Cited by 429Tryptophan and brain disordersVagus Nerve Stimulation ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Immune–neural connections: how the immune system’s response to infectious agents influences behavior

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McCusker, Robert H., Kelley, Keith W.·2013·Journal of Experimental Biology

DOI 10.1242/jeb.073411PMC PMC3515033

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Abstract

Summary: Humans and animals use the classical five senses of sight, sound, touch, smell and taste to monitor their environment. The very survival of feral animals depends on these sensory perception systems, which is a central theme in scholarly research on comparative aspects of anatomy and physiology. But how do all of us sense and respond to an infection? We cannot see, hear, feel, smell or taste bacterial and viral pathogens, but humans and animals alike are fully aware of symptoms of sickness that are caused by these microbes. Pain, fatigue, altered sleep pattern, anorexia and fever are common symptoms in both sick animals and humans. Many of these physiological changes represent adaptive responses that are considered to promote animal survival, and this constellation of events results in sickness behavior. Infectious agents display a variety of pathogen-associated molecular patterns (PAMPs) that are recognized by pattern recognition receptors (PRRs). These PRR are expressed on both the surface [e.g. Toll-like receptor (TLR)-4] and in the cytoplasm [e.g. nucleotide-binding oligomerization domain (Nod)-like receptors] of cells of the innate immune system, primarily macrophages and dendritic cells. These cells initiate and propagate an inflammatory response by stimulating the synthesis and release of a variety of cytokines. Once an infection has occurred in the periphery, both cytokines and bacterial toxins deliver this information to the brain using both humoral and neuronal routes of communication. For example, binding of PRR can lead to activation of the afferent vagus nerve, which communicates neuronal signals via the lower brain stem (nucleus tractus solitarius) to higher brain centers such as the hypothalamus and amygdala. Blood-borne cytokines initiate a cytokine response from vascular endothelial cells that form the blood–brain barrier (BBB). Cytokines can also reach the brain directly by leakage through the BBB via circumventricular organs or by being synthesized within the brain, thus forming a mirror image of the cytokine milieu in the periphery. Although all cells within the brain are capable of initiating cytokine secretion, microglia have an early response to incoming neuronal and humoral stimuli. Inhibition of proinflammatory cytokines that are induced following bacterial infection blocks the appearance of sickness behaviors. Collectively, these data are consistent with the notion that the immune system communicates with the brain to regulate behavior in a way that is consistent with animal survival.

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Authors: McCusker, R. H., & Kelley, K. W.
Affiliations: University of Illinois Urbana-Champaign (US)
Corresponding author: McCusker, Robert H.
ORCID: McCusker, Robert H.
Kelley, Keith W.
Venue: Journal of Experimental Biology
Publisher: The Company of Biologists
Published: 2013-01-01
Volume: 216
Issue: 1
Pages: 84-98
ISSN: 0022-0949 (ISSN-L)
1477-9145
DOI: 10.1242/jeb.073411
PMC: PMC3515033
OpenAlex: W2096615733
Cited by: 429
References: 118
Citations by year: 2026: 13 · 2025: 18 · 2024: 22 · 2023: 35 · 2022: 21 · 2021: 33 · 2020: 32 · 2019: 31 · 2018: 37 · 2017: 39 · 2016: 40 · 2015: 38 · 2014: 33 · 2013: 17
FWCI: 1.88
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Journal of Experimental Biology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute on Aging (AG029573, R01AG029573)
National Institute of Mental Health (MH083767, R01MH083767)
Topics: Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: sickness behavior, innate immunity, pathogen-associated molecular patterns, pattern recognition receptors, TLR4, NOD-like receptors, cytokines, vagus nerve, nucleus tractus solitarius, blood-brain barrier, circumventricular organs, microglia, fever, anorexia, fatigue
MeSH terms: Animals, Behavior, Animal, Brain, Depression, Humans, Immune System, Infections, Neuroimmunomodulation, Cytokines

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Immune–neural connections: how the immune system’s response to infectious agents influences behavior

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