A systems approach to the cellular and molecular organization of neural circuits for representation of space

Lead Research Organisation: University of Edinburgh
Department Name: Centre for Integrative Physiology

Abstract

One of the most challenging problems in science is to understand how the molecules expressed by nerve cells in the brain enable thoughts and actions to take place. This is of fundamental importance for understanding how brains work. It will also underpin future industrial development of therapies for neurological and psychiatric disorders, and of biologically inspired computing technologies. Synthesis of molecules and assembly of cells is similar in the brain and other organs of the body, but the brain is distinguished by its ability to efficiently perform computations of considerable complexity. These computations rely upon communication of electrical signals between nerve cells. Some important computations are carried out by groups of nerve cells organized into modules, but how these modules relate to organization of electrical signaling between nerve cells is not known. This is important because molecules that control electrical signaling are a critical molecular link between gene expression and cognitive processes.

We will focus on a sub-region of the brain called the entorhinal cortex. During exploration, nerve cells at the upper end of this region form a module that encodes an animal's location at a relatively high resolution of approximately 30 cm. Lower down within this region, different modules of nerve cells encode location at lower resolutions. As existing approaches rely on recording electrical activity from neurons in live animals it is currently exceptionally challenging to examine their physical basis. We aim to solve this problem by instead using in vitro experiments in combination with quantitative and predictive computational models.

We will first establish if electrical properties of single nerve cells or their connections have a modular organization. We will use electrodes to record from many nerve cells in single slices of tissue. If electrical properties contribute to modular organization, then we expect cells from the same network to be more similar to one another than cells from different networks. We will next evoke coordinated network activity while making electrical recordings simultaneously from four cells at a time. We expect to identify cells that are part of the same module by specific correlations in their activity. To identify molecules that organize electrical properties and connectivity, we will identify candidate genes that mark modules. We will then determine if they label specific subgroups of neurons based on their electrical properties and connectivity.

Data obtained at each stage of experimentation will guide development of computer models. By comparison of the experimental results with the model predictions we will be able to refine and improve the predictive power of the models, while also identifying functions that the model may not yet explain and that will therefore require further investigation. In this way we aim to reveal new computational principles for brain operation and to ultimately enable direct links to be established between gene expression, electrical signaling and brain function.

The models and experimental results generated will be of benefit and application in several areas. 1) By establishing basic links between genes, electrical signaling and computation by nerve cells, the study will be important for understanding the healthy brain. They will form a key foundation for further investigations of how specific genes influences brain function. 2) The brain region that we will focus on is an important target for drug discovery. The computational models that we build will enable dry lab testing of potential therapeutic strategies in development by pharmaceutical or biotechnology companies. 3) The principles uncovered may stimulate future design of biologically based computational devices. For example, to improve navigation by robots, and to develop neurally inspired architectures to improve the energy efficiency of computational hardware.

Technical Summary

We propose to investigate the cellular and molecular substrates for computations based on organization of neurons into discrete modules. We will focus on a sub-region of the brain called the medial entorhinal cortex (MEC). Neurons in the dorsal MEC form a module that represents an animal's location through grid like firing fields with relatively high resolution. At increasingly ventral locations neurons form modules with progressively lower spatial resolution. This modular organization is thought to be of exceptional computational significance, but we lack the cellular and molecular understanding of modules required to address this experimentally.

The main objectives of the proposed work are to establish whether intrinsic neuronal properties or local circuit connections have a modular organization, to identify molecules that distinguish populations of MEC neurons with distinct and possibly modular properties, and to develop and test biophysically constrained computational models of modular grid firing. These models will be used to evaluate and predict the roles of specific circuit properties in modular computations. We will investigate substrates for modularity by recording intrinsic membrane properties and gamma frequency oscillatory activity from multiple neurons in single brain slices. We will use these in vitro assays to establish whether identified candidate molecules label neuronal populations with distinct intrinsic properties or connectivity.

Data obtained at each stage of our analysis will be used to refine and improve the predictive power of computational models of grid firing, while also identifying functions that models may not yet explain and that will therefore require further investigation. The proposed work will direct new understanding of relationships between gene expression, electrical signaling and neural computation, and will enable future experiments to establish the computational and cognitive roles of neuronal modules.

Planned Impact

The proposed work will reveal fundamental principles for cellular and molecular organization of computations in a brain area that is critical for navigation, learning and memory, and that is believed to be of great importance for healthy aging and as a target for drug discovery. Potential beneficiaries range from technology and pharmaceutical industries in the commercial private sector, through researchers in applied fields, in particular those oriented towards lifelong health solutions, to the general public as a whole. We describe below benefits in each area of impact. In some cases the critical path to impact may be direct, for example by immediate application of our research outputs to commercial development of new technologies. In other cases it will be through application of our fundamental findings to further applied research either in industry or academia. In our separate Pathways to Impact statement we describe diverse activities that we will employ to facilitate impact in each area. Academic impact is outlined elsewhere in the proposal.

1. Alterations in neural circuits are believed to be central to cognitive changes that accompany aging, but our lack of understanding of how circuit organization enables neural computations is a substantial obstacle to establishing which aspects of the aging process one should focus in order to promote healthy aging. Because the entorhinal cortex is one of the brain areas believed to be most important for cognitive changes that accompany aging, our results will therefore be of benefit to a wide range of specialists and organizations with an interest in developing strategies to promote healthy aging.

2. It is widely recognized that the drug discovery process is severely hindered by a lack of basic understanding of the cellular and molecular organization of brain areas important to healthy neurological and mental function. Biotechnology and pharmaceutical industries will therefore benefit from the new knowledge and research tools generated by the project. For example, a molecular understanding of modular organization of brain circuits may enable new diagnostic and treatment strategies, while our detailed computational models may help design and predict effects of pharmacological tools.

3. Technology industries are increasingly applying biologically inspired solutions to commercially important problems. Areas that may benefit from the proposed research include development of self-navigating systems, for which it may be beneficial to incorporate principles used for computation in animals, and development of computer hardware, for which computation in the brain may serve as a model for more energy efficient technologies.

4. The proposed project will also contribute to UK capacity building in systems biology. This has been identified by the BBSRC as a strategic priority of long-term benefit to the UK. The proposed work will provide training for the postdoctoral research associates employed to work on the project and for PhD, Masters and undergraduate students who will have the opportunity to work on computational models and experimental systems that develop from the project. The University of Edinburgh is particularly well placed for the project to contribute to postgraduate training, with several successful PhD and Masters programs, both within the host School (Biomedical Sciences) and within the School of Informatics.

5. Understanding the brain is widely recognized as one of the most important challenges in modern science and public demand for knowledge of how our brains work is reflected in the high media profile given discoveries in neuroscience research. Because of their relevance to human cognition and aging, the results of the proposed study therefore have the potential to contribute to public engagement with systems biology and research into the brain.

Publications

10 25 50
 
Description 1. We established molecular principles for organisation of circuits in the medial entorhinal cortex (Ramsden et al. PLoS Computational Biology 2015; Surmeli et al. Neuron 2015).

2. We used computational approaches to investigate the consequences of varying connectivity for computation and oscillatory activity of neurons in the medial entorhinal cortex (Solanka et al. eLife 2015).

3. We have identified candidate molecular markers of modular organisation of entorhinal circuits. Their evaluation is in progress.

4. We have developed and our applying functional assays for modular organisation of synaptic connectivity.

5. We have obtained datasets that address modular organisation of intrinsic electrical properties of entorhinal neurons. We are preparing a manuscript to describe this component of the project.
Exploitation Route Investigation of circuit mechanisms for neural computation is a very active research area and the medial entorhinal cortex is a popular model system. Are results are therefore likely to be of interest to many researchers and likely will stimulate further research addressing these fundamental issues.

Because the circuits we are investigating are also modified in disorders including Alzheimer's and schizophrenia, and as our results provide very fundamental information about the organisation of these circuits, it is likely that our results will contribute to new research approaches in these areas. We are currently exploring this possibility through development of new research collaborations.
Sectors Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description The experience we gained in development and application of viral vector-based tools contributed to initiation of a collaboration with an industrial partner.
First Year Of Impact 2014
Sector Manufacturing, including Industrial Biotechology
 
Description BBSRC funding committee A
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description BBSRC funding committee A
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Cross-disciplinary workshop
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
 
Description New York Academy of Sciences - Takeda Innovator Award jury member
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
 
Description Wellcome Trust funding panel
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Collaborative Research Grant (Development of molecular tools for investigation of lateral entorhinal cortex networks in health and disease)
Amount £44,363 (GBP)
Organisation Carnegie Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2015 
End 05/2016
 
Description Pathfinder grant (Validation of rAAV-focused commercial opportunities)
Amount £10,216 (GBP)
Funding ID BB/N005120/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 07/2015 
End 10/2015
 
Description Project grant (A platform for high throughput, cell type-restricted in vivo knockdown of pre- or postsynaptic gene expression)
Amount £467,296 (GBP)
Funding ID BB/M025454/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 05/2015 
End 04/2018
 
Description Wellcome Trust Investigator Award
Amount £1,589,107 (GBP)
Funding ID 200855/Z/16/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2016 
End 08/2021
 
Title Methods for investigating spatial learning in mice using virtual reality 
Description We designed and implemented virtual reality-based methods for investigating how mice estimate their location. The innovation is in the development and use of virtual reality environments to evaluate spatial memory, which allows the first experimental dissociation of task strategies used for spatial learning. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2018 
Provided To Others? Yes  
Impact We used the tools and methods to provide the first quantitative characterization of key psychophysical properties of location estimation and to identify roles for a specific neuronal subpopulation. 
 
Title Computational models and tools for analysis of E-I networks 
Description The model enables simulation of generation of spatial firing patterns and oscillatory activity by networks of excitatory and inhibitory neurons. Tools enable parallel simulation and analysis of many networks. 
Type Of Material Computer model/algorithm 
Year Produced 2015 
Provided To Others? Yes  
Impact Provided the first demonstration of the roles of noise and variation in network properties on spatial computations. Has contributed to an ongoing debate about the neural mechanisms for spatial computation. 
URL https://senselab.med.yale.edu/modeldb/showmodel.cshtml?model=183017
 
Title Computational models of entorhinal cortex circuits 
Description We have developed models that account for spatial firing and oscillatory activity observed in the entorhinal cortex. 
Type Of Material Computer model/algorithm 
Year Produced 2013 
Provided To Others? Yes  
Impact The model is available freely from an archive and we do not monitor its use. We're aware of the model being used by other research groups and as a tool in teaching. 
URL https://senselab.med.yale.edu/ModelDB/ShowModel.asp?model=150031
 
Title RNA sequencing data 
Description Datasets to compare expression of genes between parts of the brain that encode location at different spatial resolution. 
Type Of Material Database/Collection of data 
Year Produced 2014 
Provided To Others? Yes  
Impact This data enabled identification of molecular markers for neuronal cell types important for spatial navigation. 
URL https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE63300
 
Title Software for large scale parametric analysis of neural circuit models 
Description The software enables parametric investigation of properties of neural circuit models using supercomputer resources. 
Type Of Technology Grid Application 
Year Produced 2015 
Impact The software was used to demonstrate the first time mechanistic links between phenomena associated with cognition and disease, and lower level cellular and circuit mechanisms. 
URL https://github.com/MattNolanLab/ei-attractor
 
Description Advisor to a children's science theatre project 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact The project is called We're Stuck and is being developed by China Plate Theatre. Its goal is to develop theatre shows aimed at engaging children with scientific ideas. I advise the development team on how to incorporate ideas related to our research into brain circuits for spatial navigation.
Year(s) Of Engagement Activity 2015
URL http://www.chinaplatetheatre.com/were-stuck
 
Description Light fantastic 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Talk as part of Light Fantastic event at the Edinburgh International Science Festival (2015). Included BBSRC funded work.
Year(s) Of Engagement Activity 2015
 
Description Talk to a public science group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The talk was to a general interest science group based in Ormskirk, Lancashire. There were about about 80-100 attendees. The talk described key elements of a research project at a level that could be understood by members of the public. The talk generated many questions and considerable discussion, both related to the project in particular, and to more general related areas such as future applications of neurotechnologies and genetic engineering methods.
Year(s) Of Engagement Activity 2015
 
Description Workshop symposium 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I organized a symposium titled: Spatial computation: from neural circuits to robot navigation. The symposium brought together experts from the fields of robotics and neuroscience to discuss areas of conceptual convergence and divergence between these fields. Attendees were from academia and industry, from the US, UK and mainland Europe, and ranged in experience from PhD students to professors.
Year(s) Of Engagement Activity 2015