Background
Behavioural disorders affect more than 25 per cent of people at some point during their lives, but our understanding of why these disorders arise is limited. This is, in part, because we know little about the basic genetic and neural pathways that regulate social interaction.
Behaviour results from complex interactions between genetic and environmental components. Every individual has a unique collection of experiences to draw upon; therefore we each behave slightly differently in a similar situation. This makes disentangling the genetic components of behaviour in humans challenging.
One way to control for environmental influence is to study behaviours that are highly stereotyped between individuals and are reproducibly initiated irrespective of prior experience. These, often called instinctive or innate behaviours, are critical for survival and successful social integration, and are therefore likely to be under a strong genetic influence. Furthermore, similar instinctive behaviours are found in many different species, suggesting there are common underlying neural mechanisms even if the social signals themselves vary significantly.
Mice display a highly stereotyped repertoire of instinctive behaviours that they regulate using pheromones: chemical signals that transmit socially relevant information between individuals. We can precisely alter both the genome and social environment of a mouse, as well as purify and isolate specific pheromones, making it an excellent model to identify the genes and pathways that underpin instinctive behaviours.
Research
Our aims
Sensory neurons in the nose express just one olfactory receptor. In this mouse two distinct receptor genes are fluorescently tagged, red and green.
Olfaction, our sense of smell, is mediated by thousands of specialised sensory neurons in the nose. Each neuron selects just one olfactory receptor gene, or in some cases a few, to express on its surface. Each receptor is structurally distinct, and therefore recognises a very limited set of odours. Some neurons express a sub-class of receptors that detect pheromones, which are specialised odours emitted by one individual that initiate an innate behavioural response when detected by another.
The central hypothesis of our work is that instinctive behaviour in mice is encoded in this two component system: pheromones and pheromone receptors. We aim to decode the system and genetically classify the neural circuits that underpin essential social interactions.
The vomeronasal organ (VNO, blue crescents) in a coronal section of the mouse nose.
Our approach
We and others have identified families of genes that encode pheromones for behaviours such as aggression, fear, mating and kin recognition. We have studied one of these, the major urinary proteins (Mups), in great detail and found them to have the potential to promote a surprising range of instinctive behaviours.
Protein pheromones such as Mups are detected by the vomeronasal organ (VNO), an olfactory sub-system found in the nasal cavity. Collectively the neurons of the VNO express ~250 pheromone receptors, around half of which are thought to bind protein pheromones. However identifying the specific receptor that detects each pheromone has proven difficult using traditional methods.
There are twelve sub-families in the V2R pheromone receptor class, all of unknown function.
To address this, we are systematically ablating candidate pheromone receptors by gene targeting. We examine the resultant mutant mice for both dysfunction in social behaviours, and for altered neural activity in response to known pheromones. By comparing receptor-deficient mice to their non-deficient siblings we can pair pheromones with their cognate receptors.
In addition, we are using a range of sequencing technologies to identify and assess genomic, transcriptional and post-transcriptional variation in the genes that regulate instinctive behaviour. By comparing large repertoires of candidate genes across different behavioural cohorts (for example, males versus females or juveniles versus adults) we aim to identify key gene networks that collectively regulate behaviours characteristic of that cohort. This approach sheds light on how distinct sets of instinctive behaviours evolved, are maintained, and are encoded in the genome of different individuals of the same species.
Selected Publications
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Olfactory mechanisms of stereotyped behavior: on the scent of specialized circuits.
Current opinion in neurobiology 2010;20;3;274-80
PUBMED: 20338743; PMC: 2883022; DOI: 10.1016/j.conb.2010.02.013
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The vomeronasal organ mediates interspecies defensive behaviors through detection of protein pheromone homologs.
Cell 2010;141;4;692-703
PUBMED: 20478258; PMC: 2873972; DOI: 10.1016/j.cell.2010.03.037
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Species specificity in major urinary proteins by parallel evolution.
PloS one 2008;3;9;e3280
PUBMED: 18815613; PMC: 2533699; DOI: 10.1371/journal.pone.0003280
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Identification of protein pheromones that promote aggressive behaviour.
Nature 2007;450;7171;899-902
PUBMED: 18064011; DOI: 10.1038/nature05997
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Olfactory mucosa-expressed organic anion transporter, Oat6, manifests high affinity interactions with odorant organic anions.
Biochemical and biophysical research communications 2006;351;4;872-6
PUBMED: 17094945; PMC: 1810587; DOI: 10.1016/j.bbrc.2006.10.136
The Team
Team members
- Andrew Bard
- ab31@sanger.ac.ukunknown
- Gabi Gurria
- gg7@sanger.ac.ukPostdoctoral Fellow
- Ximena Ibarra Soria
- xs1@sanger.ac.ukPhD Student
- Elizabeth Wynn
- Advanced Research Assistant
Andrew Bard
ab31@sanger.ac.uk unknown
Currently studying Biochemistry at the University of Bristol, with previous experience in Cahir O'Kane's group at the University of Cambridge, working on a Drosophila model of Huntingdon's disease.
Research
Working on genetics of olfaction, with projects on isovaleric acid sensing and characterising currently un-annotated olfaction-related genes in mice.
Gabi Gurria
gg7@sanger.ac.uk Postdoctoral Fellow
I studied undergraduate physics at Mexico's National University before moving into the study of hormones and behaviour. For my Ph.D. at Cambridge University I examined the effect of female hormones on social olfactory learning. This was followed by a postdoctoral position at the Babraham Institute, Cambridge, involving research into the neural processing of learning and olfaction. In January, 2011, I joined Sanger's Genetics of Instinctive Behaviour group.
Research
I am coordinating research into the ways in which social cues and pheromones trigger stereotypical instinctive conducts such as aggression or defensive behaviour. I am also studying how the brain detects and processes these olfactory signals, and what genes are involved in these processes.
References
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Roles of α- and β-estrogen receptors in mouse social recognition memory: effects of gender and the estrous cycle.
Laboratory of Molecular Signalling, Cognitive and Systems Neuroscience Group, The Babraham Institute, Babraham, Cambridge CB22 3AQ, UK.
Establishing clear effects of gender and natural hormonal changes during female ovarian cycles on cognitive function has often proved difficult. Here we have investigated such effects on the formation and long-term (24 h) maintenance of social recognition memory in mice together with the respective involvement of α- and β-estrogen receptors using α- and β-estrogen receptor knockout mice and wildtype controls. Results in wildtype animals showed that while females successfully formed a memory in the context of a habituation/dishabituation paradigm at all stages of their ovarian cycle, only when learning occurred during proestrus (when estrogen levels are highest) was it retained after 24 h. In α-receptor knockout mice (which showed no ovarian cycles) both formation and maintenance of this social recognition memory were impaired, whereas β-receptor knockouts showed no significant deficits and exhibited the same proestrus-dependent retention of memory at 24 h. To investigate possible sex differences, male α- and β-estrogen receptor knockout mice were also tested and showed similar effects to females excepting that α-receptor knockouts had normal memory formation and only exhibited a 24 h retention deficit. This indicates a greater dependence in females on α-receptor expression for memory formation in this task. Since non-specific motivational and attentional aspects of the task were unaffected, our findings suggest a general α-receptor dependent facilitation of memory formation by estrogen as well as an enhanced long-term retention during proestrus. Results are discussed in terms of the differential roles of the two estrogen receptors, the neural substrates involved and putative interactions with oxytocin.
Hormones and behavior 2011;59;1;114-22
PUBMED: 21056567; DOI: 10.1016/j.yhbeh.2010.10.016
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The main olfactory system and social learning in mammals.
The Babraham Institute, Cognitive and Behavioural Neuroscience, Cambridge, UK.
There is increasing evidence for specialised processing of social cues in the brain. This review considers how the main olfactory system of mammals is designed to process social odours and the effects of learning in a social context. It focuses mainly on extensive research carried out on offspring, mate or conspecific learning carried out in sheep and rodents. Detailing the roles of the olfactory bulb and its projections, classical neurotransmitters, nitric oxide, oestrogen and neuropeptides such as oxytocin and vasopressin in mediating plasticity changes in the olfactory system arising from these different social learning contexts. The relative simplicity of the organisation of the olfactory system, the speed and robustness of these forms of social learning together with the similarity in brain regions and neurochemical contributions across the different learning paradigms make them important and useful models for investigating general principles of learning and memory in the brain.
Behavioural brain research 2009;200;2;323-35
PUBMED: 19150375; DOI: 10.1016/j.bbr.2008.12.021
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Neural encoding of olfactory recognition memory.
Cognitive and Behavioural Neuroscience, The Babraham Institute, Cambridge, UK.
Our work with both sheep and mouse models has revealed many of the neural substrates and signalling pathways involved in olfactory recognition memory in the main olfactory system. A distributed neural system is required for initial memory formation and its short-term retention-the olfactory bulb, piriform and entorhinal cortices and hippocampus. Following memory consolidation, after 8 h or so, only the olfactory bulb and piriform cortex appear to be important for effective recall. Similarly, whereas the glutamate-NMDA/AMPA receptor-nitric oxide (NO)-cyclic GMP signalling pathway is important for memory formation it is not involved in recall post-consolidation. Here, within the olfactory bulb, up-regulation of class 1 metabotropic glutamate receptors appears to maintain the enhanced sensitivity at the mitral to granule cell synapses required for effective memory recall. Recently we have investigated whether fluctuating sex hormone levels during the oestrous cycle modulate olfactory recognition memory and the different neural substrates and signalling pathways involved. These studies have used two robust models of social olfactory memory in the mouse which either involve social or non social odours (habituation-dishabituation and social transmission of food preference tasks). In both cases significant improvement of learning retention occurs when original learning takes place during the proestrus phase of the ovarian cycle. This is probably the result of oestrogen changes at this time since transgenic mice lacking functional expression of oestrogen receptors (ERalpha and ERbeta, the two main oestrogen receptor sub-types) have shown problems in social recognition. Therefore, oestrogen appears to act at the level of the olfactory bulb by modulating both noradrenaline and the glutamate/NO signalling pathway.
The Journal of reproduction and development 2005;51;5;547-58
PUBMED: 16284449
Ximena Ibarra Soria
xs1@sanger.ac.uk PhD Student
I got my bachelor's degree on Genomic Sciences, from the National Autonomous University of Mexico (UNAM). I have a combined background on biology and genetics as well as bioinformatics and maths. During my time at UNAM, I was involved in two main research projects. The aim of the first one was to assess if it was possible to reprogram dopaminergic neurons into neural precursors, and the second one intended a methodology to reliably identify structural variation in personal genomes.
Research
Currently, I am a PhD student in the Genetics of Instinctive Behaviour Group. I am interested in studying the plasticity of the olfactory system in response to a changing environment.
References
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Context-dependent individualization of nucleotides and virtual genomic hybridization allow the precise location of human SNPs.
Centro de Ciencias Genómicas, Universidad Nacional Autónoma de México, Cuernavaca, Morelos 62210, Mexico.
We have entered the era of individual genomic sequencing, and can already see exponential progress in the field. It is of utmost importance to exclude false-positive variants from reported datasets. However, because of the nature of the used algorithms, this task has not been optimized to the required level of precision. This study presents a unique strategy for identifying SNPs, called COIN-VGH, that largely minimizes the presence of false-positives in the generated data. The algorithm was developed using the X-chromosome-specific regions from the previously sequenced genomes of Craig Venter and James Watson. The algorithm is based on the concept that a nucleotide can be individualized if it is analyzed in the context of its surrounding genomic sequence. COIN-VGH consists of defining the most comprehensive set of nucleotide strings of a defined length that map with 100% identity to a unique position within the human reference genome (HRG). Such set is used to retrieve sequence reads from a query genome (QG), allowing the production of a genomic landscape that represents a draft HRG-guided assembly of the QG. This landscape is analyzed for specific signatures that indicate the presence of SNPs. The fidelity of the variation signature was assessed using simulation experiments by virtually altering the HRG at defined positions. Finally, the signature regions identified in the HRG and in the QG reads are aligned and the precise nature and position of the corresponding SNPs are detected. The advantages of COIN-VGH over previous algorithms are discussed.
Proceedings of the National Academy of Sciences of the United States of America 2011;108;37;15294-9
PUBMED: 21876154; PMC: 3174668; DOI: 10.1073/pnas.1112567108
Elizabeth Wynn
- Advanced Research Assistant
I did a BSc in Natural Sciences at the University of Bath. After graduating in 2008 I joined the mutant mouse generation team at the Sanger.
Research
I currently work on the Genetics of Instinctive Behaviour project. My main role is developing targeting vectors to knock out receptor clusters in the mouse vomeronasal organ.
Dr Darren Logan
