1. Research Background:

The overall aim of our research group is to unravel the fundamental regulatory principles of organismal longevity with a specific focus on the ageing brain. 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. We are particularly interested in understanding the epigenetic mechanism(s) of microglia-neuron interaction and its role in 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 addressed by the group and possible project(s):

1. We are interested in identifying organ and cell type-specific contributions to longevity. We recently identified epigenetic protein coding and non-coding genes that regulate longevity in mice. Using cell type-specific gene manipulations, we wish to address which tissues/cell types contribute to the significant increase in organismal longevity.
2. 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.
3. Neuronal activity is governed by various neurotransmitters that control our behavior. We identified a novel mechanism of neurotransmitter function that involves the brain immune cells – the microglia. We discovered the ability of microglia to respond to specific neurotransmitters in a brain regions specific fashion. We found that dopamine receptor expression on microglia is essential to modulate dopamine-dependent behaviors including addiction and reward in mice. We aim to address the mechanisms of how microglia acquire the neurotransmitter receptor expression and what is its specific function. We are particularly interested in its contribution to Parkinson’s disease, which is caused by the loss of the neurotransmitter dopamine
4. 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. We aim to identify the mechanisms of suppressive microglia on neuronal activity and neuroinflammation. These studies may help to develop new strategies for the intervention with a variety of age-associated neurological disorders, including neurodegeneration. 
5. The progression of neurodegeneration in mice and humans depends on the clearance/accumulation of protein aggregate. One of the main pathways of protein clearance involves endocytosis of protein aggregates by microglia. We have identified a novel epigenetic mechanism of toxic aggregate clearing. We aim to address the principles underlying this novel function and to develop novel targeting approaches to protect against age-associated neurodegeneration. 
6. We identify a subpopulation of microglia that may have neuroprotective features and protect mice and humans against neurodegeneration. We identified a unique set of surface receptors that can be used to identify and manipulate this population. We will aim to target these cells for the purpose of protecting the brain against neurodegenerative diseases.
7. 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 are setting up the stage for age associated neuronal changes. How do early life experiences, such as peripheral infections, can shape that state of the brain immunity and impact brain function later in life?

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. Applied Methods and model organisms:

Model Organisms:

• Transgenic mouse models, in vitro cell systems

Methods:

• 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

4. Desirable skills and qualifications:

Molecular biology, biochemistry, imaging, electrophysiology, neuroscience, behavior analysis and genetics

5. References and key publications:

1. 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
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: 31350310
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