A head injury can lead immune-system brain
cells to go on “high alert” and overreact to later immune challenges by
becoming excessively inflammatory – a condition linked with depressive
complications, a new animal study suggests.
The findings could help explain some of the
midlife mental-health issues suffered by individuals who experience multiple
concussions as young adults, researchers say. And these depressive symptoms are
likely inflammation-related, which means they may not respond to common
An added complication is that ageing already
increases brain inflammation. So on top of normal ageing concerns, people who
have had a traumatic brain injury (TBI) experience added inflammation caused by
magnified immune responses to so-called “secondary challenges", such as a
second head injury, infections or other stressors.In
mice, these high-alert cells in the brain – called microglia – had an
exaggerated response to an immune challenge one month after a moderate brain
injury. This increased brain inflammation corresponded with the development of
depressive behaviours that were not observed in uninjured mice.
A multiplier effect
“If we had waited three, six or nine
months, the symptoms probably would have gotten even worse,” said lead author
Jonathan Godbout, associate professor of neuroscience at The Ohio State
University and a researcher in the Institute for Behavioural Medicine Research.
“A lot of people with a history of head
injury don’t develop mental-health problems until they’re in their 40s, 50s or
60s. That suggests there are other factors involved, and that’s why we’re
looking at this two-hit idea – the brain injury being the first and then an
immune challenge. It’s as if one plus one plus one equals 15. There can be a
The research is published online in the
journal Biological Psychiatry.
This work applies to concussive brain
injuries that result in a diffuse – or spread out – trauma to the brain. These
are also concussive injuries from which people and animals recover fairly
quickly, typically showing no problems with thinking or moving about a week
after the injury to the brain.
In the study, researchers compared
uninjured mice with mice that had experienced a moderate TBI. Injured mice
showed some initial coordination problems, but those resolved within a week.
The injured mice also showed signs of
depressive symptoms that improved within one month. Godbout and colleagues
attributed those symptoms to the expected neuro-inflammation that occurs after
a traumatic brain injury. In these mice, most of the inflammation had cleared
within seven days.
Thirty days after injury, researchers
examined the brains of the injured mice to determine whether immune cells had
remained on high alert since the injury. As expected, the injured brains
contained microglia that had stayed in a “primed” state – meaning they were on
standby to respond to a challenge to the immune system. The cells in the brains
of uninjured mice did not have the same characteristics.
More about microglia
Under normal circumstances, microglia are
the first line of defence and help protect the brain after injury or infection
by making proteins and other chemicals that generate just enough inflammation
to repair the problem. When they are primed, however, these cells are in a
higher state of alert and when they are activated, they generate an amplified
immune response that lasts longer than necessary. When these systems are
activated with nothing to fight, the circulating chemicals and proteins
generate excessive inflammation.
“The young adult mice that have a diffuse
head injury basically recover to normal, but not everything is normal. The
brain still has a more inflammatory makeup that is permissive to hyper-activation
of an immune response,” Godbout said.Injection with LPS
At 30 days after TBI, the mice were injected
with lip-polysaccharide (LPS) – the dead, outer cell wall of bacteria that
stimulates an immune reaction in animals. Tests showed that over the course of
24 hours after the injection, TBI mice were much less social than uninjured
mice – one type of depressive symptom in these animals. The brains of the TBI
mice also had dramatically higher levels of two inflammation-related proteins
than did brains from normal mice.
72 hours after the LPS challenge,
injured mice showed additional depressive symptoms, including minimal interest
in sugar water – a sign that they avoided what is typically a pleasurable
activity. They also showed increased resignation, or a sign of “giving up".
Uninjured mice behaved normally and the
levels of inflammatory proteins in their brains had returned to baseline over
the same time period.
Development of depressive symptoms
“These results tell us the TBI mice are
having an amplified and prolonged activation of microglia, and that was
associated with development of depressive symptoms in the mice,” Godbout said.
His lab is now investigating potential
treatments that could either prevent the priming of microglia immediately after
injury or later reverse the high-alert characteristics of these cells.
This work was supported by the National
Institute on Ageing and a Med to Grad scholarship from the Howard Hughes Medical
Co-authors include Ashley Fenn, Yan Huang
and Phillip Popovich of Ohio State’s Department of Neuroscience; John Gensel of
the University of Kentucky; and Jonathan Lifshitz of Phoenix.
Children’s Hospital. Godbout and Popovich
also are members of Ohio State’s Centre for Brain and Spinal Cord Repair.