Vasopressin and the anterior olfactory nucleus

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

Abstract

Most mammals recognise other individuals by smell. Sometimes, some of these individuals are accorded a special status, such as when a bond is formed between a mother and offspring or between sexual partners in monogamous species, and in these cases an olfactory memory is forged in the olfactory bulb. Neuropeptides - a class of messenger molecules that mediate prolonged interactions between neurones, play a very important part in the formation of such memories. For example, oxytocin released in the mother's brain during parturition helps to establish the olfactory signatures of the offspring as memorable.

The converse of social attachment is rejection of, or aggression towards, individuals who are recognized as intruders or competitors. For this, another neuropeptide, vasopressin, is important. Vasopressin is involved in the processing and/or integration of olfactory stimuli, and in particular it seems to couple socially relevant olfactory cues to an appropriate behavioural response.

The anterior olfactory nucleus is the key part of the brain involved in processing odour information and sending that information to brain areas involved with behaviour and memory. Our work is focused on newly discovered nerve cells within this nucleus that make and release vasopressin. The aim of this proposal is to understand vasopressin's role in social recognition and how it can trigger a change in aggressive behaviour; we will study how vasopressin affects the olfactory system and how it is involved in forming olfactory memories there.

In this proposal we will be studying how the activity of the vasopressin neurons in the olfactory system is affected by socially relevant olfactory stimuli, how vasopressin influences the processing of information in the olfactory system, and how blocking the actions of vasopressin in this system affects social behaviour. These studies will all be performed in rats, and will use a range of tests devised to study social behaviours.

In the elderly, progressively increasing social dysfunction is a major aspect impairing quality of life. At present it is hard to judge the contribution of neural and cognitive degradation to this, as we have only a fragmentary understanding of the neurobiology of social behaviour. By studies of the neurobiology of social behaviour in the simpler system of rats, we expect to contribute to the foundations of an understanding that will inform a more sophisticated understanding of the neurobiology of social behaviour in humans.

Other nerve cells release many different neuropeptides, and these have very diverse and powerful effects on other emotions and behaviours, including stress-related behaviours and appetite. Understanding how neuropeptides act is important because drugs that mimic them may be valuable therapeutically for particular behavioural disorders.

Technical Summary

The neurobiology of social behaviour is a topic of great public interest as well as being a major theme in contemporary neuroscience. Olfactory cues linked to social recognition can elicit dramatic emotional responses in an experience-dependent manner, whereas other cues like predator odours seem to have pre-programmed emotional salience eliciting defence/escape responses at first exposure. In this project, we propose that the neuropeptide vasopressin, produced in a newly discovered subpopulation of cells in the anterior olfactory nucleus, acts at sites within the olfactory system to trigger functional changes in nerve cell networks. Our hypothesis is that learned associations are processed similarly to pre-programmed associations, and that the key role of vasopressin in the limbic brain is to couple these associations of emotional salience with particular olfactory signals. We will test the theory that functional re-wiring, through a mechanism called priming, underlies the coding of social olfactory cues and changes in behaviour. Priming produces a temporary functional "re-wiring" of neural networks a mechanism that we first described in the hypothalamus by the dendritic release of oxytocin and vasopressin. To address these contemporary questions in neuroscience we are planning to use whole animal approaches as well as in vitro approaches. In particular we will use transgenic rat models, one in which green fluorescent protein is expressed in vasopressin cells, and another in which the diphtheria toxin receptor is expressed in vasopressin cells, allowing acute localised ablation of specific vasopressin cell populations. We will use a range of techniques, including microdialysis, molecular neuroanatomy, in vivo electrophysiology and behavioural testing.

Planned Impact

The neurobiology of social behaviour is a topic of great public and academic interest; PubMed lists 29 review articles, published since 2009, that link vasopressin and social behaviour specifically in human studies and animal models. This project is thus timely and should have major impact at both academic and societal levels. To deliver that impact, it is important that the research is disseminated as effectively as possible. The target audiences are academics, health professionals, industry, schools and the wider public

(i) academics
Our previous work has led to high impact publications and this has given us a high profile in the academic community. Presenting at major conferences will be a priority throughout the grant: In 2011, ML has given talks at the German Neuroscience Meeting in Goettingen, the British Endocrine Society meeting in Birmingham and the European Congress of Endocrinology in Rotterdam. GL has already been invited to give the Annual Public Lecture at the meeting of the Physiological Society in Edinburgh in 2012, a plenary lecture at the Federation of European Physiological Societies Meeting in Turkey in 2011, and a plenary lecture at the Japanese Endocrine Society meeting in Nagoya in 2012.

(ii) health professionals
Because peptides can modify certain behaviours in a specific, coherent manner, they offer inviting possibilities for therapeutic exploitation. Vasopressin and oxytocin have been linked to several neurological disorders such as social anxiety disorder and autism spectrum disorder, while disorders of appetite regulation, libido, and mood are among many potential targets of other peptide-based therapies. We have proposed a model of a behaviourally relevant, temporally and spatially-specific facilitation of vasopressin release by priming mechanisms in olfactory processing. This model may be of clinical interest. Specifically, the AON which is the focus of our studies is also one of the first sites of visible pathology in Parkinson's disease, a disease primarily characterized by deficits in motor control but which also involves abnormal social cognition. Timescale for increased understanding in fields relevant to at least some of the diseases 18+ months; strategy - interactions via the Patrick Wild Centre.

(iii) industry
There is a significant interest in vasopressin and oxytocin by industry as major drug targets for behavioural disorders, and we have strong links with pharmaceutical companies that will be used if opportunities arise (GL has collaborated with Merck & Co for many years). Timescale is difficult to judge, and should follow new findings.

(iv) schools
The future of science depends on enthusiastic young scientists. ML is involved in University open days, making explanations of science accessible to parents and prospective students. Timescale: impact will be visible only as increased applications to study science at University; feedback from students on open days has been very positive with respect to their final decision to apply to Edinburgh University to study science.

(v) the wider community
All applicants are committed to engaging public interest. ML has written articles for the online magazine 'spiked'. The applicants will also contribute to the 'Neuroendocrine Briefings' (ML is the new Editor for the briefings) which are published for this purpose. GL is a member of the executive of Citizendium, an open access, web encyclopaedia for enhancing public understanding of science. Both have been interviewed frequently for radio, television and by journalists, have written for the popular press, and have spoken at several public events. GL will give the Annual Public Lecture at the meeting of the Physiological Society in Edinburgh in 2012.

Publications

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Leng G (2016) Intranasal Oxytocin: Myths and Delusions. in Biological psychiatry

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Ludwig M (2015) Multiple signalling modalities mediated by dendritic exocytosis of oxytocin and vasopressin. in Philosophical transactions of the Royal Society of London. Series B, Biological sciences

 
Description We have determined the contribution of the AON to olfactory signalling by mapping activated circuits using immediate early gene expression.
We have established the ultrastructural morphology, cellular relationships and connectivity of vasopressin cells in the MOB and AON.
We have define how vasopressin affects neural network properties in the AON in vivo.
Exploitation Route We will published all the original recordings making them available for network modelling.
Sectors Healthcare

URL https://www.ncbi.nlm.nih.gov/pubmed/?term=Intranasal+application+of+vasopressin+fails+to+elicit+changes+in+brain+immediate+early+gene+expression%2C+neural+activity+and+behavioural+performance+of+rats
 
Description I have given several public lectures regarding the importance of neuropeptides in behaviour, including the role of vasopressin in olfactory recognition.
Sector Communities and Social Services/Policy,Healthcare
 
Description Viral transfection studies 
Organisation Heidelberg University
Country Germany 
Sector Academic/University 
PI Contribution Testing of provided transfection systems
Collaborator Contribution Providing expertise with viral transfection studies and providing transfection systems
Impact Paper submitted to Current Biology (impact factor >10)
Start Year 2014
 
Description validation of transgenic rats 
Organisation University of Occupational and Environmental Health
Country Japan 
Sector Academic/University 
PI Contribution We initiated the development of a transgenic rat line where DREADDs under the vasopressin promotor.
Collaborator Contribution A breeding colony is currently set up of above rats.
Impact There are no outcomes yet.
Start Year 2019