Scientists at the Krembil Brain Institute, part of University Health Network
(UHN), in collaboration with colleagues at the Centre for Addiction and
Mental Health (CAMH), have used precious and rare access to live human
cortical tissue to identify functionally important features that make human
neurons unique.
This experimental work is among the first of its kind on live human neurons
and one of the largest studies of the diversity of human cortical pyramidal
cells to date.
"The goal of this study was to understand what makes human brain cells
'human,' and how human neuron circuitry functions as it does," says Dr.
Taufik Valiante, neurosurgeon, scientist at the Krembil Brain Institute at
UHN and co-senior author on the paper.
"In our study, we wanted to understand how human pyramidal cells, the major
class of neurons in the neocortex, differ between the upper and bottom
layers of the neocortex," says Dr. Shreejoy Tripathy, a scientist with the
Krembil Centre for Neuroinformatics at CAMH and co-senior author on this
study.
"In particular, we wanted to understand how electrical features of these
neurons might support different aspects of cross-layer communication and the
generation of brain rhythms, which are known to be disrupted in brain
diseases like epilepsy."
With consent, the team used brain tissue immediately after it had been
removed during routine surgery from the brains of patients with epilepsy and
tumours. Using state-of-the-art techniques, the team was then able to
characterize properties of individual cells within slices of this tissue,
including visualizations of their detailed morphologies.
"Little is known about the shapes and electrical properties of living adult
human neurons because of the rarity of obtaining living human brain tissue,
as there are few opportunities other than epilepsy surgery to obtain such
recordings," says Dr. Valiante.
To keep the resected tissue alive, it is immediately transferred into the
modified cerebrospinal fluid in the operating room then taken directly into
the laboratory where it is prepared for experimental characterization.
It is rare to study human tissue because accessing human tissue for
scientific inquiries requires a tight-knit multidisciplinary community,
including patients willing to participate in the studies, ethicists ensuring
patient rights and safety, neurosurgeons collecting and delivering samples,
and neuroscientists with necessary research facilities to study these
tissues.
After initial analysis, members of the Krembil Centre for Neuroinformatics
used further large-scale data analysis to identify the properties that
distinguished neurons in this cohort from each other. These properties were
then compared to those from other centres doing similar work with human
brain tissue samples, including the Allen Institute for Brain Sciences in
Seattle, Washington.
Noted in the team's findings:
A massive amount of diversity among human neocortical pyramidal cells
Distinct electrophysiological features between neurons located at different
layers in the human neocortex
Specific features of deeper layer neurons enabling them to support aspects
of across-layer communication and the generation of functionally important
brain rhythms
The teams also found notable and unexpected differences between their
findings and similar experiments in pre-clinical models, which Dr. Tripathy
believes is likely reflective of the massive expansion of the human
neocortex over mammalian and primate evolution.
"These results showcase the notable diversity of human cortical pyramidal
neurons, differences between similarly classified human and pre-clinical
neurons, and a plausible hypothesis for the generation of human cortical
theta rhythms driven by deep layer neurons," says Dr. Homeira Moradi Chameh,
a scientific associate in Dr. Valiante's laboratory at Krembil Brain
Institute and lead author on the study.
In total, the team was able to characterize over 200 neurons from 61
patients, reflecting the largest dataset of its kind to-date and
encapsulating almost a decade's worth of painstaking work at UHN and the
Krembil Brain Institute.
"This unique data set will allow us to build computational models of the
distinctly human brain, which will be invaluable for the study of distinctly
human neuropathologies," says Dr. Scott Rich, a postdoctoral research fellow
in Dr. Valiante's laboratory at the Krembil Brain Institute and co-author on
this work.
"For instance, the cellular properties driving many of the unique features
identified in these neurons are known to be altered in certain types of
epilepsy. By implementing these features in computational models, we can
study how these alterations affect dynamics at the various spatial scales of
the human brain related to epilepsy, and facilitate the translation of these
'basic science' findings back to the clinic and potentially into motivations
for new avenues in epilepsy research."
"This effort was only possible because of the very large and active epilepsy
program at the Krembil Brain Institute at UHN, one of the largest programs
of its kind in the world and the largest program of its kind in Canada,"
says Dr. Valiante.
The study is published in Nature Communications.
Reference:
"Diversity amongst human cortical pyramidal neurons revealed via their sag
currents and frequency preferences," Nature Communications, DOI:
10.1038/s41467-021-22741-9