Tuning claustrum circuits to restore cognitive function

Objetivo

Cognitive dysfunction is a major contributor to disability in several neurodevelopmental and psychiatric disorders, including schizophrenia, autism spectrum disorder and attention deficit hyperactivity disorder. These conditions often involve deficits in executive functions such as working memory, cognitive flexibility and attentional control. Despite their impact on daily functioning, current medications largely rely on global neurotransmitter modulation and remain only modestly effective at improving cognitive symptoms.

Our ERC-funded work identified a genetically defined population of glutamatergic projection neurons in the claustrum (CLA) that plays a key role in executive behavior. Manipulating these neurons in adult wild-type mice reproduces cognitive and physiological deficits observed in mouse models of neurodevelopmental disorders. Conversely, restoring CLA neuronal activity in adulthood rescues neural activity in both the CLA and prefrontal cortex and restores behavior, including working memory and cognitive flexibility. These findings suggest that cognitive dysfunction may arise from reversible instability within CLA circuits.

The CLAUSTUNE project will translate these findings into a proof of concept by testing whether CLA circuits can be therapeutically targeted to restore cognitive function. We will first determine whether systemic administration of a candidate therapeutic compound identified through our work can restore CLA neuronal activity and improve cognitive flexibility in a genetic model displaying intrinsic CLA dysfunction. We will then determine whether targeted modulation of claustrum neurons can restore executive performance in an independent mouse model of neurodevelopmental disorder characterized by CLA circuit dysfunction. By evaluating pharmacological and circuit-based interventions across distinct disease models, CLAUSTUNE will assess whether the claustrum can function as a therapeutic control node for restoring cognitive function.

Ámbito científico (EuroSciVoc)

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