Periodic Reporting for period 1 - SOCIALBRAINCIRCUITS (Neuroanatomical substrates of social deficit in a mouse model of 22q11 deletion syndrome)
Periodo di rendicontazione: 2018-09-01 al 2020-08-31
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 ».
The project was splitted in several main objectives and included dissemination and communication activities, distributed throughout the duration of the project. (1) Investigations on the impact of the early exposure to exogenous OT in the proper development of mPFC output consisted in determining the exact OT- and GABA-related impairments in LgDel+/-, compared to wild-type littermates, and their possible reversal by OT perinatal treatment. Using an approach combining pharmacological and molecular studies, specific early alterations were identified in the mPFC, thereby providing possible molecular markers of social deficit in 22q11.2DS. (2) Investigations on the early role of OT in the proper implementation of mPFC inputs to subcortical brain regions involved in social behavior were implemented through the study of the expression of glutamate markers together with DA-related proteins and following perinatal treatment with OT. Once again, specific alterations were identified. Interestingly, these impairments possibly result from altered mPFC output and could predict symptom emergence in 22q11.2DS. (3) Investigations on the relationship between neuroanatomical features of “social brain circuitry” and normal and altered social behavior were conducted through social profiling of LgDel+/- mice compared to their wild-type littermates, which was correlated with the molecular features collected from aforementioned investigations. This set of studies allowed a better definition of the specific social behaviors altered in 22q11.2DS and results in a strong database to establish causal relationship between social brain circuits and social behavior, in both control and 22q11.2DS conditions. The results and activities of the project were disseminated mainly through social media and several posts were published on platforms such as Facebook, Twitter and IIT Talk webpage to communicate the results of the project in an informal and accessible way. A publication is currently under revision while other articles are under progress. Due to the current Covid-19 situation the attendance, as well as a poster presentation and a short talk, at the Dopamine congress 2020 in Montreal have been cancelled (the congress has been postponed to 2021).
22q11.2 microdeletion is currently considered as the highest genetic-based vulnerability factor for neuropsychiatric disorders. Indeed, children carrying 22q11.2 microdeletion face an increased risk for developing autism spectrum disorder (16%), attention deficit hyperactivity disorder (16%), anxiety disorders (25%) and schizophrenia (41%) at adulthood. Accordingly, 22q11.2DS patients present a patchwork of heavy psychiatric disabilities, that might result from alterations in the development of brain trajectories relevant to normal brain functioning. In particular, while there is an impairment in motor/speech delays, learning abilities, attention, executive function, working memory, visual spatial abilities and motor skills, the most debilitating symptoms of 22q11.2DS are deficits in face memory and social cognition. Considering the current lack of treatment to alleviate the negative symptoms (including social interaction deficits) of schizophrenia, which remains the most frequent neuropsychiatric disorder related to 22q11.2DS defining a proper therapeutic strategy to cure social impairment should be considered one of the utmost challenges in the fight against 22q11.2DS. Notably, the identification of the neuroanatomical substrates of social deficits in 22q11.2DS appears critical to develop effective therapies. In this context, the developmental trajectories of the oxytocin (OT) and dopamine (DA) systems in normal and 22q11.2DS brains might offer very promising prospects for the identification of pharmacological targets for the therapeutic care of 22q11.2DS social deficits. In the present project, behavioral exploration (social habituation/dishabituation, sociability, social novelty, emotion recognition tests…etc) demonstrated the existence of specific deficits in the social profile of LgDel+/- mice compared to their wild-type littermates. Molecular investigations achieved so far indicate an altered expression of molecular markers of the GABA and glutamate systems within the social brain circuitry of LgDel+/- mice, some of which being reversed by the perinatal treatment with oxytocin. In addition, the project’s outcomes outlined that some components of the dopaminergic system are impaired in subcortical brain regions receiving direct inputs from the mPFC. These latter findings provide mechanistic insights into the dopaminergic impairments observed, within the framework of an international collaboration, in patients bearing 22q11 genetic variation. Altogether the results achieved so far allow a better definition of the social disabilities and likely-related molecular imbalance occurring in 22q11 genetic variation. Furthermore, these findings provide interesting insights into the therapeutic potential of early oxytocin treatment in 22q11 deletion syndrome to prevent the development of « social brain » imbalance and ultimately, social deficits at adulthood. Besides the scientific impact, the project substantially impacted the researcher’s career. The new scientific and soft skills acquired over the course of the project increased technical competence and enhanced the preparation of the researcher for an independent career. The communication and dissemination activities resulting from the project contributed to the improvement of the researcher’s track record. Overall, the project strengthened the researcher’s motivation and prospects to apply for researcher positions.