A brain cytokine-independent switch in cortical activity marks the onset of sickness behavior triggered by acute peripheral inflammation

Abstract

Systemic inflammation triggers protective as well as pro-inflammatory responses in the brain based on neuronal and/or cytokine signaling, and it associates with acutely and protractedly disrupted cognition. However, the multiple mechanisms underlying the peripheral–central inflammatory signaling are still not fully characterized. We used intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) in freely moving mice with chronically implanted electrodes for recording of local field potentials (LFP) and electrocorticography (ECoG) in the hippocampus and neocortex, respectively. We show here that a sudden switch in the mode of network activity occurred in both areas starting at 10–15 min after the LPS injection, simultaneously with a robust change from exploration to sickness behavior. This switch in cortical mode commenced before any elevations in pro-inflammatory cytokines IL-1β, TNFα, CCL2 or IL-6 were detected in brain tissue. Thereafter, this mode dominated cortical activity for the recording period of 3 h, except for a partial and transient recovery around 40 min post-LPS. These effects were closely paralleled by changes in ECoG spectral entropy. Continuous recordings for up to 72 h showed a protracted attenuation in hippocampal activity, while neocortical activity recovered after 48 h. The acute sickness behavior recovered by 72 h post-LPS. Notably, urethane (1.3 mg/kg) administered prior to LPS blocked the early effect of LPS on cortical activity. However, experiments under urethane anesthesia which were started 24 h post-LPS (with neuroinflammation fully developed before application of urethane) showed that both theta–supratheta and fast gamma CA1 activity were reduced, DG delta activity was increased, and sharp-wave ripples were abolished. Finally, we observed that experimental compensation of inflammation-induced hypothermia 24–48 h post-LPS promoted seizures and status epilepticus; and that LPS decreased the threshold of kainate-provoked seizures beyond the duration of acute sickness behavior indicating post-acute inflammatory hyperexcitability. Taken together, the strikingly fast development and initial independence of brain cytokines of the LPS-induced cortical mode, its spectral characteristics and simultaneity in hippocampus and neocortex, as well as inhibition by pre-applied urethane, strongly suggest that the underlying mechanisms are based on activation of the afferent vagus nerve and its mainly cholinergic ascending projections to higher brain areas.

RIPK3 promotes neuronal survival by suppressing excitatory neurotransmission during CNS viral infection

“…More recently, the molecular basis of memory formation has also been shown to involve innate immune sensing of endogenous genomic damage induced by neural activity 50 . In the context of disease, pathogen sensors and inflammatory cytokines have been implicated in a variety of neurologic and behavioral outcomes 51-55 , including sickness behavior 56-58 , and inflammation generally is known to drive pathologic processes in neurons including aberrant synaptic pruning 6,59,60 , excitotoxicity 23,61,62 , and epileptogenesis 63,64 . Our results describe a nexus of neuroimmune signaling in which activation of RIPK3 dampens neuronal excitability, which in turn promotes survival in the presence of excitotoxic levels of glutamate during CNS viral infection.…”

Getting Excited About Chloride Cotransporters: Neuroinflammation and Inhibition

“…For example, inflammatory factors or neuroinflammatory processes in the brain can enhance seizure susceptibility, which can contribute to long-term progression of epilepsy and aggravation of seizures. Previous evidence indicates that acute neuroinflammation can reduce sharp-wave ripples in the CA1 area of the hippocampus but enhance slow-wave activity in the dentate gyrus (DG) 1 which may contribute to cognitive impairment and hippocampal hyperexcitability. Although there is vast evidence demonstrating the DG’s critical role in seizure circuitry, whether and how (ie, by which mechanisms) neuroinflammatory processes compromise DG functions to promote hyperexcitability are still unknown.…”

The telencephalon is a neuronal substrate for systemic inflammatory responses in teleosts via polyamine metabolism

“…Similarly, in rats, LPS injection triggers astrocyte activation within the striatum and hippocampus with significant volumetric expansions occurring in the splenium, retrosplenial cortex, and pericallosal hippocampal cortex at 2 hours post-injection (hpi) (19). Combined, mammalian studies indicate that systemic inflammation disturbs several higher-order cortical areas (13, 15, 20, 21), their connectivity across the entire brain yet to be fully resolved.…”