Mark J. Wagner, Ph.D.

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Stadtman Investigator
Address
Neocortex-cerebellum Circuitry Unit

Bldg 49 Rm 2A35
49 Convent Dr
Bethesda MD 20814

Dr. Wagner joined NINDS as a Stadtman Investigator in August 2021. Before joining the NIH, Dr. Wagner studied bioengineering at Harvard University, researching human motor control with Maurice Smith during a combined B.A./M.S., then obtained a Ph.D. in Neuroscience from Stanford University under Mark Schnitzer, as well as postdoctoral training with Liqun Luo also at Stanford, developing novel strategies to study cortex-cerebellum circuitry in learning and behaving mice.

Click here to visit Dr. Wagner's lab page.

How do we learn to play the piano or tennis — complex and unnatural skills that aren’t linked to the evolution of our species? These are examples of our remarkable knack for general learning. In tackling this mystery, we’ve homed in on the two brain learning sites that make up ~99% of all human neurons: the cortex and cerebellum. Cortex and cerebellum differ in nearly every way: dissimilar types of neurons, wired into contrasting network architectures, using different learning mechanisms. Yet, somehow, cortex and cerebellum became inextricably linked — they’ve expanded together over mammalian evolution and interconnect by universally conserved pathways. We hypothesize that cortex and cerebellum have joined forces to implement algorithms that lie at the heart of our talent for general learning. We therefore devise new strategies to directly observe and perturb cortex-cerebellum interactions while animals learn novel skills over weeks. We believe that cracking the cortex-cerebellum algorithm will remake our understanding of the normal brain and of brain dysfunction, with potential applications as far afield as A.I.

 

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A key piece of the cortex-cerebellum puzzle is the reencoding of cortical transmissions to the cerebellar input layer: granule cells. We developed the first recordings from these tiny, densely packed neurons in animals performing learned, reward-driven tasks via two photon microscopy.
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To understand how granule cell activity relates to things happening in the neocortex, we devised the first simultaneous recordings of both output cells of the premotor cortex (left) and cerebellar granule cells (right), using dual-site two-photon imaging . By watching these two brain areas co-evolve over weeks of skill learning, we found that behavioral representations developed jointly in cortex and cerebellum, hinting at a paired learning process.​​​​​​

 

 

 

 

 

 

 

 

 

 

 

 

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To piece these central circuit components into an integrated model of cortex-cerebellum transmission, we’ve developed the first simultaneous recordings of cerebellar granule cell and climbing fiber activity throughout skill learning, using two-color, two-depth two-photon imaging.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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dual site and manipulandum
We observe neural interactions between the cortex and cerebellum directly and simultaneously (left) over days to weeks as naïve animals learn to acquire novel skills, for example directing the handle of a robotic arm (right).

 

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l5grchist
All cortex layer 5 cells (green on the left) that project out of the cortex will then disynaptically contact cerebellar granule cells (green on the right)

 

 

 

 

 

 

 

 

 

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cbl
The cerebellum is a highly folded sheet of layered neurons with a universally conserved, crystalline microcircuit
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histo
Granule cells (green) are >50% of mammalian neurons and carry information from outside cerebellum to Purkinje cells (red) which compute predictions that relayed to the rest of the brain and body.

 

   

 

 

 

Postdoctoral Fellows

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Martha Garcia-Garcia

 

Martha Garcia-Garcia, Ph.D.
Ph.D., M.S., Biomedical Engineering, Univ of Toronto
B.S., Biomedical Engineering, Univ Iberoamericana

 

 

 

 

 

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Yingtao Liu

 

Yingtao Liu, Ph.D.
Ph.D., M.S., Biophysics, University of Tokyo
B.S., Astrophysics, Peking University

 

 

 

 

Students

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Ben Filio

 

Benjamin Filio
Ph.D student, NIH-Brown University Neuroscience Program
B.S., Neuroscience, Wesleyan Univ

 

 

 

 

Post-baccalaureate Fellows

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Dariel Cordero

 

Dariel Cordero
B.S., University of Puerto Rico, Aguadilla

 

 

 

 

 

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Subhiksha Srinivasan

 

Subhiksha Srinivasan
B.A., Biochemistry & Neuroscience, Lawrence University

 

 

 

 

 

 

Alumni

 

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Tobi Akinwale

 

Tobi Akinwale
Masters Student, Bioinformatics, Johns Hopkins
B.S., Cell. Molec. Biol., Towson Univ

 

 

 

 

 

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Lina Takemaru

 

Lina Takemaru 
Ph.D Student, UPenn Computational Biology
M.S., B.S., Statistics, Cornell Univ

 

 

 

 

 

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Akash Kapoor

 

Akash Kapoor
M.D. Student, Columbia University
B.S., Neuroscience, UCLA

 

 

 

 

 

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Samantha Berg

 

Samantha Berg
Ph.D. student, Clinical Psych, Univ MD Baltimore County
B.S., Psychology, Univ Central Florida

 

 

 

 

 

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Casey Paton

 

Casey Paton 
M.D. student, Univ. of Rochester
M.A., Neuroscience, Fisk Univ
B.S., Human Biol Health & Soc, Cornell Univ

Principal publications

MJ Wagner, J Savall, O Hernandez, G Mel, H Inan, O Rumyantsev, J Lecoq, TH Kim, JZ Li, C Ramakrishnan, K Deisseroth, L Luo, S Ganguli, MJ Schnitzer. A neural circuit state change underlying skilled movements. Cell 184(14), 3731-3747 (2021). 10.1016/j.cell.2021.06.001

SA Shuster✱, MJ Wagner, N Pan-Doh, J Ren, SM Grutzner, KT Beier, TH Kim, MJ Schnitzer, L Luo. The relationship between birth timing, circuit wiring, and physiological response properties of cerebellar granule cells. PNAS 118(23) (2021). 10.1073/pnas.2101826118

MJ Wagner, L Luo. Neocortex-cerebellum circuits for cognitive processing. Trends in Neurosciences 43(1), 4254 (2020). 10.1016/j.tins.2019.11.002

MJ Wagner, J Savall, TH Kim, MJ Schnitzer, L Luo. Skilled reaching tasks for head-fixed mice using a robotic manipulandum. Nature Protocols 15, 1237–1254 (2020). 10.1038/s41596-019-0286-8

MJ Wagner, TH Kim, J Kadmon, ND Nguyen, S Ganguli, MJ Schnitzer, L Luo. Shared cortex-cerebellum dynamics in the execution and learning of a motor task. Cell 177, 669682 (2019). 10.1016/j.cell.2019.02.019

MJ Wagner, TH Kim, J Savall, MJ Schnitzer, L Luo. Cerebellar granule cells encode the expectation of reward. Nature 544, 96100 (2017). 10.1038/nature21726
                
Coverage: Nature Rev. Neurosci. 18, 263 (2017); Nature Neurosci. 20, 633-634 (2017); Current Biology 27, 415-418 (2017); Trends in Neurosci 12:874-877 (2018).

MJ Wagner & MA Smith. Shared internal models for feedforward and feedback control. Journal of Neuroscience 28(42), 10663-10673 (2008). 10.1523/jneurosci.5479-07.2008
                Coverage: Nature 456, 679 (2008)

Additional publications

Rudolph, S., Badura, A., Lutzu, S., Pathak, S.S., Thieme, A., Verpeut, J.L., Wagner, M.J., Yang, Y.M. and Fioravante, D. Cognitive-Affective Functions of the Cerebellum. J Neurosci, 43(45), 7554-7564 (2023). 10.1523/JNEUROSCI.1451-23.2023

S Muscinelli, MJ Wagner, A Litwin-Kumar. Optimal routing to cerebellum-like structures. Nature Neuroscience 26(9):1630-1641 (2023). 10.1038/s41593-023-01403-7

T Li, TM Fu, KK Wong, H Li, Q Xie, DJ Luginbuhl, MJ Wagner, E Betzig, L Luo. Cellular bases of olfactory circuit assembly revealed by systematic time-lapse imaging. Cell 184(20):5107-21 (2021). 10.1016/j.cell.2021.08.030

DT Pederick, JH Lui, EC Gingrich, C Xu, MJ Wagner, Y Liu, Z He, SR Quake, L Luo. Reciprocal repulsions instruct the precise assembly of parallel hippocampal networks. Science 372(6546):1068-73 (2021). 10.1126/science.abg1774

Y Takeo, A Shuster, L Jiang, M Hu, DJ Luginbuhl, T Rülicke, X Contreras, S Hipponmeyer, MJ Wagner, S Ganguli, L Luo. GluD2 and Cbln1-mediated competitive synaptogenesis shapes the dendritic arbors of cerebellar Purkinje cells. Neuron 14(20), 933-8 (2021). 10.1016/j.neuron.2020.11.028

JH Lui, ND Nguyen, SM Grutzner, S Darmanis, D Peixoto, MJ Wagner, WE Allen, JM Kebschull, EB Richman, J Ren, WT Newsome, SR Quake, L Luo. Differential encoding in prefrontal cortex projection neuron classes across cognitive tasks. Cell 184(2), 489-506 (2021). 10.1016/j.cell.2020.11.046

T Zhang, O Hernandez, R Chrapkiewicz, A. Shai, MJ Wagner, Y Zhang, C Wu, JZ Li, M Inoue, Y Gong, B Ahanonu, H Zeng, H Bito, MJ Schnitzer. Kilohertz two-photon brain imaging in awake mice. Nature Methods 16(11), 1119-1122 (2019). 10.1038/s41592-019-0597-2

MJ Wagner. Cognitive signaling in cerebellar granule cells. Neuropsychopharmacology 43, 222-223 (2018). 10.1038/npp.2017.186

Y Gong, MJ Wagner, JZ Li, MJ Schnitzer. Imaging neural spiking in brain tissue using FRET-opsin protein voltage sensors. Nature Communications 5, 3674 (2014). 10.1038/ncomms4674

LC Parra, C Christoforou, AD Gerson, M Dryholm, A Luo, MJ Wagner, MG Philiastides, P Sajda. Spatiotemporal linear decoding of brain state. IEEE Signal Processing Magazine 25, 107-115 (2008). 10.1109/msp.2008.4408447