brainstem dysfunction has indicated the presence of vasospasms
[83]
glutamatergic circuits are part of the neuronal substrates in the medial cerebral arteries and ischemic strokes in
that rapidly reduce food intake under inflammatory brain gray matter as well as white matter edema. [90-92]
[93]
conditions. (see for review ) Post mortem examination of brains
of patients who died from sepsis revealed intracerebral
Potential neural substrates of bacterial LPS-induced hemorrhage, necrotic vessels with infiltrating leukocytes,
reduced exploration increased perivascular spaces, microglial activation,
Interestingly, all intervention strategies restoring social cerebral IL-1β and TNF-α expression, neuronal apoptosis
exploration after intraperitoneal LPS injection also as well as perivascular dissociation of myelinated fibers
reduce induction of the cellular transcription activation and demyelination. [91,94,95] Clinical research thus clearly
marker c-Fos in the central nucleus of the amygdala indicates the occurrence of neuroinflammation that may,
(CEA) and the oval bed nucleus of the stria terminalis in turn, lead to neurodegeneration.
(ovBNST). [46,60,66] The amygdala and the bed nucleus
of the stria terminalis project to the ventrolateral Recently, several groups have employed cecal ligature
periaqueductal gray (vlPAG) [Figure 1D] in the pons, and puncture (CLP) in rodents to study CNS dysfunction
[84]
the stimulation of which induces immobility and reduced associated with sepsis. In these models, food intake
social interactions. Thus, c-Fos expressing neurons in and social interactions were found to be reduced during
[85]
the CEA and ovBNST may inhibit GABAergic neurons the first days, while activity and body temperature were
projection to the vlPAG resulting in immobility and altered and some conditioning learning tasks impaired
reduced social interactions. In addition, reduced for several weeks after sepsis induction. [96-99] Increased
[53]
exploration of different environments and devices has cerebral pro-inflammatory cytokine expression, impaired
been shown to be associated with c-Fos expression BBB function, cortical perivascular edema, glial cell
in the ventral tuberomammillary nucleus [Figure 1D] activation, brain leukocyte adhesion and infiltration as
after peripheral bacterial LPS injection. [86,87] Reduced well as neuronal death and degeneration in cortical
activation of the ventral tuberomammillary nucleus may and subcortical areas have all been observed from the
therefore be part of the neural substrates underlying first day of CLP onwards. [96-105] Thus, relevant animal
reduced environmental exploration during sickness. models of sepsis have been shown to result both in
transient sickness behavior and in long-term learning
The realization that endogenous IL-1β can act in the brain deficits that are accompanied by neuroinflammation
to bring about sickness behavior raised the question and neurodegeneration.
as to where in the brain it binds to the signaling IL-1
receptor to reduce social and environmental exploration. CONCLUSION
Although the hippocampus is one of the most prominent
sites of neuronal IL-1 receptor expression (see transport During the systemic inflammatory response to acute
of circulating IL-1 across the BBB), no published infection, and when in a safe environment, endothermic
study to date seems to have critically addressed the mammals typically display reduced activity and food
involvement of hippocampal IL-1 receptors in mediating intake, increased sleep, and the adoption of a curled-
sickness behavior. It is important to point out that this up position. These changes in behavior, in concert
is not because such approaches are not available. with fever, are adaptive in that they contribute to
Indeed, several groups have employed hippocampal host survival. Although the precise neurobiological
overexpression of the IL-1ra. These studies addressed substrates still need to be worked out, they are
the role of hippocampal IL-1 in mediating responses to brought about by immune-to-brain signaling pathways
psychological stressors, such as electrical shocks and that involve rapid activation of peripheral nerves and
chronic isolation, and not those occurring upon exposure glutamatergic brainstem circuits as well as slower IL-
Neuroimmunology and Neuroinflammation ¦ Volume 3 ¦ September 26, 2016 211