Infraslow dynamics of cortical microcircuits

Lead Research Organisation: University of Leicester
Department Name: Neuroscience, Psychology and Behaviour

Abstract

Neuroscientists seek to explain how brain activity gives rise to perceptions (e.g., recognising pictures, sounds and smells), movements (e.g., getting up from a chair), and memories (e.g., recalling your yesterday's whereabouts). These cognitive processes occur in a fraction of a second, so most neuroscience research is focused on neural signalling that happens on this and faster timescales. Some neural processes, however, happen on much slower timescales. Sleep is one such example: one cycle takes about 24 hours. In fact, neural dynamics is not limited to one or just a few specific timescales but has prominent features on all timescales - seconds, minutes and hours included.

Our preliminary work shows that individual brain nerve cells ('cortical neurons') spontaneously vary their activity over tens of seconds and minutes, and that there are marked differences even among neighbouring cells in the way this occurs. The functions and mechanisms of these slow changes received very little attention and are not well understood. The aim of this project is to relate the activity of individual cortical neurons to the activity of large ensembles of cortical neurons on timescales of tens of seconds to several minutes. This will give us new insight into cognitive processes that happen on these timescales, such as changes in attention, motivation, introspection, vigilance, as well as how these slow processes modulate the fast cognitive processes.

We will use high density arrays of miniature electrodes to record for up to 10 hours the individual activity of dozens of neighbouring nerve cells in different areas of the mouse cortex. This will allow us to understand how changes in activity of single neurons are related to changes occurring in their neighbours. We will also study how the very slow changes in activity depend on the neurons' location in the cortex and on the state of the animal, for example during waking and sleeping.

In the second part of the project we will examine how the slow changes in activity are generated. We will record and manipulate the electrical potential inside individual nerve cells. These experiments will reveal the mechanisms that regulate nerve cell activity, e.g., by 'resting' after a period of intense activity, and will tell us why different cells generate different slow behaviour.

Finally, we will develop statistical methods to analyse our complex experimental observations. Preliminary work suggests that this is best achieved using frequency domain approaches which rely on the so called Fourier transform that decomposes signals into sums of sinusoids of different frequencies.

This work will answer fundamental questions about nerve cell functions, but there is an additional important reason for wishing to understand the slow changes in activity of cortical neurons. This reason concerns 'functional magnetic resonance imaging' - the most advanced method for non-invasively observing neural activity, which is widely used in both science and medicine. Functional magnetic resonance imaging (fMRI) measures neural activity indirectly, via its effect on the blood supply to the brain, and is consequently limited to revealing only the slowest components of neural activity. As a result of fMRI's widespread use, much is known about slow changes in activity of cortical areas, and this information is beginning to be used for diagnosis and treatment of neurological conditions. What is sorely lacking, however, is an understanding of how individual nerve cells give rise to the high level activity patterns. Our study will help filling this gap in our knowledge, and thus provide a better understanding of the origins of fMRI signals.

Technical Summary

Cortical dynamics in the 0.01-1 Hz band has not received much attention outside the fMRI community, and has thus been studied only at the mesoscale spatial resolution. We seek to understand the dynamics of individual neurons and microcircuits in this frequency band. Our recent experiments show that individual cortical neurons exhibit prominent and highly heterogeneous slow firing rate changes. We will investigate (1) how single cell activity relates to mesoscale infraslow cortical dynamics, (2) which cellular mechanisms contribute to it, and (3) which statistical methods can describe the dynamics of cortical populations across multiple timescales.

To examine the relationship between individual neurons and mesoscale infraslow dynamics we will use chronic silicon probe recordings to study how individual cells couple to their local population in the infraslow frequency band. Surprisingly, preliminary data shows that in a significant proportion of cells population coupling on fast time scales is unrelated to population coupling on slow timescales. We will build on the preliminary findings to consider the effects of brain state, as well as possible differences across cortical layers and areas.

To examine the cellular mechanisms that shape the infraslow dynamics of individual neurons we will use simultaneous silicon probe, LFP and intracellular recordings. We will test the hypothesis that intrinsic conductances and spike frequency adaptation in particular are primary factors in slow activity changes. We will also study how different cell types differ in their infraslow dynamics.

To have succinct statistical summary of neuronal activity across multiple timescales we will develop frequency domain models for characterising and modelling population spiking dynamics. We will also investigate hybrid time-frequency models, where fast dynamics is parametrised in the time domain, while slow dynamics is parametrised in the frequency domain.

Planned Impact

The proposed work is at the level of fundamental science and its main impact is in the generation of essential knowledge about how the brain works.

Since the project will directly contribute to our understanding of the nature of cortical activity that drives resting state fMRI signals, it may have an impact on the different uses of fMRI. Cortical resting state fMRI signals are altered in a variety of neurological conditions, such as drug addiction, schizophrenia, autism spectrum disorders, and others. This project may therefore contribute to our understanding of the basis for these abnormal changes, influence clinical practices and lead to design of compensatory and therapeutic interventions. In the long run, improved understanding of the neural activity underlying fMRI signals might benefit the manufacturers of MRI scanners. The statistical tools that we will develop to study population activity might be useful for quantitative analysis of fMRI, particularly by radiologists.

The project falls under the Responsive Mode Priority "Data driven biology" because one of the three objectives of the project is to develop a new computational approach to describe neuronal population activity. The project also falls under the "Systems approaches to the biosciences" Priority because it entails a multidisciplinary approach that integrates elements of experimental neurophysiology, computational neuroscience and signal processing. Furthermore, both the experimental and the modelling parts of the project involve components on different hierarchical levels, starting from membrane potentials and spikes of individual neurons, up to population and LFP signals which represents the activity of hundreds or thousands of neurons.

The project will provide the postdoctoral research associate with a great opportunity to develop an extensive experimental and computational skillset, which will greatly enhance her/his future employment opportunity in both academic and industry sectors.
 
Description Neural microcircuits differ from computer microcircuits in several fundamental ways. One of them is that the former use signals over a large range of timescales, whereas the latter operate on a single timescale controlled by a central clock. So far, most research on neural circuits in the brain considered timescales of up to ~1 second, which suffices for a vast range of sensory-motor and cognitive behaviours, such as recognising pictures and sounds, getting up or sitting down, or recalling a memory. However, recent findings revealed that neuronal circuits also exhibit spontaneous structured activity on the so-called infraslow timescales of tens and hundreds of seconds. Our research on the way activity is structured in neuronal microcircuits of the cortex is structured, revealed that there are qualitative differences in the way activity of different neurons is related to each other on fast and infraslow timescales. These differences also provide clues to the different biophysical mechanisms that are involved in the regulation of neuronal activity on fast and infraslow timescales.

Our conclusions on the structure of infraslow changes in firing rate of the neurons were published in 2019. We are now studying the structure of infrasow dynamics across multiple brain regions (cortex, thalamus and hippocampus). Our research was substantially delayed because of the pandemic.

In addition to the above direction we have investigated the changes to neuronal activity caused by classical psychedelics, which is a very rapidly developing research area these days, and closely aligns with the original questions of the grant, as changes caused by psychoactive substances occur on timescales of many minutes. Our research revealed a generic structure of changes to firing rates of neuronal populations, shared by both naturally occurring brain state changes and those caused by psychoactive substances, as described in our bioRxiv preprint (presently under review): doi.org/10.1101/2021.08.22.457198
Exploitation Route They form a foundation for further research into the mechanisms and structure of infraslow cortical dynamics, as well as for applications (e.g. fMRI).
Sectors Manufacturing

including Industrial Biotechology

Pharmaceuticals and Medical Biotechnology

URL http://doi.org/10.1093/cercor/bhz023
 
Description - Led to collaboration with industry - Contributed to training of postdoctoral researchers and PhD, MSc and undergraduate students
First Year Of Impact 2018
Sector Education,Pharmaceuticals and Medical Biotechnology
Impact Types Societal

Economic

 
Title Neuropixels 2.0 
Description A new generation of the Neuropixels high-density silicon probe with > 5000 recording sites 
Type Of Material Technology assay or reagent 
Year Produced 2020 
Provided To Others? No  
Impact It will have a transformative effect on the way neurophysiological studies are performed. 
 
Title m-okun/Dearnley_et_al_2023: Release1 
Description No description provided. 
Type Of Material Database/Collection of data 
Year Produced 2023 
Provided To Others? Yes  
Impact Open science practice of data sharing, as part of our Cell Reports 2023 publication. 
URL https://zenodo.org/record/8207531
 
Description IMEC/Neuropixels 
Organisation Howard Hughes Medical Institute
Department Janelia Research Campus
Country United States 
Sector Academic/University 
PI Contribution Testing of Neuropixels 1.0 and 2.0 high-density silicon probes
Collaborator Contribution Development and testing of Neuropixels 1.0 and 2.0 probes
Impact Neuropixels 1.0 and 2.0 available as a commercial product from IMEC. Papers on the capabilities of the probes, published in Nature (2017) and Science (2021).
Start Year 2017
 
Description IMEC/Neuropixels 
Organisation Interuniversity Micro-Electronics Centre
Country Belgium 
Sector Academic/University 
PI Contribution Testing of Neuropixels 1.0 and 2.0 high-density silicon probes
Collaborator Contribution Development and testing of Neuropixels 1.0 and 2.0 probes
Impact Neuropixels 1.0 and 2.0 available as a commercial product from IMEC. Papers on the capabilities of the probes, published in Nature (2017) and Science (2021).
Start Year 2017
 
Description IMEC/Neuropixels 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Testing of Neuropixels 1.0 and 2.0 high-density silicon probes
Collaborator Contribution Development and testing of Neuropixels 1.0 and 2.0 probes
Impact Neuropixels 1.0 and 2.0 available as a commercial product from IMEC. Papers on the capabilities of the probes, published in Nature (2017) and Science (2021).
Start Year 2017
 
Title ChronuxGPU 
Description Chronux is a MATLAB package for frequency domain analysis of continuous and discrete (e.g. spike) data, widely used in the neuroscience community. We released a version of the package updated to perform the core computations on a GPU, speeding them up several fold. 
Type Of Technology Software 
Year Produced 2018 
Open Source License? Yes  
Impact We used the software for data analyses carried out for the project. 
 
Description Departmental open day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Open day annually held by my department, showcasing the different research activities in neuroscience and psychology taking part, demonstrations of easily understandable psychophysical experiments, explanation on the use of animals in research.

I contribute by presenting a poster focused on the technology behind and the uses of Magnetic Resonance Imaging (MRI), and functional MRI.
Year(s) Of Engagement Activity 2018,2019
 
Description Participation in departmental open day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Open day of Dept. of Psychology. Its purpose is to present the department and the research of its academics to prospective students and their family members.
Year(s) Of Engagement Activity 2022
 
Description Public lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact A talk to the general public about sleep, its relationship to memory and learning, presented by two colleagues and me. This was timed to the world sleep day. In particular the aim was to demonstrate to the general public using the case of sleep the importance of understanding the brain mechanisms behind brain dynamics on timescales of minutes and hours (the topic of the grant).
Year(s) Of Engagement Activity 2019
URL https://t.co/4lhehCZmaq?amp=1