Close

Sparse recurrent excitatory connectivity in the microcircuit of the adult mouse and human cortex

Stephanie C Seeman, Luke Campagnola, Pasha A Davoudian, Alex Hoggarth, Travis A Hage, Alice Bosma-Moody, Christopher A Baker, Jung H. Lee, Stefan Mihalas, Corinne Teeter, Andrew L Ko, Jeffrey G Ojemann, Ryder P Gwinn, Daniel L Silbergeld, Charles Cobbs, John Phillips, Ed Lein, Gabe Murphy, Christof Koch, Hongkui Zeng, Tim Jarsky

Posted on: 31 May 2018

Preprint posted on 8 May 2018

Article now published in eLife at http://dx.doi.org/10.7554/elife.37349

New work from @AllenInstitute compares synaptic connectivity in human cortex to the commonly studied mouse visual cortex. Very insightful study from preproduction data -- looking forward to the full production data release!

Selected by Mahesh Karnani

Categories: neuroscience

Summary

This preprint from Tim Jarsky’s team at the Allen Institute for Brain Science shows synaptic connectivity profiles within cortical layers in neurosurgical samples of human brain and compares them thoroughly to samples from mouse brain. Compared to the commonly studied mouse visual cortex, the human frontal and temporal cortex has more synaptically connected neurons forming a denser recurrent microcircuit. The conclusions are compatible with previous work and help place findings from the mouse in a translational perspective.

 

Context

Understanding how the brain generates activity patterns that underlie thought and behaviour necessitates knowledge of communication protocols in local microcircuits that are composed of synaptically connected neurons. Synaptic communication in microcircuits of the rodent brain has been studied for decades, using multi-cell patch clamp recordings in acutely isolated brain slices. This work has resulted in detailed – although still incomplete – knowledge of connectivity patterns in rodent sensory cortex 1,2 and an ongoing transition toward studying how the microcircuit layout affects dynamics of brain activity and cortical computations. Similar work in the human cortex is yet to be done, although some laboratories do have access to neurosurgical samples of human brain, resected during removal of brain tumours, for example.

One such laboratory is at the Allen Institute for Brain Science, which has already contributed big datasets from many large-scale projects to the neuroscience community, creating comprehensive databases of meso-scale connectivity, marker expression, and morphologies of human and mouse neurons 3. The institute is currently working on several highly interesting projects and accelerates dissemination of results through its online database and preprinting regularly on Biorxiv. Their latest work compares connectivity in human frontal and temporal cortex to mouse visual cortex. The presented dataset is from a “pipeline’s system integration test” and is expected to lead to a comprehensive dataset, as the team starts routine operation of the workflow.

 

 

Key findings

This study is very exciting because it shows increased connectivity and synaptic weights in human cortex compared to the mouse visual cortex. The study confirms previous reports of high connectivity in human cortex 4 and gives a translational perspective compared to results obtained in mouse cortex. Whereas previous work identified complex multisynaptic events triggered by single action potentials in human cortex 4,5, this study aimed to minimize their occurrence since they can interfere with assessment of monosynaptic connectivity. Lowering the occurrence of complex events was achieved by modifying experimental variables such as decreased recording temperature and calcium and potassium concentrations of the extracellular medium compared to the previous studies.

Recurrent synaptic connectivity in human L2/3 is relatively dense. From Seeman et al., 2018, Figure 2 (under CC-BY-NC-ND 4.0).

 

While lower than in human cortex, connectivity in the mouse visual cortex was high compared to a previous study 2. The authors have two results that bear on this and similar discrepancies in the literature. Firstly, connectivity is highly distance dependent and should thus be reported as a function of distance in order to compare across labs. Secondly, led by co-first-author Luke Campagnola, the team have devised a machine learning based method for estimating synapse detection limits during paired recordings. This approach can be used to compare results from different labs if the raw data are made available.

 

Why I chose this preprint 

I work on connectivity in the mouse brain, and often think about how applicable these results are to our efforts to understand our own brains. Evolutionary and structural arguments suggest there is a “translational bridge”, but it is very important to have direct comparative data. The key physiological differences include the high connectivity in human cortex reported in this preprint and enlarged excitatory synapses on inhibitory interneurons 5–7. Together these endow human cortex the propensity for complex multisynaptic events triggered by single action potentials. This is exceedingly rare in rodent microcircuits 8 and could partly explain the ability of the human neocortex to perform highly complex tasks. However, it seems from this preprint that the complex events are quite sensitive to extracellular medium composition. It would be interesting to see more direct, controlled comparisons of complex events across recording conditions and species.

 

What next?

The authors have made a powerful pipeline for generating important results from human cortex. While it will be highly informative to use their protocols with single action potentials and firing trains in one cell at a time to characterize synaptic responses, even more could be learned through simultaneous firing protocols in multiple cells. This could reveal cooperatively scaling excitation and disynaptic inhibition 9,10 which may be drastically different in human cortex, given the differences noted so far. The presented human data are within layers and across pyramidal cells only, and it will be interesting to see in future publications how connectivity across layers and interneurons compares to mouse.

 

References:

  1. Lefort, S., Tomm, C., Floyd Sarria, J.-C. & Petersen, C. C. H. The Excitatory Neuronal Network of the C2 Barrel Column in Mouse Primary Somatosensory Cortex. Neuron 61, 301–316 (2009).
  2. Jiang, X. et al. Principles of connectivity among morphologically defined cell types in adult neocortex. Science. 350, aac9462-aac9462 (2015).
  3. http://www.brain-map.org/.
  4. Molnár, G. et al. Complex events initiated by individual spikes in the human cerebral cortex. PLoS Biol. 6, e222 (2008).
  5. Szegedi, V. et al. High-Precision Fast-Spiking Basket Cell Discharges during Complex Events in the Human Neocortex. eNeuro 4, ENEURO.0260-17.2017 (2017).
  6. Szegedi, V. et al. Plasticity in Single Axon Glutamatergic Connection to GABAergic Interneurons Regulates Complex Events in the Human Neocortex. PLoS Biol. 14, e2000237 (2016).
  7. Molnár, G. et al. Human pyramidal to interneuron synapses are mediated by multi-vesicular release and multiple docked vesicles. Elife 5, e18167 (2016).
  8. Brecht, M. Neuronal communication: firing spikes with spikes. Curr. Biol. 22, R633-5 (2012).
  9. Kapfer, C., Glickfeld, L. L., Atallah, B. V & Scanziani, M. Supralinear increase of recurrent inhibition during sparse activity in the somatosensory cortex. Nat. Neurosci. 10, 743–53 (2007).
  10. Berger, T. K., Silberberg, G., Perin, R. & Markram, H. Brief Bursts Self-Inhibit and Correlate the Pyramidal Network. PLoS Biol. 8, e1000473 (2010).

Tags: human brain, synaptic connectivity

Read preprint (No Ratings Yet)

Author's response

Tim Jarsky shared

We are thankful for the opportunity to discuss and receive feedback on our recent manuscript through preLights. We share Mahesh’s excitement regarding the increased rate of connectivity and strength of recurrent excitatory connections in human, compared to mouse. We anticipate building out our human datasets to include the short-term dynamics in near physiological (~1.3 mM) external calcium concentrations. We believe this type of data will be useful for building a network model that will inform our understanding of human cortical processing.

The challenge of characterizing local cortical connectivity with the detail necessary to build useful computational models is enormous. We’ve taken a modest step to help bring the community closer to this goal by gathering a relatively large, standardized data set from a range of synapse types and layers in adult mouse and human, that we intend to share. We are also interested in accelerating progress by helping and working with the larger scientific community. We wish to open a dialog with laboratories performing similar experiments (publicly on preLights would be fantastic) so that we can work toward building datasets that can be compared and combined more easily. We believe that a comprehensive integrated data set gives us the best chance to answer many of the interesting questions raised in this preLight and ultimately a better understanding of human cognition.

Have your say

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Sign up to customise the site to your preferences and to receive alerts

Register here

Also in the neuroscience category:

The RNA binding protein HNRNPA2B1 regulates RNA abundance and motor protein activity in neurites

Joelle Lo, Katherine F. Vaeth, Gurprit Bhardwaj, et al.

Selected by 24 September 2024

Felipe Del Valle Batalla

Neuroscience

Pharyngeal neuronal mechanisms governing sour taste perception in Drosophila melanogaster

Bhanu Shrestha, Jiun Sang, Suman Rimal, et al.

Selected by 23 September 2024

Matthew Davies

Cell Biology

Triglyceride metabolism controls inflammation and APOE4-associated disease states in microglia

Roxan A. Stephenson, Kory R. Johnson, Linling Cheng, et al.

Selected by 22 August 2024

Gustavo Stelzer, Marcus Oliveira

Biochemistry

preLists in the neuroscience category:

2024 Hypothalamus GRC

This 2024 Hypothalamus GRC (Gordon Research Conference) preList offers an overview of cutting-edge research focused on the hypothalamus, a critical brain region involved in regulating homeostasis, behavior, and neuroendocrine functions. The studies included cover a range of topics, including neural circuits, molecular mechanisms, and the role of the hypothalamus in health and disease. This collection highlights some of the latest advances in understanding hypothalamic function, with potential implications for treating disorders such as obesity, stress, and metabolic diseases.

 



List by Nathalie Krauth

‘In preprints’ from Development 2022-2023

A list of the preprints featured in Development's 'In preprints' articles between 2022-2023

 



List by Alex Eve, Katherine Brown

CSHL 87th Symposium: Stem Cells

Preprints mentioned by speakers at the #CSHLsymp23

 



List by Alex Eve

Journal of Cell Science meeting ‘Imaging Cell Dynamics’

This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.

 



List by Helen Zenner

FENS 2020

A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020

 



List by Ana Dorrego-Rivas

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)

 



List by Madhuja Samaddar et al.

SDB 78th Annual Meeting 2019

A curation of the preprints presented at the SDB meeting in Boston, July 26-30 2019. The preList will be updated throughout the duration of the meeting.

 



List by Alex Eve

Autophagy

Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.

 



List by Sandra Malmgren Hill

Young Embryologist Network Conference 2019

Preprints presented at the Young Embryologist Network 2019 conference, 13 May, The Francis Crick Institute, London

 



List by Alex Eve
Close