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Environmental enrichment mitigates hypothalamic inflammation and improves metabolic function across the lifespan of mice

Ali, Seemaab
http://orcid.org/0000-0002-5337-8782
http://rave.ohiolink.edu/etdc/view?acc_num=osu1587632494811204

Abstract Details

2020, Doctor of Philosophy, Ohio State University, Neuroscience Graduate Studies Program.
Aging population demographics show that the age structure of the United States is shifting, with more individuals over the age of 65 than those under 18 projected as soon as 2034. These trends are expected to continue, mirroring population changes happening globally. The obesity epidemic is also worsening, and high body mass index and associated complications continue to contribute significantly to morbidity and mortality. Obesity in the United States impacts the middle-aged most severely, and research shows obesity is one of the strongest predictors of mortality at midlife. The conjunction of these population trends is a progressing public health concern. Environmental enrichment (EE), a housing model for animals implemented for animal welfare, has been shown to improve health in aging mice. Recent evidence suggests that age-related metabolic decline, obesity, and age- and obesity-associated illness stems from shared pathophysiology. This dissertation addresses hypothalamic inflammation as an overlapping etiology of aging and obesity and defines how it is impacted by environmental enrichment.

Enrichment housing of female C57BL/6 mice over 12 months starting in middle age improves metabolism and reduces adiposity. We examined hypothalamic neuroinflammatory markers and observed reduced inflammation following EE. Microglia are the resident immune cells of the brain which are chronically and progressively more pro-inflammatory across the lifespan. Based on these studies, we prepared and visualized immunohistochemical staining of microglia. After 7.5 months of EE started in middle age, microglia throughout the brain exhibited increased ramification. This suggests microglial surveillance of the central nervous system (CNS) parenchyma is enhanced or activated by EE. Morphometric analyses performed using FIJI, an image processing package of ImageJ provided by the National Institutes of Health, showed increased area, branch number, and branch length of microglia. These features were region- and nucleus- specific, but were pronounced in the hypothalamus, hippocampus, and amygdala.

Microglia are also CNS-supportive glia. As resident macrophages in the brain, they aid in synaptic formation, elimination, and plasticity by providing trophic support and phagocytosing apoptotic cells and circuit debris. We investigated the role of microglia in the CNS changes important for EE metabolic outcomes. Specifically, EE activates the hypothalamic-sympathoneural-adipocyte axis, in which brain-derived neurotrophic factor (BDNF) is produced by the hypothalamus and activates the sympathetic nervous system, which signals onto adipocytes for adipolysis and lowering circulating leptin. Using the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX5622, we depleted microglia from the CNS of middle-aged female mice before housing them in either standard or EE housing. PLX5622 did not impair or enhance the hypothalamic expression of BDNF in response to enrichment. Removal of microglia in middle age in combination with EE resulted in a robustly improved metabolic phenotype when compared to either PLX5622 or EE alone. The ability of PLX5622 to remove pro-inflammatory microglia in the CNS, and to reduce specific classes of adipose tissue macrophages in the periphery, may both play a role in the enhanced combined effect of the housing and drug interventions.

BDNF is the key mediator of the improved whole-body metabolism seen in EE. Hypothalamic expression of BDNF with an adeno-associated virus (AAV-BDNF) in young male mice reduced adiposity and neuroinflammatory markers. Microglia expressed reduced fractalkine receptor (CX3CR1) in response to EE, and this increased CX3CR1 expression was recapitulated in dissected block hypothalamus by AAV-BDNF. Blockade of neuronal BDNF with an AAV expressing a dominant negative version of the BDNF receptor (AAV-TrkB.T1) in neurons resulted in the reversal of these trends: increased weight gain and increased hypothalamic inflammation. AAV-TrkB.T1 was sufficient to block adiposity reduction by EE in middle-aged mice, and AAV-TrkB.T1 treatment resulted in significant microgliosis in the hypothalamus.

Together this research demonstrates the utility of EE in improving health in animals. Modulation of microglia by EE has implications for other neuroinflammatory conditions, and reducing hypothalamic inflammation may be one mechanism through which EE and lifestyle interventions can improve metabolism. Complex neuron-microglia communication in the hypothalamus is impacted by neuronal BDNF signaling. We are continuing to explore this and other lines of research.
Lei Cao (Advisor)
Christin Burd (Committee Member)
Jonathan Godbout (Committee Member)
Monica Venere (Committee Member)
213 p.
Endocrinology; Immunology; Neurobiology; Neurosciences
environmental enrichment; aging; obesity; microglia; morphology; brain derived neurotrophic factor; BDNF; hypothalamus; adipose tissue; macrophage

Recommended Citations

Citations

  • Ali, S. (2020). Environmental enrichment mitigates hypothalamic inflammation and improves metabolic function across the lifespan of mice [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1587632494811204

    APA Style (7th edition)

  • Ali, Seemaab. Environmental enrichment mitigates hypothalamic inflammation and improves metabolic function across the lifespan of mice. 2020. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1587632494811204.

    MLA Style (8th edition)

  • Ali, Seemaab. "Environmental enrichment mitigates hypothalamic inflammation and improves metabolic function across the lifespan of mice." Doctoral dissertation, Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1587632494811204

    Chicago Manual of Style (17th edition)

osu1587632494811204
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