Peripheral endotoxin causes long-lasting changes in locus coeruleus activity via IL-1 in the brain

Abstract

Activity of locus coeruleus (LC) neurons, the major noradrenergic cell-body group in the brain whose axons give rise to approximately 70% of norepinephrine (NE) in the brain, is believed to play an important role in attention/vigilance, cognitive functions and behavioral disorders, particularly depression. Results described here show that in the rat, intraperitoneal (i.p.) injection of lipopolysaccharide (LPS, a bacterial endotoxin) causes long-lasting changes in electrophysiological activity of LC neurons that are mediated by interleukin-1 (IL-1) acting locally in the LC region. First, it was found that IL-1, when microinjected into the LC region or stimulated/expressed in that brain region, increased activity of LC neurons. The only exception to this was that a very low dose of microinjected IL-1 (5 pg) decreased LC activity, which could be blocked by an antagonist to corticotropin-releasing hormone (CRH), thus suggesting that the decrease was due to IL-1 stimulation of CRH release. All of these effects could be blocked by injection and/or infusion of IL-1 receptor antagonist (IL-1RA) specifically into the LC region. Next, intraperitoneal (i.p.) injection of a low dose of LPS(10 µg/kg or 100 ng/kg) was also found to increase LC activity. The excitation of LC produced by 10 µg/kg i.p. LPS increased progressively for at least 1 week, with LC neurons firing at more than twice their normal rate at 1 week after the i.p. LPS injection. Alteration of LC activity lasted for 3 weeks after a single i.p. injection of 10 µg/kg LPS. The effects of i.p. LPS on LC activity at any time after i.p. injection could be blocked by a brief microinfusion of IL-1RA into the LC region, thereby indicating that changes in LC activity seen after the i.p. LPS were caused by IL-1 acting in the LC region. Finally, i.p. injection of peptidoglycan, representing gram-positive bacteria, and polyinsinic-polycytidylic acid [poly(I):(C)], representing viral infection, also caused increases in LC activity, and the effects of peptidoglycan [but not those of poly(I):(C)] were blocked by microinfusion of IL-1RA into LC. These findings suggest that bacterial infections can give rise to prolonged changes in brain activity through cytokine action in brain.

Immune and Neuroprotective Effects of Physical Activity on the Brain in Depression

“…Microinjection of IL-1 into the LC region increased firing activity of LC neurons in the rat brain, an effect that was blocked by an IL-1 antagonist. Intraperitoneal injection of a low dose of lipopolysaccharide increased LC firing activity, an effect that lasted 3 weeks after injection (Borsody and Weiss, 2002 ). IL-2 and IFN-α administration altered LC electrical activity (De Sarro et al, 1990 ; Nisticò and De Sarro, 1991 ; Nisticò, 1993 ).…”

The functional role of locus coeruleus microglia in the female stress response

“…While microglia are highly present through the brain, one region in which they are concentrated is the noradrenergic LC in which bidirectional regulation of norepinephrine and microglial cell reactivity plays a key role in the stress response (Iravani et al, 2014). Microglial activity can be regulated by adrenergic receptor signaling (Färber et al, 2005; Johnson et al, 2005) while, conversely, the release of proinflammatory cytokines leads to activation of the norepinephrine-producing LC cells (Borsody & Weiss, 2014). Further, inflammatory mediated regulation of LC activity has been associated with hypervigilant and depressive-like behaviors (Kurosawa et al, 2016; Christoph Naegeli et al, 2018).…”

Site-Specific Knockdown of Microglia in the Locus Coeruleus Regulates Hypervigilant Responses to Social Stress in Female Rats

“…The LC is well-recognized to regulate hypervigilant burying behavior in the context of stress as chemical depletion of LC-NE tone inhibits CRF- and stress-evoked burying (Howard et al, 2008). Despite longstanding knowledge from electrophysiological studies that IL-1β activates LC neuronal firing through IL-1 receptor (Borsody & Weiss, 2002a, 2002b; Morris et al, 2020), the role of LC microglia in the context of social stress was unknown. Persistently increased LC activity is linked to anxiety (Morris et al, 2020), suggesting that stress-induced activation of LC microglia may promote anxiety disorders.…”