Our Research

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.

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.
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.​​​​​​

 

 

 

 

 

 

 

 

 

 

 

 

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.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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).

 

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)

 

 

 

 

 

 

 

 

 

cbl
The cerebellum is a highly folded sheet of layered neurons with a universally conserved, crystalline microcircuit
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.