Research Interests
Project 1. Targeting neuroinflammatory responses in the aged brain to improve cognitive function.
We are exploring how to promote effective microglial responses in the aged brain.
Over an animal’s lifespan, microglia become more reactive or ‘primed’. This worsens pathological outcomes when aged animals encounter immune challenges (e.g. infection, surgery, or injury). We are investigating mechanisms that underlie microglia priming with age, and are exploring strategies to dampen priming of aged microglia.
In particular, in modern society, unusually sterile conditions may worsen neuroinflammation. The “old friends” hypothesis states that the immune system co-evolved with microorganisms that help program immunity during development, and that underexposure to these organisms can harm immune function. Reintroduction of microorganisms in a “clean” environment can improve the composition of the microbiome and quell hyperactive inflammatory responses. Despite the therapeutic potential of specific small microbes, few studies have assessed whether the immunoregulatory benefits of microbial based treatments target the central nervous system.
Here we will investigate the mechanisms by which vaccination with a widely distributed soil bacterium, Mycobacterium vaccae (M. vaccae; NCTC11659), prevents exacerbated neuroinflammatory and behavioral deficits in aging.
This work is supported by NIH R01 AG062716.
Figure captions. Aging is associated with compensatory shifts in CNS physiology and function, which collaborate to increase neuroimmune priming and pro-inflammatory bias. Left schematic: The neuroimmune system involves several key components: (1) parenchymal neuroimmune cells; (2) glymphatic flow, communication, and clearance via lymphatic vessels, dural venous sinuses, and cervical lymph nodes; and (3) bi-directional communication with the periphery via the vagus nerve, the gut-CNS axis, and other routes (omitted for clarity). Letters A-C highlight representative areas described in the right panel. Letters A-C highlight representative areas described in the right panel. A. The healthy adult CNS parenchyma contains homeostatic microglia and astrocytes, which maintain low baseline inflammatory tone, efficiently phagocytose cells and debris, and resolve sickness and inflammatory responses. The healthy aged CNS parenchyma includes neuroimmune cells with a “primed” phenotype - these cells are hyperreactive to insult, show impaired phagocytic capacity and processing, and have less effective immune resolution ability. The aged CNS also exhibits increased accumulation of inflammatory mediators, such as cytokines and damage-associated molecular patterns (DAMPs). Aging is also associated with aberrant parenchymal accumulation of immune cells typically found in the periphery, such as T cells. B. The healthy adult BBB maintains a cohesive barrier, enabling bi-directional active transport of specific proteins. The glymphatic system clears debris and excess metabolites. In the aged CNS, BBB integrity is reduced, enabling aberrant entry of toxins and cells, in parallel with reduced solute-specific transport. Glymphatic flow is less efficient at clearing debris; this amplifies accumulation of immunomodulatory mediators. C. CNS-periphery communication in the healthy adult contributes to low inflammatory tone at baseline; with aging, increased T cell numbers and shifted T cell proportions contribute to increased pro-inflammatory bias. From: Fonken, LK & Gaudet AD. (2022) Neuroimmunology of healthy brain aging. Current Opinion in Neurobiology: In press.
Project 2. Circadian regulation of neuroimmune function.
We aim to understand how the circadian system regulates neuroinflammatory function and how disruption of rhythms at key developmental stages can lead to pathology.
In Dr. Fonken’s postdoctoral research, she established that microglia express circadian timekeeping mechanisms which can gate the inflammatory response. Circadian rhythms dampen with age and Alzheimer’s disease and may contribute to heightened neuroinflammation and disease pathology.
The immune system is tightly regulated by the circadian clock, generating daily cycles of immune cell migration throughout the body which leads to temporal windows of high and low immune reactivity. The immune system also critically regulates CNS function; peripheral inflammation disrupts behavior and impairs cognition. During aging, the CNS immune system gradually shifts from a balance between pro- and anti- inflammatory function towards a more reactive inflammatory state. Importantly, trafficking of adaptive immune cells to immune-brain interfaces regulates neuroinflammation and cognition. Thus, we hypothesize that circadian rhythms in immune cell trafficking to the CNS are disrupted with age and AD-like pathology, leading to cognitive and behavioral changes.
This work is supported by start NIH R01 AG078758.
Selected publications (Full list)
Fonken, L.K., Frank, M.G., D’Angelo, H.M., Heinze, J.D., Watkins, L.R., Lowry, C.A., & Maier, S.F. (2018). Mycobacterium vaccaeimmunization protects aged rats from surgery-elicited neuroinflammation and cognitive dysfunction. Neurobiology of Aging 71, 105-114.
Fonken, L.K., Frank, M.G., Kitt, M.M., D’Angelo, H.M., Norden, D.M., Weber, M.D., Barrientos, R.M., Godbout, J.P., Watkins, L.R., & Maier, S.M. (2016). The alarmin HMGB1 mediates age-induced neuroinflammatory priming. The Journal of Neuroscience 36 (30): 7946-7956.
Fonken, L.K., Frank, M.G., Kitt, M.M., Barrientos, R.M., Watkins, L.R., & Maier, S.F. (2015). Microglia inflammatory responses are controlled by an intrinsic circadian clock. Brain, Behavior, and Immunity 45: 171-179.
Fonken, L.K., Xu, X., Weil, Z.M., Chen, G., Sun, Q., Rajagopalan, S., & Nelson, R.J. (2011). Air pollution impairs cognition, provokes depressive-like behaviors, and alters hippocampal cytokine expression and morphology. Molecular Psychiatry. 16 (10): 987-995.
Fonken, L.K., Workman, J.L., Walton, J.C., Weil, Z.M., Morris, J.S., Haim, A., & Nelson, R.J. (2010). Light at night increases body mass by shifting the time of food intake. Proceedings of the National Academy of Sciences, 107 (43): 18664-18669.