The DOI matches its Crossref record; 115 of the 118 references it cites were found in a registry or an index.
Immune–neural connections: how the immune system’s response to infectious agents influences behavior
Open accessAbstract
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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“cytokines as well as PAMPs (eg, LPS) are capable of activating afferent vagal nerve fibers in the periphery, which leads to activation of neural pathways in brain regions implicated in motivation and mood (McCusker and Kelley, 2013).”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as McCusker and Kelley, 2013
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“…at the BBB in response to circulating PAMPs and that cytokines could enter the brain by volume diffusion at the circumventricular organs (Fig.4) (Quan and Banks, 2007), it was clear that behavioral responses that occur in response to i.v. and s.c. PAMPs or cytokines are transcribed by the brain…”
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Metadata
- Authors
- McCusker, R. H., & Kelley, K. W.
- Affiliations
- University of Illinois Urbana-Champaign (US)
- Corresponding author
- McCusker, Robert H.
- 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
- 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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