Periodic Reporting for period 4 - PSYCHOCELL (Cellular substrate of abnormal network maturation in neuropsychiatric disorders)
Période du rapport: 2020-12-01 au 2022-11-30
The long-lasting burden of major neuropsychiatric disorders, such as schizophrenia, results from disruption of cognitive performance in daily life. Impairment of long-range communication between two brain regions, the prefrontal cortex and hippocampus, has been identified as the core substrate of disease-specific mnemonic and executive deficits. While it has been hypothesized that this impairment emerges long before the first clinical symptoms, technical and ethical limitations of non-invasive investigations in high-risk infants precluded the elucidation of ontogenetic mechanisms underlying the pathophysiology of disease. Using mouse models of disease’s etiology, we recently identified the de-coupling of prefrontal-hippocampal networks during early development as potential mechanism underlying adult circuit dysfunction. However, it is still unknown, which neuronal populations are particularly affected and critically contribute to the disease-related defects of long-range communication in the brain. The proposal aims to uncover the cellular identity of circuits that are compromised early in life in mouse models of schizophrenia and elucidate the long-lasting impact of early dysfunction on the cognitive performance at adult age. The results of the project identify a specific neuronal population in the prefrontal cortex as vulnerable to the dual action of genetic deficits and environmental stressors early in life. Through a tight connectivity with the hippocampus and other cortical areas, these prefrontal neurons critically contribute to the early wiring of circuits involved in cognitive processing. On a flip side, their dysfunction during the time window when the circuits are shaped, has major long-lasting consequences on the cognitive performance. The vulnerability of these prefrontal neurons (“psychocells”) accompanied by a identification of underlying molecular and synaptic mechanisms bears also a chance to develop future therapies.
The main results of the project are listed below together with the applied methodology and possible exploitation:
• Identification of neuronal populations disrupted during early development in mouse models of schizophrenia (Methods: development of the protocols for optogenetic manipulation of developing circuits)
• Elucidation of molecular and synaptic mechanisms (e.g. involvement of microglia) of early neuronal disruption and identification of strategies made to rescue the circuit dysfunction (Exploitation: extending the investigation from the early stage of development to later ones that might addressed in prodromal humans)
• “Dissection” of developmental circuits and cellular interactions underlying the cognitive deficits in schizophrenia (Exploitation: facilitation of research aiming to identify “targets” of dysfunction in humans)
• Tracking of long-lasting functional and behavioral consequences of early impairment of circuits (Methods: development of the protocols for chronic monitoring and optogenetic manipulation of developing circuits)
• Implementation, development and optimization of highly innovative techniques to monitor and manipulate the brain activity
• Identification of neuronal populations disrupted during early development in mouse models of schizophrenia (Methods: development of the protocols for optogenetic manipulation of developing circuits)
• Elucidation of molecular and synaptic mechanisms (e.g. involvement of microglia) of early neuronal disruption and identification of strategies made to rescue the circuit dysfunction (Exploitation: extending the investigation from the early stage of development to later ones that might addressed in prodromal humans)
• “Dissection” of developmental circuits and cellular interactions underlying the cognitive deficits in schizophrenia (Exploitation: facilitation of research aiming to identify “targets” of dysfunction in humans)
• Tracking of long-lasting functional and behavioral consequences of early impairment of circuits (Methods: development of the protocols for chronic monitoring and optogenetic manipulation of developing circuits)
• Implementation, development and optimization of highly innovative techniques to monitor and manipulate the brain activity
The project added major insights into the developmental mechanisms of cortical dysfunction in psychiatric disorders. They enabled to identify possible rescue strategies of the functional and behavioral deficits that have not been expected when starting the project.