Cellular and neurophysiological mechanisms of sensory-driven behaviour

Lead Research Organisation: MRC National Inst for Medical Research

Abstract

Our senses are our brains' window to the world - they are also the scientists' window to understanding the brain. By investigating how information about the external world is processed by networks of neurons, we aim to elucidate how the brain performs its variety of tasks.
Specifically, we use the sense of smell of mice to explore how networks of neurons in the olfactory system process information endowing the animal with the ability to discriminate, identify and memorize odours. Based on detailed anatomical and functional models we perform targeted opto- and pharmakogenetic modifications. We probe the resultant alterations using physiological and imaging techniques as well as quantitative behavioural paradigms. Thus, with continuous refinement of our models of sensory processing we will get quantitative insight into how neural circuits compute in the healthy brain. Moreover, in particular behavioural paradigms in social environments together with detailed models of brain function will give us the tools at hand to efficiently and sensitively detect when and how this information processing is perturbed in cognitive disease.

Technical Summary

Understanding how complex behaviour emerges from the properties of molecules, cells and ensembles of cells is one of the key challenges in Neuroscience. Our work tackles this question employing the olfactory system of mice as a model system.
To understand how smells are processed we modify specific selected groups of neurons in the first relay station of the olfactory system, the olfactory bulb. Cellular specificity is achieved by combining transgenic mice, engineered to express Cre recombinase in defined groups of cells. This will be combined with injections of viruses conditionally expressing a variety of pharmako- and optogenetic tools into the olfactory bulb. Subsequently, we investigate how such targeted manipulations affect odour related behaviour, such as odour detection, identification, discrimination or memory. To this end we develop a variety of highly automatized and quantitative behavioural paradigms tailored to sensitively detect small perturbations. To unravel the cellular and network mechanisms underlying behavioural alterations we employ in vitro and in vivo physiological approaches where whole-cell patch recordings are used to map odour response properties of individual neurons and imaging techniques are employed to study the spatial distribution of activity. Previously, we have found that genetic modifications to the synapses between principal projection neurons (mitral cells, MC) and the dominant group of interneurons (granule cells, GC) resulted in sensitive alterations to odour discrimination ability: Increasing calcium influx at the MC-GC synapse through targeted ablation of the glutamate receptor subunit GluA2 increased inhibition and reduced discrimination times, i.e. the time needed in a behavioural experiment to accurately discriminate two similar odorants. Conversely, ablating the NMDA receptor subunit resulted in decreased Ca influx, decreased inhibition and slowed down odour discrimination. Our current research aims to identify the mechanisms behind this bidirectional alteration of odour discrimination by employing inducible (optogenetic) modifications to GCs during physiological recordings in behaving mice in vivo, thus providing a mechanistic link between cellular properties and behaviour.
Combining these genetic, physiological and behavioural techniques with computational modelling approaches we aim to elucidate the cellular basis of olfactory behaviour and ultimately more general complex behaviours. This will provide us with the tools and concepts necessary to tackle the question how circuit function might be altered in complex cognitive disease such as autism spectrum disorders or schizophrenia.

Publications

10 25 50
 
Description HFSP Grant
Amount $750,000 (USD)
Funding ID RGP0048 
Organisation Human Frontier Science Program (HFSP) 
Sector Charity/Non Profit
Country France
Start 09/2013 
End 08/2017
 
Description Biomimetic nanoelectrodes for stable intracellular neural recordings 
Organisation Stanford University
Country United States 
Sector Academic/University 
PI Contribution Electrophysiological evaluation of novel biomimetic nanoelectrodes
Collaborator Contribution Devleopment of biomimetiv nanoelectrodes
Impact Multidisplinary: Surface science, materials engineering, neuroscience, physiology Publication: Angle et al, 2014, US Patent filed 14/937,740 filed on Nov 10, 2015 (joined with Melosh, Angle, Hanna - Stanford)
Start Year 2012
 
Description Higher-order feature detection in olfactory bulb 
Organisation Cornell University
Country United States 
Sector Academic/University 
PI Contribution Experimental analysis of olfactory bulb connectivity and integration using optogenetic and electrophysiological tools
Collaborator Contribution Models of olfactory bulb function and behavioural tests
Impact Two distinct channels of olfactory bulb output Fukunaga I, Berning M, Kollo M, Schmaltz A, Schaefer AT. Neuron. 2012 Jul 26;75(2):320-9. PMID:22841316 Multidisplinary: Theoretical neuroscience, experimental psychology, physiology
Start Year 2010
 
Description Mechanisms of inhibitory processing in the olfactory bulb 
Organisation Heidelberg University
Country Germany 
Sector Academic/University 
PI Contribution Developed automated conditioning system and behavioural tasks, implement optogenetic probes to investiagte role of interneurons, in vivo physiological analysis, modelling of OB function.
Collaborator Contribution Devise viral molecular targeting strategies, in vitro physiological analysis
Impact Maintaining accuracy at the expense o speed: stimulus similarity defines door discrimination time in mice. Abraham NM, Spors H, Carleton A, Margrie TW, Kuner T, Schaefer AT. Neuron. 2004 Dec 2;44(5):865-76. PMID: 15572116 Synaptic inhibition in the olfactory bulb accelerates door discrimination in mice. Abraham NM, Egger V, Shimshek DR, Renden R, Fukunaga I, Sprengel R, Seeburg PH, Klugmann M, Margrie TW, Schaefer AT, Kuner T. Neuron. 2010 Feb 11;65(3):399- PMID: 20159452 Kuner & Schaefer 2012 Multidisplcinary: Molecular biology, behavioural neuroscience, physiology
 
Description Olfactory Bulb connectomics 
Organisation Max Planck Society
Department Max Planck Institute for Brain Research
Country Germany 
Sector Academic/University 
PI Contribution Acquire data and analyse data from Olfactory bulb connectomics.
Collaborator Contribution MPI: Provide support for analysing large data sets (>100 TB) NIH: Help with development of specific histoogical protocols and advise on data acquisition
Impact Publications expected but not yet occurred.
Start Year 2015
 
Description Olfactory Bulb connectomics 
Organisation National Institutes of Health (NIH)
Country United States 
Sector Public 
PI Contribution Acquire data and analyse data from Olfactory bulb connectomics.
Collaborator Contribution MPI: Provide support for analysing large data sets (>100 TB) NIH: Help with development of specific histoogical protocols and advise on data acquisition
Impact Publications expected but not yet occurred.
Start Year 2015