1. Research Background:
Aging in human and animals is commonly associated with behavioral changes and cognitive decline driven by pathological changes in neuronal function. This decline can take a particularly dramatic turn in case of neurodegenerative diseases such as Alzheimer’s or Parkinson’s disease, which are associated with the abnormal function and death of a large number of neurons and profound behavioral abnormalities. For many years, studies of age-related neurodegeneration were focused primarily on neuron intrinsic processes and largely ignored neuronal dependence on glia and immune cells in the brain. Immune cells in the brain are represented by the innate macrophages-like cells in the CNS, the microglia, as well as by traversing peripheral B and T cells. Recent studies show that these immune cells may play a critical role in the maintenance of brain longevity. Conversely, during ageing and diseases, these cells can impair brain functions by targeting brain cells in a fashion that resembles autoimmune diseases in the periphery and involves immune cell cytotoxicity. We are interested in understanding the mechanism(s) that govern microglia function in heath and diseases. Recently we have discovered that microglia can adapt to specific neuronal phenotypes and that alteration in these adaptive processes may lead to aberrant microglia activation and neuronal death. We also found that microglia can control neuronal activity in a neuron-like fashion by using metabolic mediators commonly involved in immunomodulation in the organism periphery. The overall aim of our research group is to unravel the fundamental regulatory principles of microglia-neuron interaction and its role in the ageing brain. We are particularly interested in understanding the epigenetic mechanism(s) of microglia adaptation to the neuronal environment as well as the mechanism(s) that drive microglia-mediated neuronal pathology. We are keen on defining the key microglia processes that could be used for treatment and possibly prevention of neurodegenerative diseases in human.
2. Research questions addresses by the group:
Microglia, the innate immune cells of the brain, are a highly heterogenous cell population with remarkable brain region specificity. We show that this brain region specificity plays a major role in the regulation of specialized neuron function and longevity. One of our goals is to understand the mechanisms that deter the brain region microglia specificity and its significance in neuronal function. We are particularly interested in defining the neuromodulators of microglia specification as well as the epigenetic mechanisms that would enable phenotype “fluidity” of microglia.
The apparent phenotypic plasticity of microglia raises the question of microglia modulation by environmental impacts, including peripheral inflammation and infection, that have a well-known role in promoting brain aging. Our aim is to generate the spatio-temporal map of brain cells responses to peripheral insults and to use this information for the understanding of the environment-driven wiring of microglia activity and associated neuronal networks in general. One of the goals of this program is to find our whether peripheral impacts at early life can epigenetically alter microglia and neurons for the duration of the life time and to set up the stage for age associated neuronal changes. We found that microglia can act as a bona fide neuronal suppressor cells, in an almost interneuron-like fashion, by producing metabolites that suppress neuronal activity. This function of microglia may contribute both to neuromodulation and possibly to the suppression of aberrantly active microglia as well as other immune cells. In the future, we plan to address the mechanisms of microglia-driven neuromodulation and immunoregulation in the brain. These studies may help to develop new strategies for the intervention with a variety of age-associated neurological disorders including neurodegeneration.
Our studies are highly multidisciplinary and involve approaches that included biochemistry and celluar biology, cutting-edge molecular techniques, large scale genomic research and epigenetics, mouse genetics, immunology and neurobiology.
3. Possible projects:
- Spatio-temporal mapping of brain cell responses to peripheral inflammation and virus infections.
- Identification of neuronal circuits that control sickness behavior and its modulation by microglia.
- How do early life experiences, such as peripheral infections, can shape that state of the brain immunity and impact brain function later in life?
- Identify the mechanisms of suppressive microglia on neuronal activity and neuroinflammation.
- Epigenetic mechanisms of microglia phenotypic plasticity and specification
4. Applied Methods and model organisms:
- Model Organisms:
- Transgenic mouse models, in vitro cell systems
- Cell type-specific ribosome-bound RNA profiling (TRAP) and single cell/nuclei RNA sequencing
- Chromatin studies, Cut&Run, ATAC-seq, ChIP-sequencing analysis
- Mouse genetics and behavioral analysis
- Neuron Glia culture and activity assays (Axiom, Incucyte, Imaris)
- Immunostaining, brain clearance, in-situ, imaging analysis
- Molecular systems neuroscience, optogenetics, Ca-imaging in vivo.
- High resolution microscopy
5. Desirable skills and qualifications:
Molecular biology, biochemistry, neuroscience, and genetics
- Badimon A, Strasburger H, Ayata P, ChenX, NairA, IkegamiA, Hwang P, Chan A, GravesS, Uweru J, Ledderose C, Kutlu M, WheelerM, Kahan A, IshikawaM, WangY,LohY, JiangJ, SurmeierDJ, RobsonS, Junger W, SebraR, Calipari E, KennyP, Eyo U, ColonnaM, QuintanaF, WakeH, GradinaruV, Schaefer A. Negative feedback control of neuronal activity by microglia.Nature, 2020 Oct;586(7829):417-423. doi: 10.1038/s41586-020-2777-8. Epub 2020 Sep 30. PMID: 32999463
- Ayata P, Schaefer A. Innate sensing of mechanical properties of brain tissue by microglia. Curr Opin Immunol. Review. 2020 Feb 10;62:123-130. doi: 10.1016/j.coi.2020.01.003. PMID: 2058296
- Kana V, Desland FA, Casanova-Acebes M, Ayata P, Badimon A, Nabel E, Yamamuro K, Sneeboer M, Tan IL, Flanigan ME, Rose SA, Chang C, Leader A, Le Bourhis H, Sweet ES, Tung N, Wroblewska A, Lavin Y, See P, Baccarini A, Ginhoux F, Chitu V, Stanley ER, Russo SJ, Yue Z, Brown BD, Joyner AL, De Witte LD, Morishita H, Schaefer A, Merad M. CSF-1 controls cerebellar microglia and is required for motor function and social interaction. J Exp Med. 2019 Jul 26. PMID: 31350310
- Gunner G, Cheadle L, Johnson K, Ayata P, Badimon A, Mondo E, Nagy A, Liu L, Bemiller S, Kim K, Lira SA, Lamb BT, Tapper AR, Ransohoff RM, Greenberg ME, Schaefer A, Schafer DP. Sensory lesioning induces microglia-mediated elimination of thalamocortical synapses via neuronal ADAM10 and fractalkine signaling. Nature Neuroscience, 2019 Jul;22(7):1075-1088. PMID: 31209379
- Ayata P, Badimon A, Strasburger HJ, Duff MK, Montgomery SE, Loh YE, Ebert A, Pimenova AA, Ramirez BR, Chan AT, Sullivan JM, Purushothaman I, Scarpa JR, Goate AM, Busslinger M, Shen L, Losic B, Schaefer A. Epigenetic regulation of brain region-specific microglia clearance activity. Nature Neuroscience. 2018 Jul 23. doi: 10.1038/s41593-018-0192-3. PMID: 30038282
- von Schimmelmann M, Feinberg PA, Sullivan JM, Ku SM, Badimon A, Duff MK, Wang Z, Lachmann A, Dewell S, Ma'ayan A, Han MH, Tarakhovsky A, Schaefer A. Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration. Nature Neuroscience. 2016 Oct;19(10):1321-30. doi: 10.1038/nn.4360. Epub 2016 Aug. 15. PMID: 27526204