Source found for immune system effects on learning, memory
eurekalert.orgDURHAM, N.C. - Immune system cells of the brain, which scavenge pathogens and damaged neurons, are also key players in memory and learning, according to new research by Duke neuroscientists.
Earlier studies by Staci Bilbo, an assistant professor in psychology & neuroscience, had shown that laboratory rats experiencing an infection at an early age have an aggressive immune response to subsequent infections, which also harms their learning and memory.
In a study published in the Oct. 26 Journal of Neuroscience, Bilbo’s team identifies the source of the learning difficulties and traces it back to the immune system itself.
The researchers found that specialized immune system cells in the brain called microglia release a signaling molecule called Interleukin-1, or IL-1, in response to an infection. IL-1 is also crucial to normal learning and memory in the hippocampus region of the brain. But too much IL-1 can impair learning and memory in laboratory animals.
“These same molecules go up in response to any brain infection. I don’t really understand why you would build a brain that way, except that there are clearly benefits in other aspects of immunity, outside the brain,” Bilbo said.
Bilbo believes the early infection triggers a permanent change in gene expression, and is now looking at the role of microglial cells in addiction, and the interactions between maternal care and immune function.
Estrogen receptor modulates microglia-mediated inflammation
Image credits Wilma Friedman Lab
Females have an increased susceptibility to develop autoimmune diseases. Female patients who develop multiple sclerosis for example largely outnumber male patients in a ratio of 3 to 1. This study, presented in a recent issue of Cell by Saijo and colleagues, explores a molecular mechanism that could possibly explain why gender is such an important factor in the development of MS. Saijo and colleagues also explore in a series of elegant experiments how microglia regulate inflammation in response to various stimuli in the CNS.
Abstract of the study:
Microglia and astrocytes play essential roles in the maintenance of homeostasis within the central nervous system, but mechanisms that control the magnitude and duration of responses to infection and injury remain poorly understood. Here, we provide evidence that 5-androsten-3b,17b-diol (ADIOL) functions as a selective modulator of estrogen receptor (ER)b to suppress inflammatory responses of microglia and astrocytes. ADIOL and a subset of synthetic ERb-specific ligands, but not 17b-estradiol, mediate recruitment of CtBP corepressor complexes to AP- 1-dependent promoters, thereby repressing genes that amplify inflammatory responses and activate Th17 T cells. Reduction of ADIOL or ERb expression results in exaggerated inflammatory responses to TLR4 agonists. Conversely, the administration of ADIOL or synthetic ERb-specific ligands that promote CtBP recruitment prevents experimental autoimmune encephalomyelitis in an ERb-dependent manner. These findings provide evidence for an ADIOL/ERb/ CtBP-transrepression pathway that regulates inflammatory responses in microglia and can be targeted by selective ERb modulators
Full paper here
Neuroscience: Immunity functions of microglia affects memory and learning
Microglia are specialized immune cells located in our brain. These cells function by scavenging pathogens, protecting neurons from infection. In addition, they clean up debris created from damaged neurons. Recent research carried out Duke neuroscientist Staci Bilbo and her team indicates that microglia behavior has a vital impact on memory and learning.
Previous research by Assistant Professor Bilbo had demonstrated that lab rats subjected to infections at an early age, responded by producing a strong immune reaction against any subsequent infections. During this induction of immunity, microglia release a signaling molecule called Interleukin-1, or IL-1 for short. However, high levels of IL-1 has been known to affect learning abilities and memory development in laboratory animals.
These observations were obtained during a series of experiments that spanned close to a decade, in which very young rats were exposed to infection and challenged again with a similar yet harmless infection later in life. The second challenge is often followed by a highly effective immune response.
The extra IL-1 production by microglia takes place even if the second infection occurs outside the brain. In order to determine how this immune response affects memory, the team placed lab rats in a novel environment, before exposing them to a sound followed closely by a mild electric shock. Control rats that were not subjected to infection at an early age, remembers the novel environment and the subsequent shock treatment after one exposure. Placing normal rats into the novel environment a second time results in them almost immediately freezing in place out of fear. The converse was observed in previously infected rats, which were observed to run around curiously through the new environment almost as if they had never seen the area before.
The rats that were exposed to infection were aged proportionately to a third trimester human fetus, though Dr Bilbo believes more research is required before an accurate prediction of effects can be made for the human brain.
Microglia and Memory
Morphological intricacy of neurons and glia in a mouse hippocampal organotypic slice. Credit to Dr. Chris Henstridge.
Nobel laureate Mario Cappecchi was the first to show a neuro-immune connection in psychiatric diseases. In this provocative and very interesting study Williamson and colleagues make a link between immunity and memory. They report that neonatal bacterial infection can have long-lasting negative effects on learning and memory later in adult life. Here is the abstract of the study published in October in the Journal of Neuroscience.
The proinflammatory cytokine interleukin-1β (IL-1β) is critical for normal hippocampus (HP)-dependent cognition, whereas high levels can disrupt memory and are implicated in neurodegeneration. However, the cellular source of IL-1β during learning has not been shown, and little is known about the risk factors leading to cytokine dysregulation within the HP. We have reported that neonatal bacterial infection in rats leads to marked HP-dependent memory deficits in adulthood. However, deficits are only observed if unmasked by a subsequent immune challenge [lipopolysaccharide (LPS)] around the time of learning. These data implicate a long-term change within the immune system that, upon activation with the “second hit,” LPS, acutely impacts the neural processes underlying memory. Indeed, inhibiting brain IL-1β before the LPS challenge prevents memory impairment in neonatally infected (NI) rats. We aimed to determine the cellular source of IL-1β during normal learning and thereby lend insight into the mechanism by which this cytokine is enduringly altered by early-life infection. We show for the first time that CD11b+ enriched cells are the source of IL-1β during normal HP-dependent learning. CD11b+ cells from NI rats are functionally sensitized within the adult HP and produce exaggerated IL-1β ex vivo compared with controls. However, an exaggerated IL-1β response in vivo requires LPS before learning. Moreover, preventing microglial activation during learning prevents memory impairment in NI rats, even following an LPS challenge. Thus, early-life events can significantly modulate normal learning-dependent cytokine activity within the HP, via a specific, enduring impact on brain microglial function.
Read the full study here
Synaptic Pruning by Microglia Is Necessary for Normal Brain Development
Image from Mildner et al.2008.Microglia expressing GFP and surrounding a neuron (in red).
Microglia have been shown to be extremely dynamic after insult to the nervous system (they are very good at clearing damaged cellular debris for example). However it remains less clear what role microglia play in physiological conditions. Recent findings published this month in Science reveal an incredible role for the little monocytic cells in synaptic maturation in the brain. Just like garderners, microglia prune the connections between neurons shaping how the brain is wired. Impressive! From sciencedaily.com:
Looking at the developing mouse brain under the microscope, Gross and colleagues found proteins from synapses — the connections between neurons — inside microglia, indicating that microglia are able to engulf synapses too.
To probe further, the scientists introduced a mutation that reduced the number of microglia in the developing mouse brain.
“What we saw was similar to what others have seen in at least some cases of autism in humans: many more connections between neurons,” Gross says. “So we should be aware that changes in how microglia work might be a major factor in neurodevelopmental disorders that have altered brain wiring.”
The microglia-limiting mutation the EMBL scientists used has only temporary effects, so eventually the number of microglia increases and the mouse brain establishes the right connections. However, this happens later in development than it normally would, and Gross and colleagues would now like to find out if that delay has long-term consequences. Does it affect the behaviour of the mice behaviour, for example? At the same time, Gross and colleagues plan to investigate what microglia do in the healthy adult brain, where their role is essentially unknown.
This work was carried out in collaboration with the groups of Davide Ragozzino at the University of Rome and Maurizio Giustetto and Patrizia Panzanelli at the University of Turin.
Read the original article by Gross and colleagues here
