Elsevier

Brain, Behavior, and Immunity

Volume 27, January 2013, Pages 22-32
Brain, Behavior, and Immunity

Named Series: Neurogenesis and Inflammation
Neurogenesis, inflammation and behavior

https://doi.org/10.1016/j.bbi.2012.09.003Get rights and content

Abstract

Before the 1990s it was widely believed that the adult brain was incapable of regenerating neurons. However, it is now established that new neurons are continuously produced in the dentate gyrus of the hippocampus and olfactory bulb throughout life. The functional significance of adult neurogenesis is still unclear, but it is widely believed that the new neurons contribute to learning and memory and/or maintenance of brain regions by replacing dead or dying cells. Many different factors are known to regulate adult neurogenesis including immune responses and signaling molecules released by immune cells in the brain. While immune activation (i.e., enlargement of microglia, release of cytokines) within the brain is commonly viewed as a harmful event, the impact of immune activation on neural function is highly dependent on the form of the immune response as microglia and other immune-reactive cells in the brain can support or disrupt neural processes depending on the phenotype and behavior of the cells. For instance, microglia that express an inflammatory phenotype generally reduce cell proliferation, survival and function of new neurons whereas microglia displaying an alternative protective phenotype support adult neurogenesis. The present review summarizes current understanding of the role of new neurons in cognition and behavior, with an emphasis on the immune system’s ability to influence adult hippocampal neurogenesis during both an inflammatory episode and in the healthy uninjured brain. It has been proposed that some of the cognitive deficits associated with inflammation may in part be related to inflammation-induced reductions in adult hippocampal neurogenesis. Elucidating how the immune system contributes to the regulation of adult neurogenesis will help in predicting the impact of immune activation on neural plasticity and potentially facilitate the discovery of treatments to preserve neurogenesis in conditions characterized by chronic inflammation.

Highlight

► New neurons are continuously produced in two regions of the adult brain, the hippocampus and the olfactory bulb. This review discusses current understanding of how the immune system affects adult neurogenesis and the implications for cognitive function.

Section snippets

Introduction to adult neurogenesis

Before the 1990s, it was widely thought that neurons in the adult human brain did not regenerate. Consequently, it was thought that if neurons died during your adult life for any reason (e.g., oxidative stress, stroke, neurodegenerative disease, head trauma, normal aging), they would never be replaced. However, in the 1960s, Altman and colleagues challenged this idea, reporting that new neurons are continuously and spontaneously born in at least two regions of the adult rat brain: the

Neuroinflammation

The immune system can be divided into the innate and adaptive immune systems. While these divisions work together to orchestrate the immune response each serves distinct roles that facilitate recovery from an injury or infection. The innate immune system serves as the initial defensive to combat an infection. This response is rapid, but non-specific and is primarily mediated by cells of a myeloid origin (i.e., macrophages, neutrophils, and dendritic cells). In contrast the adaptive branch of

Phenotype-specific effects of microglia on hippocampal neurogenesis

Microglia can have both supportive and harmful effects on adulthood neurogenesis depending on their state of activation. Microglia that express a proinflammatory phenotype generally impair neurogenesis whereas as microglia that express a neuroprotective phenotype can facilitate new cell survival. The present section will cover the differential phenotypes microglia express and the distinct effects each phenotype has on influencing hippocampal neurogenesis.

Role of microglia in activity-induced increases in neurogenesis

As discussed, neurogenesis is regulated by a variety of factors. Exercise has been consistently shown to enhance hippocampal neurogenesis by increasing neuronal differentiation and new cell survival. Though the data are limited, there is reason to speculate that immune cells may participate in the enhancement of neurogenesis following exercise and environmental enrichment. For example, Ziv et al. (2006) report that interactions between T-cells and microglia participate in the environmental

Role of microglia in age-related decline in neurogenesis

Hippocampal neurogenesis persists throughout an individual’s life, as centurions show evidence of neurogenesis (Knoth et al., 2010). However, there is a substantial decline in neurogenesis with normal aging. Aging is associated with a decrease in both proliferation and survival of new cells (Blackmore et al., 2009, Kohman et al., 2011, van Praag et al., 2005). Several factors likely contribute to the age-related decrease in neurogenesis. For instance, neural progenitor cells have been reported

Potential role of neurogenesis in inflammation-induced cognitive deficits

Activation of the immune system leads to a host of well characterized behavioral changes, some of which are adaptive responses that facilitate recovery and others less so. Sickness behavior is a constellation of behavioral alterations that include a decrease in locomotion, social and sexual behavior, development of anorexia and a fever response (Dantzer, 2004). These behavioral changes are thought to reflect an altered motivation state rather than a physical disability and expedite recovery

Conclusion

The evidence clearly indicates that neuroinflammation can suppress hippocampal neurogenesis. However, we are just beginning to understand the role microglia play in regulating neurogenesis under basal conditions in the absence of an infection or injury. Clearly, microglia are not simply waiting around in the brain for an infection to occur, but rather are participating in basal neural processes, such as neurogenesis. Progress in research has created a broader view of microglia’s role within the

Funding

Supported by Grants from National Institute of Health, MH083807 and DA027487 to J.S.R and from National Institute on Aging K99AG0404184 to R.A.K.

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