Pathogens, the immune system and social behaviour

Lead author Tony Filiano (left) together with     Jonathan Kipnis

Over thirty years ago, a veterinary scientist from the University of California at Davis – Benjamin Hart – first drew the links between pathogenic infections, the immune response, and behaviour, when he formulated his theory of sickness behaviour. At the onset of a severe infection, he said, an animal or human develops a fever thanks to the action of pro-inflammatory immune messenger molecules called cytokines. The high body temperature, he said, was an evolved adaptation to efficiently fight pathogens but the cytokines that stoke fire in the body are capable of being transported to the brain, either through the bloodstream or by hitchhiking along the vagus nerve, and produce behavioural changes like depression, social withdrawal, loss of appetite and sleepiness that cause the organism to, in effect, hibernate while the infection, and immune attack against it, runs its course. Now, in a fascinating paper in Nature, Jonathan Kipnis and his co-workers provide another compelling story of evolved links between infection, the role of the immune system, and changes in social behaviour.

According to a University of Virginia (where Kipnis is director of the Center for Brain Immunology and Glia) press release, this recent work builds on the anatomical foundations laid a few years ago by a postdoctoral fellow, Antoine Louveau, whose meticulous dissection of the meninges surrounding mouse brains revealed the presence of a tracery of lymphatic vessels which formed a conduit between the brain and the lymphatic vessels of the rest of the body – a route into the brain for immune cells and their products. These meningeal vessels house a specialised population of meningeal T-lymphocytes which churn out an important pro-inflammatory cytokine, interferon-gamma. Kipnis and his team have shown that inhibitory neurons, particularly in prefrontal cortex of the brain, which is heavily involved in controlling social behaviour, respond to interferon-gamma and increase GABAergic currents which dampen down neuronal activity.

They showed that interferon-gamma deficient mice had social deficits and aberrant hyper-connectivity in fronto-cortical and insular regions (all parts of the so-called “social brain”) which could be restored by putting lymphocytes from wild-type mice into them. “Remarkably”, says the Nature paper, “a single injection of recombinant interferon-gamma into the cerebrospinal fluid of these socially deficient mice was enough to restore their social preference and reduced overall hyper-activity in the prefrontal cortex.”

So here you have a prominent pro-inflammatory cytokine, long known to be vital for fighting infections in the body, which seems also capable of modulating neuronal circuits in the brain that govern social behaviour. The team suggests that the dual role for interferon-gamma arose through co-evolutionary pressure to reconcile social behaviour and the increased danger of infection in tightly-knit social animal groups.

The importance for humans is that several psychiatric conditions, including autism spectrum disorder and schizophrenia, have been shown to involve poorly regulated neuronal circuits. So, as the team notes, “It is plausible that subtle homeostatic changes in meningeal immunity may contribute to modulating neuronal circuits that are responsible for our everyday behaviours and personality”. Whereas sickness behaviour employs pro-inflammatory cytokines like interleukins 1 and 6, and tumor necrosis factor-alpha, to modulate neuronal circuits to induce sleepiness, depression and social withdrawal while stoking a fever response in the body, interferon-gamma, it appears, has inhibitory effects elsewhere, promoting appropriate social behaviour while guarding against the inevitably increased risk of catching an infection that such social affiliation generates. The importance of this sort of research is that it demolishes the old assumption that the brain is an immune privileged zone and replaces it with powerful evidence for the role of the immune system in the brain and in behaviour.

Kipnis’ findings regarding interferon-gamma might explain the fact that many parents of children with autism spectrum disorder report that their children’s symptoms abate whenever they have an infection or are running a high temperature. It could be that the elevated levels of interferon-gamma are inhibiting those frontal cortex networks that give rise to autistic behaviour. When the infection subsides, interferon-gamma levels fall, and the symptoms return.

The University of Virginia also has this pop account of the discovery.