Mark Wagner , Ph.D.

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. Current, Dr. Wagner leads the Neocortex-cerebellum Circuitry Unit.

Research Interests:

In the Neocortex-cerebellum Circuitry Unit, the aim is to understand brain computations that help animals learn new skills. We are focused on the universally conserved circuits interconnecting the neocortex and cerebellum, which together account for ~99% of human neurons. Strikingly, cortico-cerebellar circuit anatomy is preserved across many domains of information processing, suggesting some basic computational approaches with utility across many behaviors and mammalian species. We are interrogating the transmission and transformation of information through cortico-cerebellar circuitry, and its modification with learning. We engineer new strategies to observe and manipulate circuits in learning animals, and use computational approaches to identify underlying mathematical principles. Via neural imaging, electrophysiology, optogenetics, and viral-genetic techniques, we are developing and testing hypotheses of cortico-cerebellar learning strategies.

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.

Lab Members:

Postdoctoral Fellows

• Martha Garcia-Garcia, Ph.D.
  Ph.D., M.S., Biomedical Engineering, Univ of Toronto
  B.S., Biomedical Engineering, Univ Iberoamericana
• Yingtao Liu, Ph.D.
  Ph.D., M.S., Biophysics, University of Tokyo
  B.S., Astrophysics, Peking University
• Philipp Maurus, Ph.D
  Ph.D., Biomechanics, Univ. of Calgary
  M.S., B.S., Kinesiology, Karlsruhe Institute of Tech

Students

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

Post-baccalaureate Fellows

• Amma Otchere
  B.S., Neuroscience, Yale University
• Srijan Thota
  B.S., Biochemistry, NJ Inst of Technology
• Subhiksha Srinivasan
  B.A., Biochemistry & Neuroscience, Lawrence University

Lab Alumni

• Tobi Akinwale
  M.S., Bioinformatics, Johns Hopkins
  B.S., Cell. Molec. Biol., Towson Univ
• Dariel Cordero
  B.S., University of Puerto Rico, Aguadilla
• Lina Takemaru 
  Ph.D Student, UPenn Computational Biology
  M.S., B.S., Statistics, Cornell Univ
• Akash Kapoor
  M.D. Student, Columbia University
  B.S., Neuroscience, UCLA
• Samantha Berg
  Ph.D. student, Clinical Psych, Univ MD Baltimore County
  B.S., Psychology, Univ Central Florida

Selected Publications: 

Principal Publications

MG Garcia-Garcia✱, A Kapoor✱, O Akinwale✱, L Takemaru✱, TH Kim, C Paton, A Litwin-Kumar, MJ Schnitzer, L Luo, MJ Wagner. A cerebellar granule cell–climbing fiber computation to learn to track long time intervals Neuron 112(16), (2024). 10.1016/j.neuron.2024.05.019
        Highlight: R Broersen, CI De Zeeuw (2024). Neuron 112, 2664-2666. 10.1016/j.neuron.2024.07.010.

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), 42–54 (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, 669–682 (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, 96–100 (2017). 10.1038/nature21726
                Highlights: 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
                Highlight: 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