SOCIALBRAINCIRCUITS · Neuroanatomical substrates of social deficit in a mouse model of 22q11 deletion syndrome
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2018-09-01 → 2020-08-31
- EU contribution
- €168,277
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
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Results in brief
Neuroanatomical substrates of social deficit in a mouse model of 22q11 deletion syndrome
Hemizygous deletion of chromosome 22 at the q11.2 band results in the loss of ~50 gene copies, and, with an estimated prevalence of 1 in 2,000–4,000 live births, is established as the most common microdeletion disorder. Also known as velocardiofacial or DiGeorge syndrome, 22q11.2 deletion syndrome (22q11.2DS) can lead to cardiac and palatal abnormalities, immune and autoimmune differences, endocrine, genitourinary and gastrointestinal problems, but also brain functioning alterations. Although much effort has been dedicated to defining the clinical expression of 22q11.2DS and improving its diagnosis, patients suffering from this syndrome are not yet adequately treated for their psychiatric-related conditions. Specifically, no efficient pharmacological approach or behavioral therapy has been identified to manage social deficits in 22q11.2DS to date. The objective of the SOCIALBRAINCIRCUITS project was to investigate how early alterations of the oxytocin (OT) system in 22q11.2DS could prevent the proper implementation of the GABA/glutamate balance within the medial prefrontal cortex (mPFC), thereby leading to abnormal mPFC regulation of dopamine (DA) function in subcortical brain regions. Specifically, impairments of cortical control over DA activity in the nucleus accumbens and the amygdala would result in social deficits at adulthood. This hypothesis was addressed with the LgDel+/- mouse, a solid murine model of human 22q11.2DS, bearing an equivalent full hemideletion of 22q11.2 chromosome band, and allowing the exploration of possible discrepancies in brain « social circuits ».
Data: CORDIS, © European Union
Project objective
Also known as velocardiofacial or DiGeorge syndrome, 22q11.2 deletion syndrome (22q11.2DS) is currently considered as the highest genetic-based vulnerability factor for neuropsychiatric disorders, such as autism spectrum disorder, attention deficit hyperactivity disorder, anxiety disorders and schizophrenia. Noteworthy, this microdeletion leads to a wide range of peripheral and central symptoms, including severe deficits in face memory and social cognition, which remain incurable to date. Thus, the present proposal aims at delineating the neuroanatomical substrates of social behavior in order to identify new therapeutic avenues for social deficit in velocardiofacial syndrome and its associated neuropsychiatric disorders. To this purpose, we will use a very solid murine model of 22q11.2DS, the LgDel+/- mouse, which similarly displays deficits in social interaction, to investigate the respective interventions of the oxytocin (OT) and the dopamine (DA) system in the implementation of normal versus altered social behavior, at critical time periods (first post-natal days and adolescence). Specifically, preliminary findings from the host laboratory suggest that early alterations of the OT system, by preventing proper GABA switch in the medial prefrontal cortex (mPFC), leads to abnormal mPFC regulation of DA function in the nucleus accumbens and/or amygdala, and subsequent social deficits at adulthood in LgDel+/- mice. We will address this hypothesis by using a multidisciplinary strategy encompassing genetics, molecular biology, biochemistry, tracing methods, cell culture, as well as viral and behavioral approaches.The originality of the present project, which resides in our will to identify the developmental trajectories of social behavior, together with a reciprocal transfer of theoretical, practical and transferrable skills between the host laboratory and me, will allow me to develop independent research projects and a competitive research career.
Original text from CORDIS.
Participants
- FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA · GenovaCoordinatorItaly
Links
Data: CORDIS, © European Union