1. Research Background:

Ageing in human and animals is commonly associated with behavioral changes and cognitive decline driven by pathological changes in neuronal function. On the other side, many old people appear protected against the age-associated decline in brain function. My laboratory tries to address the mechanisms underlying neuronal longevity and protection against age- associated perturbations, with a specific focus on the epigenetic mechanisms. Opposite to the majority of somatic cells, which have a relative limited number of diverging developmental trajectories, neurons have been shown to have the largest number of finite differentiated states reflecting the high degree of neuronal specification. Once established, neurons maintain their morphological and functional specification for the duration of a life time. We are interested in understanding the mechanisms that govern brain homeostasis and its aberrations during ageing and neurodegeneration. We showed that the maintenance of transcriptional neuronal specification in the adult brain has an epigenetic underpinning that defines the trajectory of the ageing neuron. We further found that neuronal phenotypes are tightly coupled to phenotypes of microglia, the innate immune cells of the brain.

For many years, studies of age-related neurodegeneration 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. 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) underlying the maintenance of neuronal specification and longevity, the 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:

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 apparentphenotypic 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 ageing. 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 altermicroglia 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:

• Epigenetic mechanisms that govern neuronal longevity during ageing and its aberrations during neurodegeneration.
• Epigenetic mechanisms of microglia phenotypic plasticity and specification.
• Identify the mechanisms of suppressive microglia on neuronal activity and neuroinflammation.
• 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?

4. Applied Methods and model organisms:

Model Organisms:

• Transgenic mouse models, in vitro cell systems

Methods:

• Cell type-specific ribosome-bound RNA profiling (TRAP) and single cell/nuclei RNA sequencing
• Chromatin studies, Cut&Run, ATAC-seq, ChIP-sequencing analysis High resolution microscopy, spatial transcriptomics
• 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.

5. Desirable skills and qualifications:

Molecular biology, biochemistry, neuroscience, and genetics

6. References:

1. Badimon A, Strasburger H, Ayata P, Chen X, Nair A, Ikegami A, Hwang P, Chan A, Graves S, Uweru J, Ledderose C, Kutlu M, Wheeler M, Kahan A, Ishikawa M, Wang Y, Loh Y, Jiang J, Surmeier DJ, Robson S, Junger W, Sebra R, Calipari E, Kenny P, Eyo U, Colonna M, Quintana F, Wake H, Gradinaru V, 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
2. 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
3. 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: 3135031
4. 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
5. 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
6. 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