Social cognition in 22qll.2 schizophrenia mouse model – role of mPFC dysfunction and oxytocin

Project Information

LgDel-mPFC

Grant agreement ID: 101066405

DOI

10.3030/101066405

Project closed

EC signature date 9 August 2022

Start date 1 March 2023

End date 28 February 2025

Funded under

• Marie Skłodowska-Curie Actions (MSCA)

Total cost

No data

EU contribution

€ 188 590,08

Coordinated by

FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA
Italy

Periodic Reporting for period 1 - LgDel-mPFC (Social cognition in 22qll.2 schizophrenia mouse model – role of mPFC dysfunction and oxytocin)

Reporting period: 2023-03-01 to 2025-02-28

Summary of the context and overall objectives of the project

Schizophrenia is a severe and disabling mental health disorder significantly impacting individuals' social interactions, including difficulties in recognizing others, interpreting emotions, and responding to social cues. These impairments considerably affect patients' quality of life, social integration, and the wellbeing of their families. The medial prefrontal cortex (mPFC) is a critical brain region involved in social cognition and emotion regulation. Dysfunction within this area is implicated in the social cognitive deficits characteristic of schizophrenia.

This project aimed to clarify how alterations in the mPFC contribute to social cognition deficits in schizophrenia using a mouse model carrying a genetic mutation (22q11.2 deletion syndrome) strongly linked to schizophrenia. The 22q11.2 deletion mouse model, known as LgDel, exhibits social and cognitive impairments analogous to those seen in human patients, making it an ideal subject for understanding schizophrenia-associated brain changes.

Specifically, the project aimed to:

Map neuronal activity and communication patterns in the mPFC during social and cognitive tasks.

Investigate fluctuations of oxytocin, a hormone crucial for social behaviors, within the mPFC during behavior.

Examine how oxytocin interacts with dopamine—another critical neurotransmitter involved in social cognition—to influence social behaviors.

This ambitious initiative utilized cutting-edge neuroscience technologies, including chronically implantable SiNAPS electrophysiological probes and fiber photometry to track real-time neurotransmitter fluctuations. Insights from this research have significant potential for improving treatments for schizophrenia and enhancing understanding of gender differences in the disorder.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The research successfully optimized electrophysiological recording setups using SiNAPS probes, allowing chronic, high-resolution recording of neuronal activity from socially housed mice. Crucial advancements included innovations in implant design, animal housing conditions, and signal processing methods, leading to stable recordings for durations of up to 90 days.

Behavioral studies demonstrated clear social cognition impairments in the LgDel mouse model. These studies involved various social and cognitive tasks, including novel object recognition, social preference, social novelty recognition, and emotion discrimination tests. Electrophysiological recordings were synchronized precisely with these behavioral tasks, producing rich datasets for analysis.

Fibre photometry recordings to detect oxytocin release initially encountered significant challenges, as available oxytocin biosensors lacked sensitivity in the mPFC region. Consequently, the research shifted focus toward examining dopamine fluctuations using a more sensitive dopamine biosensor, providing novel insights into neurotransmitter dynamics underlying social behaviors. This approach revealed distinct patterns of dopamine fluctuations associated with impaired social cognition in LgDel mice compared to wild-type counterparts.

The project also advanced neuron classification techniques through the integration of novel spike-sorting algorithms, allowing the distinction between different neuron types based on electrophysiological data, enhancing our understanding of specific neuronal population roles in social cognition.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

This project significantly advanced our ability to chronically record neuronal activity and neurotransmitter fluctuations in awake, socially interacting animal models. The developed methods overcame existing barriers in chronic electrophysiological studies, particularly the challenge of socially housing animals with neural implants, thus ensuring ethical and realistic behavioral conditions.

The findings contribute significantly to neuroscience by detailing neuronal and neurotransmitter dynamics underlying social cognitive impairments in a schizophrenia-relevant genetic model. Importantly, this research has provided the scientific community with validated technological innovations and analytical tools necessary for future studies of brain function in health and disease.

Further research is required to refine oxytocin detection methodologies and to explore detailed interactions between oxytocinergic and dopaminergic systems in the mPFC. These results pave the way for exploring targeted therapeutic interventions potentially beneficial in treating social cognitive deficits in schizophrenia, ultimately contributing to improved patient outcomes and societal integration.