Microglia Aging and Behavior

Aging doesn’t just mean wrinkles, it also means changes in microglia functioning. Because aging is associated with microglial dysfunction, ultimately affecting behavior and cognition, it is a specific factor that must be addressed in the context of health and disease.

In this section, we take a closer look at how studies have addressed some of the questions associated with aging, microglia, and behavior.

To strengthen your background understanding of microglia, the central nervous system’s immune cells, check out this introductory article Guide to Behavior and Microglia where we discuss what microglia are, including their function and various phenotypes.

Aging is a serious public health issue that needs to be addressed. About 23% of the global burden of disease is due to the disorders found in the elderly, members of the population that are 60 years old and up.^[1]

Since almost one-fourth of the global burden of disease is attributed to this specific group of the population, research efforts must somehow focus on ameliorating this burden.

For researchers that are studying behavior and cognition, aging is a key part of the equation. To understand aging, the biological basis is studied in conjunction with behavioral outcomes.

Ever since microglia, have been implicated in behavior, researchers have been trying to better understand Microglial Physiology and Behavior. In fact, aging is one of the factors that contribute to microglial dysfunctioning.

Therefore, since microglia are involved in behavior and pathophysiology, they must be taken into account when studying aging.

The effect that age has on behavior, cognition, and microglia is illustrated well in an experiment conducted by Barrientos et al.^[2]

To create a peripheral infection, Escherichia coli was injected in young and old rats. Then, the following effects were observed in the older, aging rats:

• Increased IL-1β levels in the hippocampus: The coli-exposed aging rats were found to have significantly higher IL-1β levels in the hippocampus when compared to young E.coli-exposed rats.
• Increased microglial activity: Microglial activity is responsible for the majority of IL-1β production in the brain. Thus, an increase of IL-1β levels in aging rats is indicative of increased microglial activity.
• Prolonged inflammation: In addition to having increased microglial activity, aging rats stayed in a proinflammatory state for a significant amount of time when compared with young rats.
• Impaired hippocampal-dependent memory: In the Contextual Fear Conditioning task, coli-exposed aging rats had significant deficits in remembering that a stimulus was paired with a conditioned response. Since Contextual Fear Conditioning is a hippocampal-dependent memory task, the inability of E. coli-exposed aging rats to perform this task suggests that inflammation and microglial activity negatively affected the hippocampus. By comparison, old vehicle-treated rats performed at the level of young vehicle-treated rats (which performed at the level of young E. coli-exposed rats). Thus, from the four conditions, only the aged E. coli-exposed rats showed memory deficits indicating that age is a factor that must be considered when assessing behavior, inflammation, and microglial activity.
• Decreased freezing: Specifically, the impairment in hippocampal-dependent memory is indicated through decreased instances of freezing behavior. When rats are conditioned to associate a foot shock with an auditory tone, they will automatically freeze. Freezing is a normal response that occurs when a rodent knows that it is in a dangerous and potentially harmful situation. Increased instances of freezing indicate that a rat has learned to associate the tone with a harmful shock. coli-exposed aging rats displayed a significantly lower percentage of freezing behaviors when compared with old vehicle-treated rats and young E. coli-exposed rats, suggesting that they were unable to learn that the auditory tone was indicative of a dangerous situation.

This experiment demonstrates how researchers manage to establish that aging is a factor that influences both microglial activity and behavior.

Inflammation is an area in itself when it comes to studying microglia and behavior. For more information, check out our related article: Microglia, Inflammation, and Behavior.

In order to study the effects of exercise on aging and microglia, an experiment by Kohman et al.^[3] used adult (3.5 months old) and aged (18 months old) BALB/c mice for 8 weeks by individually housing them either with or without a Running Wheel.

Thus, the behavior of interest in this experiment was exercise/locomotion, i.e. wheel running.

The researchers found many significant differences between the adult and aged mice as a result of the exercise intervention. The major findings were:

• Aged mice had a significantly higher baseline count of microglia: Aged mice had a greater count of new microglia than young mice. Thus, at baseline, there was already a difference between young and aged mice in the abundance of microglia.
• Running increases the proportion of IGF-1 expressing microglia: Insulin-like growth factor (IGF-1) is a neuroprotective factor that has anti-inflammatory effects when it acts on microglia.^[4] The aged mice that had access to the Running Wheel had significantly higher levels of microglia that expressed IGF-1, suggesting that the microglia were in their neuroprotective phenotype as a result of exercise.
• Wheel running increases new neuron survival: New neurons are more likely to survive in both adult and aged mice that have wheel running access. Thus, these results suggest that wheel running is able to promote a proneurogenic phenotype, as well as a neuroprotective microglial phenotype, in aged mice.

This experiment demonstrates the effects of exercise on the central nervous system and immune activity. Wheel running (i.e., exercise) ultimately alleviates the inflammatory effects on microglia associated with aging, ultimately shifting towards a neuroprotective phenotype instead.

Dysfunctional microglia are believed to be implicated in facilitating aging mechanisms possibly through the dysregulated overexpression of pro-inflammation mediators.

Luteolin is a flavonoid that has been shown to have anti-inflammatory effects. However, luteolin’s ability to help aged mice by reducing inflammatory mediators, inhibiting microglia activity, and improving hippocampal-dependent learning is still unknown.

A study by Jang et al. addressed these issues by feeding adult (3-6 mo) and aged (22-24 mo) mice either a control diet or a luteolin (20 mg/d) supplemented diet for a span of 4 weeks.^[5]  Then, the aged mice had their spatial working memory tested, as well as the abundance of hippocampal inflammatory markers.

The researchers found that:

• Normal aged mice have significantly higher microglial cell activity: Aged mice (22-24 mo) that were fed a control diet had significantly higher microglial cell activity when compared with the adult mice (3-6 mo) that were also on the control diet. Thus, aging contributes significantly to microglial activity in older mice.
• Luteolin improves inflammatory markers in the hippocampus: Control-fed aged mice had significantly higher levels of expressed proinflammatory IL-6 and TNF-α markers. By comparison, aged mice on the luteolin diet had significant drops in these same markers due to the flavonoid luteolin diet. This suggests that the flavonoid luteolin was able to significantly reduce the proinflammatory state of microglial activity, as indicated by a significant reduction in hippocampal inflammatory markers.
• Normal aged mice show spatial working memory deficits: Aged mice that were on the control diet regiment displayed deficits in spatial working memory when compared with control adult mice. When tested for their memory abilities using the Morris Water Maze, the normal aged mice traveled for a significantly longer distance before finding the hidden platform. This suggests that age is a factor that affects performance on spatial working memory.
• Luteolin-fed mice have improved spatial working memory: However, luteolin-fed aged mice displayed significant improvements in the spatial working memory test as a result of the dietary intervention. In the Morris Water Maze, the luteolin-fed aged mice showed a significant decrease in the distance they traveled before finding the hidden platform, indicating that they remembered the platform’s location. In fact, the luteolin-supplemented aged mice performed at the level of control adult mice.

This experiment demonstrated how a flavonoid was able to treat increased inflammation and microglial activity, ultimately leading to improved spatial working memory and behavior in aged mice.

Although aging is associated with impairments in memory, as well as altered microglial activity, research has been promising in finding how these aspects of biology can be changed for the better.

By focusing on microglial activity, behavioral researchers have been able to show how inflammation associated with aging and its impacts on behavior can be improved through interventions such as exercise or diet.

Future research will focus on disentangling how environmental factors affect microglia  and the role of microglia in disease and behavior, in order to get a full picture of how microglia function.

1. Prince, Martin J., et al. “The burden of disease in older people and implications for health policy and practice.” The Lancet385.9967 (2015): 549-562.
2. Barrientos, Ruth M., et al. “Time course of hippocampal IL-1 β and memory consolidation impairments in aging rats following peripheral infection.” Brain, behavior, and immunity 23.1 (2009): 46-54.
3. Kohman, Rachel A., et al. “Wheel running attenuates microglia proliferation and increases expression of a proneurogenic phenotype in the hippocampus of aged mice.” Brain, behavior, and immunity 26.5 (2012): 803-810.
4. Labandeira-Garcia, Jose L., et al. “Insulin-like growth factor-1 and neuroinflammation.” Frontiers in aging neuroscience 9 (2017): 365.
5. Jang, Saebyeol, Ryan N. Dilger, and Rodney W. Johnson. “Luteolin inhibits microglia and alters hippocampal-dependent spatial working memory in aged mice.” The Journal of nutrition140.10 (2010): 1892-1898.