Can the flu affect our brain?

Do you remember the last time you were sick with the flu? It is likely that you experienced symptoms such as a fever, cough, sore throat, and/or fatigue. It is also possible that you had some trouble concentrating or remembering things, which indicates that your brain was potentially impacted by the illness. These cognitive symptoms have been termed “brain fog.” Neurological and cognitive effects have been reported following the 1918 “Spanish flu”, the 2009 influenza A H1N1 pandemic, and more recently the SARS-CoV-2 pandemic. The viruses that cause these respiratory infections do not directly invade the central nervous system (CNS), and it is currently unknown how the infection can cause brain fog. Given that viral infections such as the flu are common and that a large percentage of people with Covid-19 are experiencing long-lasting neurocognitive dysfunction, it is important to understand the effects of peripheral viral infection on the CNS.

One region of the brain that is particularly vulnerable to immune challenges and that is important for cognitive function and memory formation is the hippocampus. Thus, Jurgens et al. sought to use a mouse model of influenza to determine the impact of peripheral viral infection on hippocampal structure and function.

To answer this, the authors intranasally inoculated adult male mice with live influenza A/PR8/34 (H1N1) or with saline. To determine if there were changes in hippocampal-dependent learning resulting from influenza infection, the authors used a behavioral test called the Morris water maze. In this paradigm, mice were place in a circular pool of water that contained a transparent platform hidden below the surface. The platform remained in a constant location and over a period of 5 days, mice were placed in the water and allowed to swim freely for 60 seconds or until they found the platform. If learning has occurred, it is expected that mice will be able to decrease the swimming distance needed to find the platform over the 5 days. Two days after infection, mice underwent this behavioral test, and the authors found that both non-infected and infected mice successfully learned the task at the same rate during the 5 days, indicating that both groups of mice remembered the location of the hidden platform to a high degree. However, on day 6 of testing, the authors moved the location of the hidden platform and found that infected mice showed impaired ability adapt to the new task. Infected mice spent more time returning to the old location of the platform, thus had an increase in swimming distance to the new platform location compared to non-infected mice. These results suggest that influenza-infected mice fail to update their search strategy when compared with non-infected mice.

The authors next wanted to understand what could be causing the cognitive impairment they observed in the behavioral test. They hypothesized that the influenza could have triggered an immune response in the brain, resulting in an increase of inflammatory signaling proteins and cells in the hippocampus. These inflammatory proteins and cells could alter the structural and functional integrity of the hippocampus, resulting in cognitive dysfunction. The authors tested for the presence of these immune proteins and found elevated levels of pro-inflammatory proteins (IL-1β, TNF- α, and IFN- γ) in the hippocampus of infected mice 7 days after inoculation, the same time point during which they observed cognitive deficits, thus providing correlational evidence that inflammation in the hippocampus is happening on the same time scale as cognitive impairment.

Microglia are immune cells in the brain with phagocytic properties that react to pro-inflammatory proteins and become more phagocytic. Once microglia become reactive, they can wreak havoc and result in the death of neurons and other cells in the brain that are important for cognitive function. Microglial reactivity is associated with an increase in the number of microglia or a change in morphology. To investigate the potential microglial response to influenza infection, the authors used immunostaining, a technique to visualize cells in the brain using fluorescent antibodies against specific cell markers, to see if there was a difference in the density of microglia in the hippocampus. They found an increase in the area occupied by microglia throughout the hippocampus in infected mice. This suggests that influenza infection results in an increase in microglial reactivity in the hippocampus. This increase in microglial reactivity could affect other brain cells in the hippocampus that are important for cognition.

Finally, the authors wanted to determine whether the influenza infection and resulting increase in pro-inflammatory proteins and reactive microglia could impact the function of neurons in the hippocampus. These neurons are important for learning and memory, and any change in morphology could suggest a disruption in function. The hippocampus contains subregions with different types of neurons. In each of the subregions the authors investigated using immunostaining, they found a change in the morphology of neurons in infected mice. One example of such a change occurred in a subregion called CA1, which is important for representing space in the environment. Pyramidal neurons, the main cell type in CA1, contain branched extensions called dendrites that are important for receiving signals from other neurons. The authors found that influenza infected mice had smaller dendrites that interacted with fewer neurons. This change in morphology suggests that the function of pyramidal cells was disrupted and could explain the cognitive deficits observed in the infected mice.

Ultimately, this paper demonstrated for the first time the neuroinflammatory and neurocognitive effects of peripheral influenza infection in adult mice. Infected mice displayed cognitive impairment during a memory-related task, had increased expression of pro-inflammatory molecules and cells in the hippocampus, and had altered neuronal morphology in different regions of the hippocampus (Figure 1). Understanding the impact of peripheral viral infection on the CNS can help us develop therapies to address brain fog resulting from influenza and other respiratory infections such as SARS-CoV-2.

Figure 1: Influenza infection in adult mice resulted in cognitive impairment during a memory task, increased microglia reactivity, increased levels of pro-inflammatory proteins, and altered morphology of pyramidal neurons in the hippocampus.

Edited by Tamara Chan

REFERENCES

Jurgens, Heidi A., Kaushik Amancherla, and Rodney W. Johnson. "Influenza infection induces neuroinflammation, alters hippocampal neuron morphology, and impairs cognition in adult mice." Journal of Neuroscience 32.12 (2012): 3958-3968.