1. Research Background:

Our research group studies the mechanisms underlying brain longevity and fitness. We aim to identify key molecular and cellular processes that support neuronal longevity and determine neuronal susceptibility to neurodegeneration. We strive to define the rules of physiological and pathological brain aging by investigating the intrinsic and extrinsic mechanisms of neuronal longevity. Like other cells in our body, neurons' life "ticks" along the epigenetic aging clock, which defines their true biological age. We aim to elucidate the mechanisms that govern this aging clock and its connection to neuronal metabolism and gene regulation. Our overarching hypothesis is that neuronal aging results from epigenetically determined deregulation of coordinated gene and protein expression, followed by excessive energy expenditure and aging. We also focus on the role of brain cells such as astrocytes and microglia, which support neuronal survival and function. We hypothesize that neuronal aging alters the adaptive capacity of microglia, leading to altered neuron-microglia interactions and subsequent microglia-mediated “attacks” on neurons. Many of our research aims are supported by human and mouse genetic data and involve multidisciplinary approaches and cutting-edge technologies.

2. Research questions addressed by the group and possible project(s):

1. We are interested in identifying the mechanisms that control the progression of the epigenetic aging clock. Our ultimate goal is to define the factors that drive the clock and could be used to slow it down and mitigate aging. We are particularly interested in identifying neuronal type differences in “clocking” and its possible connection to the ability of neurons to enter a transient metabolic dormancy state that temporarily slows down the aging process.
2. Microglia, the innate immune cells of the brain, are a highly heterogeneous cell population with remarkable brain region specificity. We have shown that this brain region specificity plays a major role in the regulation of specialized neuronal function and longevity. Recently, we identified a microglia subpopulation with neuroprotective activity, which may play a key role in determining the speed of neurodegenerative diseases in both animals and humans. We aim to characterize these neuroprotective microglia with the purpose of possible pharmacological modulation of microglia-driven neuroprotective states. We have identified a unique set of surface receptors that can be used to identify and manipulate this population and will target these cells to protect the brain against neurodegenerative diseases.
3. Organismal aging is linked to soluble factors found in various bodily fluids such as blood, lymph, or interstitial fluid. These factors can either accelerate or suppress aging. We speculate that the concentration of anti- or pro-aging factors may be influenced by auto-reactive antibodies that become prevalent during aging. Our aim is to test whether age-associated autoimmunity contributes to the aging process via antibody-mediated neutralization of anti- and/or pro-aging factors.
4. One of our key aims involves understanding the role of human viral diseases in brain aging. We aim to determine whether peripheral infections can lead to stable changes in neuronal and/or microglial function and their impact on brain aging. We are also keen to understand the role of brain-resident human viruses in neuronal aging and neuron-microglia interactions. One goal of this program is to investigate whether peripheral impacts during early life can epigenetically alter microglia and neurons throughout the lifespan, setting the stage for age-associated neuronal changes.

Our studies are highly multidisciplinary and include approaches such as biochemistry, cellular biology, imaging, cutting-edge molecular techniques, large-scale genomic research and epigenetics, mouse genetics, immunology, and neurobiology. Our research is highly collaborative and involves research centers around the world. All of our immunology and virus-related studies are conducted in collaboration with Dr. Alexander Tarakhovsky, a Max Planck Fellow at the Institute and Professor at the Rockefeller University in New York.

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. Paolicelli RC, Sierra A, Stevens B, Tremblay ME, Aguzzi A, Ajami B, Amit I, Audinat E, Bechmann I, Bennett M, Bennett F, Bessis A, Biber K, Bilbo S, Blurton-Jones M, Boddeke E, Brites D, Brône B, Brown GC, Butovsky O, Carson MJ, Castellano B, Colonna M, Cowley SA, Cunningham C, Davalos D, De Jager PL, de Strooper B, Denes A, Eggen BJL, Eyo U, Galea E, Garel S, Ginhoux F, Glass CK, Gokce O, Gomez-Nicola D, González B, Gordon S, Graeber MB, Greenhalgh AD, Gressens P, Greter M, Gutmann DH, Haass C, Heneka MT, Heppner FL, Hong S, Hume DA, Jung S, Kettenmann H, Kipnis J, Koyama R, Lemke G, Lynch M, Majewska A, Malcangio M, Malm T, Mancuso R, Masuda T, Matteoli M, McColl BW, Miron VE, Molofsky AV, Monje M, Mracsko E, Nadjar A, Neher JJ, Neniskyte U, Neumann H, Noda M, Peng B, Peri F, Perry VH, Popovich PG, Pridans C, Priller J, Prinz M, Ragozzino D, Ransohoff RM, Salter MW, Schaefer A, Schafer DP, Schwartz M, Simons M, Smith CJ, Streit WJ, Tay TL, Tsai LH, Verkhratsky A, von Bernhardi R, Wake H, Wittamer V, Wolf SA, Wu LJ, Wyss-Coray T.
   Microglia states and nomenclature: A field at its crossroads.
   Neuron. 2022 Nov 2;110(21):3458-3483. doi: 10.1016/j.neuron.2022.10.020. Review. PubMed PMID: 36327895.
2. 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
3. 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
4. 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
5. 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
6. 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
7. 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