Alteration of Locus coeruleus Neuronal Activity by Interleukin-1 and the Involvement of Endogenous Corticotropin-Releasing Hormone

Abstract

Activity of the locus coeruleus (LC), which is the source of most of the norepinephrine in the brain, may participate in effects of the cytokine interleukin (IL)-1. This report describes the influence of IL-1β on the electrophysiological single-unit activity of LC neurons. When microinjected into the LC, human recombinant IL-1β (50 pg to 5 ng) increased the activity of LC neurons, predominantly by increasing ‘burst’ firing, which occurs in response to a sensory stimulus. At the higher doses and/or with longer time delays after injection, the spontaneous depolarization rate was also increased. This excitation (1) did not occur if IL-1β was microinjected nearby but outside of the LC and (2) could be reversed by administration of IL-1 receptor antagonist (IL-1RA). In contrast to excitatory effects, microinjection of a very low dose of IL-1β (5 pg) into the LC inhibited LC activity, and this change could also be blocked by IL-1RA. In view of earlier findings that (1) LC electrophysiological activity could be inhibited by microinjection of corticotropin-releasing hormone (CRH) into the LC region and (2) IL-1β in the brain stimulates the release of CRH, the hypothesis was tested that the inhibition of LC activity produced by the low dose of IL-1 was mediated by CRH. Microinfusion of the CRH receptor antagonist α-helical CRH(9–41) blocked the inhibition of LC activity otherwise produced by 5 pg of IL-1β, thus indicating that IL-1β also influences the activity of LC neurons via CRH. Finally, microinjection of IL-1RA alone was found to decrease LC activity, raising the possibility that LC neurons are under the influence of tonic excitation by IL-1 in the brain. In summary, the findings described here show that the activity of LC neurons can be influenced by IL-1β through stimulation of IL-1β receptors. The potential involvement of IL-1β in stress responses by means of this cytokine influencing the activity of LC neurons is discussed.

Lipopolysaccharide induces delayed FosB/DeltaFosB immunostaining within the mouse extended amygdala, hippocampus and hypothalamus, that parallel the expression of depressive-like behavior

“…For instance, the electrophysiological activity of LC neurons is increased following an acute immune challenge (Borsody & Weiss, 2002;2004;. Accordingly, we show in the present study that the LC displays intense c-Fos labeling 6 hours following LPS injection.…”

Contribution of Interleukin-1 Receptor Accessory Protein b to Interleukin-1 Actions in Neuronal Cells

“…Serum-containing medium used in the present study could confer to the neurons the ability to respond to IL-1 ␣ as well as IL-1 ␤ , but could also contribute to neurons being partially depolarised in the presence of IL-1, which could then lead to release of IL-1-induced IL-6. It is well documented that IL-1 induces neuronal depolarisation [20,21] , and other studies also found that IL-1 can lead to synthesis and release of IL-6 from rat hippocampal neuronal cell lines [22] and mouse cortical neurons [18,19,23] . Collectively, these observations demonstrate that the external environment tightly controls neuronal responses to IL-1 and that subtle changes in the culture condition can lead to a change in the neuronal response to IL-1.…”

The Role of Cytokines in the Regulation of Neurotransmission

“…The activity of the locus ceruleus (LC), which is the most important source of noradrenaline inside the brain, was increased after in vivo IL-1 ␤ microinjection in this area; this effect was blocked by IL-1 ␤ receptor antagonist (IL-1 RA) [55,56] . Furthermore, microinjection of IL-1 RA alone was found to decrease LC activity, raising the possibility that LC neurons are under the influence of tonic excitation by IL-1 ␤ [55] .…”