Environmental Effects on Microglia and Behavior

Did you know that the environment can affect microglia? Although microglia protect the brain by providing the immune response, they can still be affected by the environment and, ultimately, significantly change behavior.

The relationship between microglia and behavior can be influenced by environmental factors such as environmental stressors, isolation or lack of sociability, and environmental enrichment.

In this article, we will take a look at what studies have shown regarding the interplay between environment, microglial activity, and behavior. Also, we pay close attention to how the experiments were carried out.

If you need to strengthen your background understanding of microglia, check out our introductory article on The Behavioral Researcher’s Guide to Microglia. In it, we discuss what microglia are, including their function and various phenotypes.

Environmental factors are of particular interest since they offer an additional pathway that could potentially explain the relationship between microglia and behavior, as well as health and disease.

Thus, since it has been established that microglia can affect behavior, any factor that can further influence microglial activity is of interest and relevance to behavioral researchers.

In fact, in addition to environmental effects, another area of potential interest for behavioral researchers has to do with how microglial physiology is related to behavior.  In order to understand how microglia influence behavior (and how the environment modulates this), the role of its physiology must first be charted out.

Early-life social isolation (ESI) is a model for inducing depressive-like behavior, but it can also affect the brain’s microglia. ESI is an environmental approach to inducing depressive-like behavior accomplished by inhibiting rodents’ natural tendency to be social.

A study by Wang et al. made use of the ESI model and found that ESI rats had:^[1]

• Increased Iba1 marker levels: ESI rats had increased levels of Iba1, a microglial activation marker, in the hippocampus. This means that there was increased microglial activation in the hippocampus in the rats that were subjected to early-life isolation.
• Decreased microglial CD200 receptor expression in the hippocampus: The microglial CD200 receptor is responsible for promoting microglial quiescence (dormancy or inactivity). Thus, decreased levels of expression for this receptor indicate that microglial cells were active and not dormant.
• Increased proinflammatory cytokine levels: ESI rats were found to have increased levels of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) which are associated with microglial activation.
• Higher instances of depressive-like behaviors: Rats that were subjected to ESI demonstrated depressive-like behaviors as confirmed by their performance in the sucrose preference test and the Forced Swim Test.
• Decreased performance in the sucrose preference test: ESI rats had a significantly lower percentage of sucrose preference when compared to controls.
• Increased immobility: ESI rats were on average 150s immobile in the Forced Swim Test while controls were immobile for 100s, a significant difference between the two groups.

When the ESI rats were treated with minocycline (an antibiotic that inhibits microglial activation), there was a:

• Decrease in microglial activation: Treatment with minocycline resulted in a significant decrease of microglial activation in the ESI group’s hippocampus.
• Decrease in proinflammatory cytokines: Furthermore, minocycline treatment in ESI rats prevented the rise of proinflammatory cytokines (IL-1β, IL-6, and TNF-α).
• Reversal of depressive-like behaviors: As a result of taking minocycline, ESI rats had a significant reduction of depressive-like behavior as measured by the sucrose preference test and the Forced Swim Test when compared to non-treated ESI rats.

Such behavioral and pharmaceutical findings demonstrate how changes in microglia correspond to a change in behavior, suggesting a physiological link between microglia and behavior. Furthermore, this experiment showed the key role that microglia plays in inflammation. To read more about this intersection of research, check out our article on Microglia, Inflammation, and Behavior.

Rich environments can also affect behavior and microglial activation. A study by Chabry et al. showed that environmental enrichment affects hippocampal microglia and cognition.

The researchers used depressed mice in order to study how inflammation is attenuated through environmental enrichment. Depression was induced through the chronic administration of corticosterone.^[3]

The researchers found that environmental enrichment attenuates microglial expression:

• Standard environment: In a standard laboratory housing, depressed mice had significantly higher levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNFα) in the hippocampus when compared to mice also chronically exposed to corticosterone but housed in an enriched environment.
• Enriched environment: In an enriched environment, rodents are housed in larger cages and are given objects (like toys, hammocks, etc.) which are frequently changed. The mice that were given corticosterone chronically had non-significant differences of IL-1β and IL-6 in the hippocampus when compared with healthy controls given saline (thus, not induced with depression) living in a standard environment. Also, the corticosterone treated mice in enriched environment housing had an increase in adiponectin in their cerebrospinal fluid. This suggests that the lower microglial activity seen in the enriched environment condition is somehow modulated by adiponectin. In the next section, we will see how the experimenters expanded their hypothesis on the interaction between adiponectin, environment, and behavior.

These findings suggest that environmental enrichment blocks the pro-inflammatory cytokines associated with chronic corticosterone induction which is a model of depression.

Adiponectin is Vital for Environmental Enrichment Benefits

Furthermore, in order to learn more about microglial communication and signaling mechanisms, the same researchers performed a second set of tests, this time using adiponectin knockout mice.^[3]

Adiponectin was of interest since a growing body of research exists showing that adiponectin is implicated in microglial functioning and also in depression.^[4]

Adiponectin can be found throughout the peripheral and central nervous systems (CNS). In the CNS, adiponectin is found in the hypothalamus, amygdala, cortex, and the hippocampus. It is also believed to have some anti-inflammatory properties.

In the study by Chabry et al., adiponectin knockout (AKO) mice lacked the gene for adiponectin and thus were adiponectin-deficient. When subjected to the same depression-inducing conditions through corticosterone injections, they demonstrated:

• Higher levels of pro-inflammatory microglia: The depressed AKO mice living in standard cages had higher levels of IL-1β, IL-6, and TNF-α in the hippocampus, indicating a pro-inflammatory microglial phenotype.
• Depressive-like behaviors: The depressed AKO mice showed high durations of immobility. When measured in the Forced Swim Test, they averaged about 175 seconds of immobility. In the Tail Suspension Test, the AKO mice averaged 125 seconds of immobility.

Environmental enrichment for AKO mice subjected to chronic corticosterone administration:

• Was not protective or anxiolytic: The benefits associated with environmental enrichment were no longer seen in AKO mice, indicating that microglial activity needs to be attenuated by adiponectin somehow in order for environmental enrichment to show its protective effects.
• Did not improve depressive-like behaviors: Environmental enrichment did not improve the depressive-like behaviors as it was able to do in the original experimental condition.

However, when the depressed AKO mice were injected with adiponectin, they demonstrated:

• The positive effects associated with environmental enrichment: Once the depressed AKO mice were given adiponectin, the benefits associated with environmental enrichment were once again observed.
• A rescued microglial phenotype: Since depression was associated with a pro-inflammatory profile, as characterized by the increase in pro-inflammatory cytokines, treating depressed AKO mice with adiponectin led to a reversal of this outcome. Adiponectin-treated mice had an anti-inflammatory microglial profile.
• Significantly lower depressive-like behaviors: Once the depressed AKO mice were injected with adiponectin, they demonstrated a significant reduction of depressive-like behaviors when compared to saline-injected depressed AKO mice. The treated mice averaged about 100 seconds of immobility in the Forced Swim Test and about 100 seconds of immobility in the Tail Suspension Test.

This experiment demonstrated many different aspects of microglia and behavior. It captured the relationship between microglial phenotypes and depressive behaviors, but also demonstrated how microglial physiology affects behavior through the manipulation of adiponectin.

The observation remarking on depressive-like behaviors is an example of how microglia can be implicated in neurocognition. To see the more conditions that microglia have been implicated in, check out the article Microglia, Diseases, and Behavior.

The environment can significantly shape microglial activity and function. Since microglia are becoming increasingly implicated in disease pathophysiology, it is important to take into account the role of the environment.

The future of this area of research will focus on how combined stressors affect behavior and microglia, as seen in the example above where air pollution and restricted maternal nesting were combined to alter microglial activation and cognition.

As scientists get a better understanding of how environmental factors affect microglia and alter behavior, more light will be shed on complex conditions such as autism spectrum disorders.^[5]

1. Wang, Hong-Tao, et al. “Early-life social isolation-induced depressive-like behavior in rats results in microglial activation and neuronal histone methylation that are mitigated by minocycline.” Neurotoxicity research 31.4 (2017): 505-520.
2. Bolton, Jessica L., et al. “Maternal stress and effects of prenatal air pollution on offspring mental health outcomes in mice.” Environmental health perspectives 121.9 (2013): 1075-1082.
3. Chabry, Joëlle, et al. “Enriched environment decreases microglia and brain macrophages inflammatory phenotypes through adiponectin-dependent mechanisms: relevance to depressive-like behavior.” Brain, behavior, and immunity 50 (2015): 275-287.
4. Liu, Jing, et al. “Adiponectin is critical in determining susceptibility to depressive behaviors and has antidepressant-like activity.” Proceedings of the National Academy of Sciences 109.30 (2012): 12248-12253.
5. Bilbo, Staci D., et al. “Beyond infection-Maternal immune activation by environmental factors, microglial development, and relevance for autism spectrum disorders.” Experimental neurology 299 (2018): 241-251.